Introduction

Approximately 10-15% of patients with Crohn's Disease (CD) experience penetrating complications during disease course, which significantly burdens patients' lives and impacts the healthcare system. Efficacy and safety of adipose-derived mesenchymal stem cell (MSC) transplantation (darvastrocel) in treating CD complicated by complex perianal fistulas are contradicting and real-world data are lacking.

Aims & Methods

Our study aimed to assess the effectiveness and safety of MSC therapy in managing perianal Crohn’s disease. This was a retrospective, multicenter cohort study enrolling CD patients with perianal fistulas. Baseline is defined as the day of MSC treatment while the follow-up is set at 6 to 12 months. Primary outcome was perianal clinical remission at w26 (defined by closure of all external openings), while secondary outcomes were clinical response rate, perianal clinical activity (defined by Perianal Disease Activity Index [PDAI]), and adverse events. Demographic, clinical, and surgical data were recorded at baseline, w12, w26, and at w52. Predictors of treatment failure were analyzed by logistic regression models.

Results

Overall, data of 69 patients (male/female ratio was 0.52 and median age was 36 [IQR 31-44]) were analyzed with a median follow-up duration of 52 [IQR 48-53] weeks. Perianal clinical remission was achieved in 49.3% until w26 and 44.9% (intention-to-treat) and 53.44% (per protocol) until w52, while baseline PDAI (OR 0.77, p = 0.043) score was associated with treatment failure. Characteristics of perianal fistulas were not linked to primary outcome. Clinical response rates were 69.6% at w26 and 78.3% (intention-to-treat) and 74.1% (per protocol) at w52. PDAI scores were decreased to w52 (5.2 [±3.1] to 3.2 [±2.8], p < 0.001). Worsening of perianal symptoms were not recorded, while improvement was reported in 78.8%, 81.1%, and 85.7% of cases at w12, w26, and w52. Total adverse events occurred in 8.7%, which were needed surgical reintervention. Furthermore, emerging stenosis, anal incontinence and severe infection were not registered.

Table 1. Baseline demographic and clinical characteristics of enrolled patients

Conclusion

Efficacy data are consisted with the registration ADMIRE study, more than 80% of patients benefit from the treatment, however the appearance of spontaneous closure is high in the literature. The safety profile is reassuring, and patients’ satisfaction is high.

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

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.

Introduction

Sporadic duodenal adenomas are uncommon in comparison to other gastro-intestinal adenomas and often an incidental finding in upper gastrointestinal endoscopy. Recent studies indicate an increasing incidence of these lesions.¹

Aims & Methods

A retrospective review of upper endoscopies performed over the past 10 years was conducted to identify cases of duodenal adenomas. Patients with polyposis syndromes and ampullary adenomas were excluded, resulting in a sample of 41 patients with sporadic duodenal adenomas. In addition, a control group of 41 randomly selected individuals from the same 10-year span, matched by age and gender, was used for comparison. Potential risk factors for duodenal adenomas were collected.

Results

The prevalence of duodenal adenomas was 0.22%. The mean age of affected individuals was 69 years, out of which 24 were males. Most of the adenomas were endoscopically removed (68.3%), three patients had recurrent adenomas and one progressed into adenocarcinoma. A significant association was observed between smoking and the presence of duodenal adenomas (p = 0.037). Family history of gastrointestinal neoplasia was related to the occurrence of duodenal adenomas (p = 0.043). In addition, in comparison to the control group, the duodenal adenoma group had a significantly higher number of affected family members with gastrointestinal neoplasia (p = 0.001). Furthermore, the duodenal adenoma group had a significantly higher number of colorectal adenomas compared to the control group (p < 0.001). No statistically significant associations or differences to the control group were found amongst other variables.

Conclusion

Although sporadic duodenal adenomas are rare, their potential for recurrence and progression to adenocarcinoma warrants careful surveillance. Smoking and family history of gastrointestinal neoplasia appear to be potential risk factors for sporadic duodenal adenomas. Additionally, the higher prevalence of colorectal adenomas in these patients highlights the importance of colorectal cancer screening in this population.

References

(1) Culver, E., & McIntyre, A. (2011). Sporadic duodenal polyps: classification, investigation, and management. Endoscopy, 43(02), 144–155. https://doi.org/10.1055/s-0030-1255925

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

Endoscopic submucosal dissection has become the preferred technique for managing large colonic lesions or those suspected of superficial tumor invasion. Macronodular lesions may present with a muscular retraction sign (MRS), which is associated with reduced curative resection rates due to lower R0 resection rates and increased rates of deep submucosal invasion. A few data are available about how to differentiate fibrosis and cancer and about technical and oncological outcomes of ESD in this situation.

Aims & Methods

We conducted a prospective study to evaluate the prevalence of the muscular retraction sign and its clinical outcomes in patients with colorectal macronodular lesions. This analysis utilized data from a large prospective French colorectal ESD cohort (FECCo).

Results

A total of 1,238 macronodular lesions were treated, of which 254 (20.5%) exhibited a muscular retraction sign. The prevalence of MRS increased with the size of the largest macronodule, reaching up to 50% for nodules larger than 40 mm. Enbloc, R0 and curative resection rates were significantly lower in the MRS+ group (82.68% vs 97.86%, 70.97% vs 89.76% and 56.31% vs 83.52%, p<0.001 respectively). MRS+ lesions were more frequently associated with at least submucosal cancer (30.32% vs 9.65%, p<0.001). Regardless of MRS, the presence of a nodule larger than 4cm is associated with a decrease in enbloc resection rates, particularly in the colon, as well as reductions in R0 resection rates and curative resection rates in comparison with nodules smaller than 4cm. The curative resection rate for lesions with ≥T1 cancer and presenting with MRS was 1.5% (p<0.001).
In multivariate analysis, protruding lesions (OR = 1.91 [1.19–3.06], p = 0.007) and nodules larger than 20mm (OR = 2.48 [1.74–3.52], p<0.001) or 40mm (OR 5.98 [3.55-10.08], p<0.001) were identified as risk factors for MRS. The size of the nodule did not increase the risk of submucosal cancer, unlike sigmoid location (OR 2.66 [1.15-6.17] p=0.022) and nodules classified as JNET 3 (OR 6.53 [2.07-20.57], p=0.001).

Conclusion

The prevalence of MRS is 20.5% in cases of macronodular lesions, a rate that increases significantly with the size of the macronodule. MRS negatively impacts the outcomes of ESD in terms of enbloc, R0 and curative resections. ESD should be reconsidered in cases of large macronodular colonic lesions, especially for sigmoid locations or in the presence of JNET 3 vascular pattern anomalies. For rectal large macronodular lesions, ESD should be proposed in expert centers with the option, if necessary, of intermuscular dissection to optimize the R0 resection rate and thereby improve the chances of proposing an organ-preservation strategy.