Digestive Health Research Institute

Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive malignancy that predominantly affects young male patients. Its nonspecific clinical presentation and low diagnostic yield from ascitic fluid cytology pose a significant diagnostic challenge, particularly when presenting as ascites of unknown origin. A 30-year-old previously healthy young man presented with a 4-week history of progressive abdominal distention, intermittent fullness, unexplained weight gain, and bloody ascites. Cytology from paracentesis and tumor markers were nondiagnostic. Imaging revealed omental caking and multiple peritoneal nodules, suggestive of peritoneal carcinomatosis. Diagnostic laparoscopy identified extensive tumor seeding, and biopsy confirmed DSRCT based on histopathology, immunohistochemistry, and the presence of an EWS-WT1 fusion transcript on cytogenetic analysis, establishing the diagnosis of DSRCT. Chemotherapy was recommended; however, the patient's condition deteriorated rapidly, and he died within a few weeks before receiving treatment. DSRCT, although rare, is noted for aggressiveness and rapid progression and therefore should ideally be considered in the differential diagnosis of bloody ascites in young male patients, even when initial cytology is negative. Early application of diagnostic laparoscopy and biopsy may facilitate timely tissue diagnosis, particularly when imaging mimics peritoneal carcinomatosis.

Background In pediatric biliary cirrhosis secondary to biliary atresia (BA), hepatic lobules are disrupted to form pseudolobules. How the hepatic circulation is reorganized remains a poorly characterized issue. Purpose To reproduce the three-dimensional (3D) structural and remodeling alterations of BA-induced pseudolobules via phase-contrast CT (PCCT) and reveal their circulatory self-rescue mechanism. Materials and Methods In this retrospective study, residual donor normal liver tissue samples and BA-affected liver samples collected between November 2013 and April 2024 were imaged with PCCT. Combined with 3D visualization technology, the spatial anatomic morphologic characteristics of the veins, arteries, and sinusoidal system within the hepatic lobules were reproduced based on liver histopathologic examination. Key indexes such as the number of inlet and outlet venules, sinusoidal volume fraction, and anisotropy, were determined to characterize the structural remodeling of the circulatory pathway, from portal and arterial inflow through the sinusoidal exchange network to hepatic venous outflow, in patients with BA. All indicators were analyzed with generalized estimating equations, and the multiple test correction was performed by conducting Holm-Bonferroni correction, with P < .05 indicating statistical significance. Results Normal livers from three donors (median age, 36 months; IQR, 12-132 months; two male donors) and 25 patients with BA (median age, 7.00 months; IQR, 5.8-10 months; 17 male patients) were analyzed. The mean number of inlet venules decreased from 253.07 ± 70.99 (SD) in normal lobules to 138.80 ± 28.12 in pseudolobules (P < .001). The mean number of inlet arterioles increased from 3.93 ± 1.39 in normal lobules to 5.65 ± 2.43 in pseudolobules (P < .001). The number of outlet venules in pseudolobules decreased by 35% compared with that in normal lobules (mean, 105.02 ± 42.47 vs 161.96 ± 42.47; P < .001). In the sinusoidal system, the volume fraction in pseudolobules increased by 51% compared with that in normal lobules (mean, 40.42 ± 6.28 vs 26.72 ± 6.32; P < .001), especially in the inlet area, where this value nearly doubled (mean, 44.47 ± 4.73 vs 23.44 ± 5.95; P < .001). Mean anisotropy decreased from 0.53 ± 0.02 in normal lobules to 0.51 ± 0.03 in pseudolobules (P < .001). Conclusion The lobular circulation remodeling mechanism in BA-induced pseudolobules, from the inlet channel to the exchange network and outlet channel, was comprehensively revealed via PCCT. © RSNA, 2026 Supplemental material is available for this article.

Eosinophils may contribute to ulcerative colitis (UC) pathogenesis through inflammation and epithelial injury. Mirikizumab, a selective IL-23 inhibitor, has shown efficacy in moderate-to-severe UC. However, the relationship between eosinophils and treatment outcomes with IL-23 inhibition remains unclear. This post-hoc analysis of the LUCENT-1 trial evaluated trends in serum and histologic eosinophils as biomarkers for early response to mirikizumab induction therapy in UC. Data from LUCENT-1 (NCT03518086) were analyzed to assess serum eosinophil counts and histologic eosinophil presence at baseline and week 12. Clinical response, remission, and endoscopic improvement were defined by modified Mayo score criteria. Logistic regression models, adjusted for factors including steroid use, prior biologic failure, disease severity, and albumin levels, assessed associations between baseline eosinophil levels and treatment outcomes. Among 928 participants, 66.6% achieved clinical response. Responders had higher baseline serum eosinophils (0.23 × 109/L vs 0.19 × 109/L, P = .001) and showed greater reductions at week 12. Elevated baseline eosinophils (≥0.57 × 109/L) were associated with higher rates of clinical response (80% vs 65.7%, aOR: 2.31, P = .013), remission (33.3% vs 25.1%, aOR: 1.91, P = .044), and endoscopic improvement (46.7% vs 33.8%, aOR: 2.33, P = .003). Reductions in histologic eosinophils were also linked to improved outcomes, especially in those with moderate/marked baseline presence. Baseline eosinophil levels may predict response to mirikizumab and guide early treatment decisions. These findings support a potential role for eosinophils as biomarkers in UC management.

Key points Over the past 2 decades, celiac disease has become the most prevalent autoimmune disorder of the gastrointestinal tract globally, with a reported seroprevalence of 1% to 2%.[1][1] However, celiac disease is often undiagnosed and many patients experience substantial diagnostic delay,

Extracellular proteases, originating from the host or the microbiota, are key signalling molecules involved in cellular communication with the environment. They signal through a wide array of mechanisms, ranging from receptor activation to protein transformation and even degradation. Protease signals are irreversible, as it involves the cleavage of proteins. Therefore, proteases are tightly controlled, and must be understood within the context of the complex networks in which they operate - their activity is tightly regulated by access to specific substrates and the presence of inhibitors. The intestine is particularly exposed to extracellular proteases, which have major roles in gut physiology: digestion, food antigen processing, barrier function, epithelial renewal and microbiome homeostasis. Dysregulated proteolytic balance is associated with intestinal pathologies including inflammatory bowel disease, irritable bowel syndrome, coeliac disease and colorectal cancer. Extracellular proteases are major contributors to a number of gut dysfunctions, including microbiota dysbiosis, barrier dysfunction, matrix remodelling, activation of mucosal immunity and nociceptive or motility abnormalities. Consequently, proteolytic homeostasis at the intestinal mucosa surface has become a goal for intestinal health, and new therapeutic options targeting the interplay among proteases, their inhibitors and their substrates have been explored.

Biochemical non-response to ursodeoxycholic acid, as a first-line therapy, is associated with a heightened risk of clinical events in primary biliary cholangitis (PBC). Herein, we determine whether biochemical non-response to second-line therapy in obeticholic acid (OCA) is also predictive of long-term event-free survival. Data were collected from patients who initiated OCA at large, high-volume centres in the UK, Italy, and Canada between August 2017 and 2019, with follow-up continuing until June 2024. Biochemical non-response was defined by POISE criteria. Clinical events were defined as hepatic decompensation, referral for transplantation, hepatocellular carcinoma, or death. Our cohort consisted of 336 patients (29% with cirrhosis), of whom n = 150 (45%) discontinued OCA over 48 months. Over 851 patient-years of OCA use, without the addition of another PBC therapy, n = 230, n = 192, n = 158 and n = 150 patients completed 12, 24, 36 and 48 months follow-up, respectively. Of this cohort, 37%, 48%, 63% and 55% attained biochemical response, with 7%, 14%, 25% and 19% normalising ALP (p < 0.01; all comparisons vs. baseline). Over 4 years, 64 patients experienced a clinical event. Twelve-month biochemical non-response associated with a heightened risk of clinical events (hazard ratio [HR]: 4.50; 95% CI: 1.74-20.23), as did cirrhosis (HR: 20.24, 10.15-40.32), hyperbilirubinaemia (HR: 2.55, 1.71-3.76), hypoalbuminaemia (HR: 0.92, 0.90-0.96) and thrombocytopenia (HR: 0.99, 0.98-0.99). The prognostic utility of biochemical non-response (HR: 3.29, 1.72-14.96) and cirrhosis (HR: 19.67, 5.09-76.08) persisted on multivariable analyses. Biochemical response stratifies risk of clinical events in PBC patients under OCA treatment. Whilst response rates increase over time, discontinuation rates underscore the need for newer treatment paradigms.

ABSTRACT Host – microbiome interactions are central to Crohn’sdisease (CD) pathogenesis; yet the early metabolic alterations that precededisease onset remain poorly defined. To explore preclinical metabolicsignatures of CD, we analyzed baseline serum metabolomic profiles in a nestedcase-control study within the Crohn’s and Colitis Canada – Genetics, Environment, Microbiome (CCC-GEM) Project, a prospective cohort of 5,122 healthyfirst-degree relatives (FDRs) of CD patients. We included 78 individuals wholater developed CD and 311 matched FDRs who remained disease-free. In an untargetedassessment of metabolomic data, we identified 63 metabolites significantlyassociated with future CD risk. Integrative analyses further identifiedmultiple associations between CD-related metabolites and proteomic markers, gutmicrobiome composition, antimicrobial antibody, fecal calprotectin andC-reactive protein. Quinolinate, a tryptophan catabolite, was elevated inindividuals who later developed CD and showed strong positive correlations withC-reactive protein, fecal calprotectin, and C-X-C motif chemokine ligand 9 (CXCL9).In contrast, higher levels of ascorbate and isocitrate were associated withreduced CD risk and were negatively correlated with C-reactive protein and CD-associated proteins.These findings identify several distinct molecular pathways that contribute toCD pathogenesis.

ABSTRACTOuter membrane vesicles (OMVs) are nanosized vesicles naturally secreted by Gram‐negative bacteria and represent a promising platform for vaccine development. OMVs possess inherent immunostimulatory properties due to the presence of pathogen‐associated molecular patterns (PAMPs), providing self‐adjuvanting capabilities and the ability to elicit both innate and adaptive immune responses. This review outlines the advantages of OMVs over traditional vaccine strategies, including their safety, modularity, and the potential for genetic engineering to enable targeted antigen delivery. We describe approaches to enhance OMVs yield and immunogenicity, such as modifications to reduce lipopolysaccharide (LPS) toxicity and systems enabling antigen localization—either on the surface or within the lumen—using fusion constructs like ClyA, Lpp‐OmpA, AIDA‐I, Hbp, and Sec/Tat signal peptides. We further summarize preclinical applications of OMVs‐based vaccines targeting bacterial pathogens, viral infections, and cancer. In addition, we address key challenges in large‐scale production, purification, and long‐term stability, and explore strategies for conjugating or encapsulating heterologous antigens. Overall, OMVs offer a versatile and scalable extracellular vesicle‐based platform with strong potential for next‐generation vaccines targeting diverse infectious diseases and beyond.