Introduction

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are the most frequently identified precursor lesions of pancreatic cancer (PDAC). Only a minority progress towards malignancy, making their identification a critical point in cancer prevention. The available guidelines are imprecise, commonly resulting in over treatment of indolent lesions.

Aims & Methods

The aim of this study (EMI-IPMN, NCT06706700) is to discover novel biological and radiological biomarkers that can distinguish malignant from benign IPMNs. We focused on Endocrine, Metabolic and Inflammatory (EMI) factors, some pathways that are characterized in PDAC but poorly investigated in IPMN progression.
Patients with a presumed diagnosis of IPMN with indication for surgical resection who underwent high-quality magnetic resonance imaging (MRI) and/or computed tomography (CT), were prospectively enrolled. Peripheral blood (PB) and cyst fluid (CF) samples were collected during surgery, and lesions were histologically classified as IPMN with low-grade dysplasia (LGD), high-grade dysplasia (HGD), or invasive cancer (IC). Malignant IPMNs were defined as those with HGD and IC. Cytokine and hormone levels were measured in both fluids using multiplex assays and compared across the diagnostic groups. Continuous variables were converted into categorical variables based on optimal cut-off values, and both univariate and multivariate logistic regression analyses were conducted.

Results

Among the 205 patients enrolled, 133 (58 females, 75 males, median age 69.2) had a histological diagnosis of IPMN: 49 (36.8%) had LGD, 44 (33.1%) HGD and 40 (30.1%) had IC. Analysis of the EMI profile revealed higher concentrations of several markers (IL-8, VEGF, GLP-1, glucagon, and C-peptide) in CF compared to PB. Specific cytokines such as MCP-1 IP-10, TNFα, and IL-8 were significantly elevated in the CF of HGD/IC cases compared to LGD (p=0.05, 0.041, 0.001 and 0.025 respectively). Similarly, IP-10, IL-8, and MDC levels in PB were higher in HGD/IC patients (p=0.006, 0.008 and 0.004 respectively).
Pancreatic fat content, assessed with mDixon Quant Fat Fraction MRI sequences, was notably higher in HGD/IC patients (13.89%) compared to LGD patients (8.38%, p<0.05), and positively correlated with MCP-1 levels in CF.
Among these biological and radiological markers TNFα in the CF demonstrated a substantial diagnostic accuracy for identifying malignant IPMN, with an area under the ROC curve (AUC) of 0.72. In the final multivariable analysis we demonstrate that high TNFα levels in CF and HbA1c were the two independent risk factors for the identification of malignant IPMN (OR 10.8 and 1.11 respectively).

Conclusion

The progression of IPMN to PDAC is associated with a proinflammatory shift in the tumor microenvironment, reflected by local (CF) and systemic (PB) elevations in key cytokines (TNFα, MCP-1, and IL-8) whose involvement in PDAC progression is well established. Elevated hormone levels in CF, along with the strong association between malignant IPMN and HbA1c, underscore the critical role of endocrine alterations in the early stages of pancreatic tumorigenesis. These findings may be harnessed to enable earlier detection of malignant transformation in IPMN. Moreover, the correlation between imaging markers and biological profiles suggests that MRI could serve as non-invasive proxies for underlying pathological changes. Together, these results offer new insights into the pathophysiology of IPMN progression and may imporve diagnostic strategies

Introduction

Epithelial barrier dysfunction is a hallmark of inflammatory bowel diseases (IBD), contributing to increased permeability, microbial translocation, and sustained mucosal inflammation^1,2. Targeting barrier restoration has emerged as a promising therapeutic strategy³. Gallic acid, a dietary polyphenol with known anti-inflammatory and antioxidative properties, has shown potential in modulating mucosal responses⁴. To investigate its impact on epithelial integrity under inflammatory stress, we utilized intestinal organoids as a physiologically relevant ex vivo model system.

Aims & Methods

The aim of this study was to investigate the potential of gallic acid to restore intestinal epithelial barrier function under inflammatory conditions, using colonic epithelial organoids and integrating transcriptomic and permeability analyses.
The study was approved by the Kaunas Regional Biomedical Research Ethics Committee (protocol no. BE-2-31). Inflamed differentiated colonic epithelial organoids were established from a patient with ulcerative colitis (UC) and non-IBD control individual by exogenous stimulation with TNF-α and IFN-γ (10 ng/mL each) for 24 hours. For gallic acid (GA) screening, organoids were pre-treated with metabolite (100 μM) for 1 hour prior to inflammation induction and co-treated during the induction period. Subsequently, organoids were either processed for mRNA sequencing (1×75 bp, NextSeq 550, Illumina) or subjected to a FITC-Dextran (4kDa) assay. RNA-seq data was processed, analyzed, and visualized using nf-core/RNAseq pipeline and RStudio. Images for permeability assay analysis were acquired using an inverted fluorescence microscope (Zeiss Axio Observer 7), processed with ImageJ, and analyzed and visualized in RStudio.

Results

Principal component analysis of transcriptomic profiles from both UC and non-IBD organoids revealed clear sample clustering driven by stimulation. Differential gene expression and Gene set enrichment (GSEA) analyses indicated a more pronounced cell response to both treatments in UC organoids compared to non-IBD organoids. Inflammation activated immune (CXCL9/10/11, CX3CL1), interferon (IFI44, SOCS1, NOS2), and defense genes (GBP4, GBP5, OAS2), while downregulating metabolic genes (FABP6, CFTR, HMGCS2) in both groups. Gene Ontology-based GSEA confirmed immune pathway enrichment and lipid metabolism suppression in inflamed cultures. In total, 3,148 and 1,479 DEGs were identified in inflamed UC and non-IBD organoids, respectively. GA treatment modulated 2,144 and 384 genes (e.g., LYPD8, MKI67, MT-ATP6, CXCL14, CCL22) in these groups, suggesting potential to rebalance inflammation and metabolism. GA co-treatment enhanced epithelial integrity in UC organoids via upregulation of cell junction, peptide hormone processing, and immune-related pathways. In non-IBD organoids, GA promoted cell adhesion pathways, supporting epithelial cohesion. Functional permeability analysis confirmed GA’s protective role, as supported by transcriptomic data. Mean percentages of FITC-Dextran-permeable organoids were 16.02% (untreated), 86.08% (inflamed), and 42.58% (inflamed + GA). A trend toward statistical significance (Wilcoxon p = 0.125) was observed in both untreated vs. inflamed and inflamed vs. inflamed + GA comparisons.

Conclusion

In conclusion, gallic acid modulates inflammatory and metabolic pathways during colonic inflammation and enhances epithelial barrier integrity.
Study was funded by the European Union and the State Secretariat for Education, Research and Innovation (SERI) (project: miGut-Health, grant no. 101095470).

References

¹Jostins, L., et al. (2012). Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 491(7422), 119–124. https://doi.org/10.1038/nature11582
²Cleynen, I., et al. (2016). Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: A genetic association study. The Lancet, 387(10014), 156–167. https://doi.org/10.1016/S0140-6736(15)00465-1
³Vieujean, S., et al. (2025). Understanding the therapeutic toolkit for inflammatory bowel disease. Nature Reviews Gastroenterology & Hepatology. Online ahead of print. https://doi.org/10.1038/s41575-024-01035-7
⁴Tian, B., Ye, P., Zhou, X., Hu, J., Wang, P., Cai, M., Yang, K., Sun, P., & Zou, X. (2025). Gallic acid ameliorated chronic DSS-induced colitis through gut microbiota modulation, intestinal barrier improvement, and inflammation. Molecular Nutrition & Food Research. Online ahead of print. https://doi.org/10.1002/mnfr.70024

Introduction

The implementation of the national bowel-screening program for colorectal cancer has had a significant impact on detecting early colorectal cancer (pT1 & pT2 carcinomas). In recent decades, there has been a shift towards minimally invasive approaches for treating T1 colon carcinomas (CC), favoring local resection techniques over major surgeries. It is unknown whether risk stratification could establish organ preservation in T2 CC.

Aims & Methods

We aimed to evaluate the incidence of lymph node metastases (LNMs) in patients with pT2 CC in the Netherlands and to develop a prediction model to estimate the risk of LNMs which could be helpful to compare the risk of LNMs against the age-specific adverse events associated with segmental surgery. A retrospective nationwide cohort study was performed including all consecutive patients diagnosed with pT2 CC who underwent (completion) surgery between 2012 and 2020 in the Netherlands. Patients were identified by use of the Dutch ColoRectal Audit (DCRA). Exclusion criteria were: (1) neoadjuvant therapy; (2) synchronous CRC; (3) hereditary predisposition (4) history of IBD; and (5) non-adenocarcinoma. Data obtained from the DCRA were linked to the Dutch Nationwide Pathology Databank (PALGA). A subgroup analysis was conducted on patients up to 70 years old, who were treated between 2018 and 2020, to examine the association between mismatch repair (MMR) status and the presence of LNMs. Predictive factors for LNMs were evaluated with univariate- and multivariate logistic regression. Four machine learning (ML) models were developed and validated to predict LNM, including generalized linear modeling (GLM), GLM-Least Absolute Shrinkage and Selection Operator (GLM-LASSO), random forest (RF), and gradient boosting (XGB).

Results

In total 9,803 patients were included. The overall 30-day complication and mortality rates were 25.2% and 2.2%, respectively. In elderly patients (age ≥ 74), the complication and mortality rates increased to 30%, and 3.5%, respectively. LNMs were found in 1877 out of 9803 patients (19.1%). Younger age (OR 0.98, 95% CI 0.979 ─ 0.990), left-sided CC (OR 1.5, 95% CI 1.4-1.7), poor differentiation (1.7, 95% CI 1.4-2.2), and lymphovascular invasion (LVI) (OR 4.1, 95% CI 3.6-4.7) were independent risk factors for LNMs. In the subgroup analysis, deficient MMR (dMMR) status was found to be associated with a significantly lower risk of LNMs (OR 0.3, 95% CI 0.2-0.5). GLM demonstrated the highest prediction accuracy, achieving AUCs of 0.67 for the full model and 0.68 for the model focusing on patients up to 70 years old. The risk of LNMs in the lower-risk group (age ≥ 74, right-sided CC, LVI absent, good/moderate tumor differentiation) was 10.7%. In the absence of other risk factors, patients with a dMMR carcinoma had a risk of LNMs of 6.1%.

Conclusion

The predicted probability of LNMs should be balanced against the risks associated with segmental colon surgery. The findings of this study could serve as valuable guidance for clinicians, enabling them to inform patients about these competing risks before making a shared decision.