Introduction

Pancreatic ductal adenocarcinoma (PDAC) represents over 90% of pancreatic cancer cases and remains a highly lethal malignancy with a five-year survival rate below 12%. Although KRAS mutations drive approximately 90% of PDAC cases, the clinical efficacy of direct KRAS inhibitors remains limited, highlighting the critical need for alternative therapeutic targets. Kinases have emerged as promising candidates for PDAC treatment. Through a kinase-focused esiRNA library screen comparing KRAS-mutant and wild-type PDAC cell lines, we identified serine/threonine kinase 31 (STK31) as a KRAS-dependent oncogenic effector that promotes tumor progression by regulating key cell cycle proteins CCNB1 and CDC25C. However, STK31’s kinase activity, downstream signaling mechanisms, and pharmacologically targetable features remain unknown, representing a significant gap in our understanding of its therapeutic potential.

Aims & Methods

This study aims to characterize the molecular mechanisms of STK31’s kinase function and evaluate STK31 inhibitors for PDAC treatment using preclinical models. We employed 4D label-free phosphoproteomics to identify potential STK31 substrates, followed by in vitro kinase assays to validate phosphorylation activity. AlphaFold 3 was utilized for structure-based virtual screening of STK31 inhibitors.

Results

Our preliminary data demonstrate that STK31 exhibits intrinsic kinase activity and phosphorylates mTORC2, potentially regulating CCNB1 and CDC25C expression through STAT1 phosphorylation. AI-driven molecular docking identified ciclopirox as a putative STK31 inhibitor, which was subsequently validated in functional assays. Ciclopirox effectively suppressed PDAC cell growth, with enhanced potency in KRAS-mutant cell lines.

Conclusion

Based on these findings, we propose that STK31 drives PDAC progression via the mTORC2-STAT1-CCNB1/CDC25C axis and that pharmacological inhibition of STK31 represents a viable therapeutic strategy.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor that significantly affects its aggressiveness and treatment resistance. Cancer-associated fibroblasts (CAFs) are key components of the desmoplastic stroma and are now recognized as dynamic, heterogeneous cells that contribute to disease progression. While CAFs play a role in creating an immunosuppressive tumor microenvironment (TME), their precise impact on survival and cellular dynamics remains unclear. This study aims to provide an unbiased classification of CAF subtypes and investigate their functional relevance and dynamics in chronic pancreatitis (CP) and PDAC.

Aims & Methods

We conducted single-cell RNA sequencing (scRNA-seq) on 40,000 fibroblasts isolated from resected human CP and PDAC tissues. We clustered the CAFs and examined the driving genes for each subtype. Validating these subtypes involved immunohistochemistry (IHC)-multiplexing on tissue microarrays (TMA) from 126 PDAC and 66 CP patients. Additionally, we performed flow cytometry on human PDAC CAFs and utilized immunocytochemistry (ICC) with our newly identified markers.

Results

Our clustering revealed 11 distinct CAF subtypes. To facilitate future mechanistic experiments, we also analyzed the surface receptor signatures of these enriched subtypes. IHC multiplexing confirmed the existence of these subtypes, with End Stage inflammatory CAFs (iCAFs) (35.7% in PDAC vs. 56.6% in CP) and End Stage myofibroblastic CAFs (myCAFs) (35.3% in PDAC vs. 25.6% in CP) being the most prevalent. Flow cytometry results corroborated IHC findings. Notably, we identified a novel subtype, Lipofibroblast, in both PDAC and CP, with RNA velocity analysis indicating its ability to differentiate into other subtypes, driven by Periostin (POSTN).

Conclusion

The discovery of a novel Lipofibroblast subtype with differentiation potential highlights a new avenue for understanding CAF plasticity and therapeutic targeting in PDAC and CP.

Introduction

EUS-guided drainage using lumen-apposing metal stents (LAMSs) and direct endoscopic necrosectomy (DEN) are primary treatment modalities for symptomatic pseudocysts and walled-off pancreatic necrosis (WOPN). However, bleeding is a frequent and serious adverse event associated with these procedures, often requiring radiological or surgical interventions also due to the limitations of conventional endoscopic hemostatic techniques. PuraStat is a novel topical hemostatic agent that has demonstrated excellent results in managing gastrointestinal bleeding.

Aims & Methods

Our aim was to evaluate the efficacy and safety of PuraStat in managing bleeding secondary to EUS-guided drainage and DEN of pancreatic fluid collections (PFCs). In this multicenter, retrospective, observational study we described 27 patients who underwent PuraStat treatment because of active bleeding during or after EUS-guided drainage or DEN sessions of pseudocysts or WOPN between 2017 and 2024.

Results

38 bleeding episodes were recorded (10 patients with WOPN experienced multiple bleeding events). The bleeding type was oozing in 36 cases and spurting in 2 cases. PuraStat was successfully applied in 100% of patients and achieved successful hemostasis in 96.5% of cases. No re-bleeding occurred. No PuraStat-related adverse events were recorded.

Conclusion

PuraStat is a safe, effective, and easy-to-use hemostatic agent for managing oozing hemorrhages related to PFCs EUS-guided drainage or DEN. Prospective and comparative studies are needed to confirm these preliminary data.

Introduction

IgG4-related disease (IgG4-RD) is a chronic fibro-inflammatory multi-systemic disease. Pancreato-biliary involvement is reported in up to 60%, which can lead to exocrine and endocrine pancreatic insufficiency. Glucocorticoids can be used to control active inflammation but are associated with substantial toxicity. B-cell depletion with anti-CD20 chimeric Rituximab (RTX) and anti-CD19 humanised Inebilizumab (INEB) are steroid-sparing and used to control disease flares. INEB is the only FDA-approved medication for the treatment of IgG4-RD.

Aims & Methods

Our aim was to compare B-cell depleting agents for the treatment of IgG4-RD. We searched PubMed, Cochrane Central Register of Clinical Trials and Embase databases for studies of maintenance therapy in IgG4-RD with a pre-defined strategy and performed a network meta-analysis to assess relapse at 12 months, occurrence of infections and infusion-related reactions.

Results

96 out of 2545 manuscripts underwent full text review after exclusions. Three studies met eligibility for the meta-analysis, two reporting the use of RTX and one of INEB (Table 1).

For the primary outcome of disease relapse at 12 months, INEB had a risk ratio (RR) of 5.8 (95% CI 0.29 - 115.02) and RTX had an RR of 2.29 (95% CI 0.19 - 28.21), with INEB being superior in preventing relapses. The RR for infections with INEB was 0.81 (95% CI 0.19 - 3.41) whilst with RTX was 0.62 (95% CI 0.13 - 3.04). The RR for infusion-related reactions with INEB was 1.27 (95% CI 0.09 - 18.76) and for RTX was 0.93 (95% CI 0.11 - 8.19). These must be interpreted in the context of study design; INEB in a phase 3 randomised trial following a stringent safety protocol for reporting of adverse events, and RTX in retrospective observational studies.

Conclusion

This Network Meta-analysis demonstrates that INEB is superior to RTX at preventing disease relapses in patients with IgG4-RD at 12 months. Adverse events, such as infection and infusion-related reactions, were comparable in lieu of the methodological differences between studies.

Disclosure

Emma L Culver has received speaker fees from Albireo/IPSEN, Advanz/Intercept, Dr Falk, Amgen, GSK, Mirum Pharma, Gilead, Chemomab, Zenus Bio, and Advisory/consultancy fees from Advanz/Intercept, IPSEN, Mirum, GSK, Dr Falk Pharma, Amgen, Zenus Bio, Sanofi, Moderna and Sail BioPharma. MC has received speaker fees from Albireo/IPSEN, Advanz/Intercept, Amgen, GSK, Mirum Pharma, Gilead, and Advisory/consultancy fees from Advanz/Intercept, Alphasigma, Albireo/IPSEN, Mirum, GSK, Dr Falk Pharma, Amgen, Mayoly, Echosens, Kowa, Moderna, Zydus.

Introduction

Differentiating mucinous (MPCLs) from non-mucinous pancreatic cystic lesions (NMPCLs) remains critical for appropriate therapeutic decisions. While carcinoembryonic antigen (CEA) levels >192 ng/mL have been the conventional benchmark, their limited sensitivity underscores the need for more accurate alternatives. Recent data suggest intracystic glucose levels may be a promising biomarker. This study prospectively evaluated the diagnostic performance of intracystic glucose compared to CEA in pancreatic cyst fluid obtained via EUS-guided fine needle aspiration (EUS-FNA).

Aims & Methods

From July 2018 to October 2024, 24 patients with pancreatic cystic lesions undergoing EUS-FNA using a 22G needle were included. Glucose and CEA concentrations were measured using standard biochemical protocols. Final diagnosis was based on surgical pathology (n=5), cytopathology (n=9), or consensus radiologic/endoscopic evaluation by two blinded expert pancreatologists (n=10). All procedures and analyses were performed in a tertiary academic gastroenterology center in Morocco.

Results

Mean patient age was 59.8 years. Diagnoses comprised 13 mucinous cysts (54.2%; including 9 IPMNs and 4 MCNs), 7 serous cystadenomas (29.2%), 2 cystic neuroendocrine tumors (8.3%), 1 pseudocyst, and 1 simple cyst.
The mean intracystic glucose level in MPCLs was 14.1 mg/dL (95% CI: 5.6–22.6), versus 90.3 mg/dL (95% CI: 82.1–98.6) in NMPCLs (p < 0.0001). A glucose threshold of ≤30 mg/dL yielded an AUC of 0.94 (95% CI: 0.84–0.99), with 92.3% sensitivity and 100% specificity.
For CEA ≥192 ng/mL, AUC was 0.71 (95% CI: 0.54–0.86), with 46.1% sensitivity and 100% specificity. No significant correlation was found between glucose levels and either CEA or cyst size.

Conclusion

Intracystic glucose represents a simple, cost-effective, and highly accurate marker for distinguishing mucinous from non-mucinous pancreatic cystic lesions. It demonstrates superior sensitivity compared to CEA and can be a valuable adjunct in the diagnostic algorithm of pancreatic cysts, particularly in resource-conscious settings.

References

 Carrara S, Ceriello A, Arcidiacono PG. Glucose in pancreatic cyst fluid: a reliable test for mucinous cysts? Endoscopy. 2022;54(1):63–70.
 Köker D, Tevethia H, Madhoun MF. Intracystic glucose: a promising low-cost tool in differentiating pancreatic cysts. Gastrointest Endosc. 2023;97(4):832–9.
 Alomari F, Hammad T, Khasawneh MA, et al. Diagnostic performance of EUS-FNA glucose vs CEA in pancreatic cysts. Pancreas. 2021;50(5):661–6.

Introduction

Chronic pancreatitis (CP) may have differences in causes, presentations and progression related to sex. There are few studies describing the sex related phenotype of CP.

Aims & Methods

We aimed to study sex differences in etiology, complications and treatment of CP in a large, North-European CP cohort. Data were extracted from the Scandinavian Baltic Pancreatic Club (SBPC) database. The collected data included sex, age, etiology, anthropometric measures, data for smoking and alcohol exposures and data on treatment and complications from CP. Differences between sexes were compared with multiple logistic regression models.

Results

We included 1922 patients in the analyses, of whom 1264 were men. Mean age of CP onset was 52.5 (SD 15.0) years in men and 51.5 (SD 16.4) years in women (p=0.2). In univariate analysis alcohol etiology and smoking was associated with male sex, whereas hereditary pancreatitis, efferent duct obstruction, autoimmune pancreatitis were associated to female sex. Numbers of men and women with non-alcoholic etiology were almost equal (461 and 422, respectively). In multivariate analysis including all etiologies, time with disease and age; alcohol etiology remained strongly associated to male sex (OR 2.92 (2.29-3.71), p<0.001), whereas duct obstruction etiology was associated with female sex (OR 0.62 (0.44-0.89), p=0.01).
Significantly more women were underweight (p<0.001), and more men were overweight (p<0.001). Concerning other complications, diabetes mellitus (DM) was strongly associated with men (OR 1.62 (1.27-2.07), p<0.001), whereas osteoporosis was strongly associated with women (OR 0.47 (0.32-0.70), p<0.001). Recurrent acute pancreatitis and exocrine insufficiency were equally distributed between the sexes. There were no differences between sexes for medical, endoscopic or surgical treatment options.

Conclusion

More men than women had alcohol induced CP, but there was almost no difference in absolute numbers of men and women with non-alcoholic CP. Among the CP patients, DM was associated with men, while osteoporosis was associated with women.

Introduction

To assess whether trans papillary drainage is the way to go for pseudocysts complicating patients with chronic pancreatitis. With our previous experience we used the technique of no injecting contrast during ERP in case of leaks complicating chronic pancreatitis causing either pseudocysts, pleural effusions or ascites. Here we are presenting a retrospective analysis of our management of pseudocysts in chronic pancreatitis.

Aims & Methods

We retrospectively analysed all cases of chronic pancreatitis having ascites, effusions and pseudocysts. We performed magnetic resonance cholangiopancreatography (MRCP) followed by therapeutic endoscopic retrograde pancreatography (ERP) without contrast. Results were observed confirming a leak from the MPD, possibility of wire crossing the leak or not and resolution of the pseudocysts. Patients with only pseudocysts were included in this analysis.

Results

We performed ERP in 1522 patients from 2000 till date. Ductal disruptions noted in 509/1522 (33.44%) out of which pseudocyst was observed in 330 cases (64.83%).
311 patients (94.2 %) experienced successful cannulation of PD. In 19 (5.8%) PD could not be cannulated. Non cannulated cases treated with EUS guided transmural drainage 14 (73.7%) and surgery 5(26.3%)
Of these 311, 24 (8.3%) had pancreas divisum and MPD was cannulated from minor papilla.
Leak did not cross but stents put in cyst (236, 75.9 %). Cyst resolution – 228 (96.6%). Cyst Not resolved 8 (3.4%). Leaks were crossed in 75 (24.1 %); Cyst resolution 69 (92%). Cyst not resolved 6 (8%).
Unresolved cysts 14 (4.5%) were treated with EUS Aspiration- 5 (35.7%), EUS Transmural drainage 8 (57.1%), Surgery -2 (14.2%).
Discussion: In chronic pancreatitis the cause of pseudocysts is ductal rupture and very minimal inflammation as compared to acute pancreatitis where the major cause is inflammation with ductal leak and necrosis of the pancreas. There is hardly any necrosis in chronic pancreatitis pseudocysts. Hence the management of both should be individualised. Transpapillary drainage in pseudocysts complicating chronic pancreatitis offers a less morbid and a simpler alternative to transmural drainage or surgery.

Conclusion

Pseudocysts complicating chronic pancreatitis can be managed very effectively using transpapillary drainage in majority of cases and should be attempted before considering transmural or surgical drainage. It saves the patient significant morbidity