Introduction

Although the role of radiotherapy in locally advanced pancreatic cancer (LAPC) is still debated, data has demonstrated encouraging results for more precise methods of radiotherapy delivery, including stereotactic body radiation therapy (SBRT) and endoscopic ultrasound (EUS) guided intra-tumoural phosphorus-32 (³²P) microparticle implantation. We compare survival and safety outcomes of patients with SBRT versus EUS-guided ³²P implantation in combination with chemotherapy in patients with LAPC.

Aims & Methods

This is a single-centre retrospective study from March 2015 – April 2025 including all patients with LAPC who underwent combination neoadjuvant chemotherapy with either EUS-guided ³²P microparticle implantation or SBRT. The primary outcome was overall survival from chemotherapy commencement. Secondary outcomes include progression-free survival (PFS), resection rate and rate of adverse effects including grade 3 (CTCAE v. 5) or above adverse effects.

Results

A total of 119 patients (58 ³²P vs. 61 SBRT) were included. Demographics and tumour characteristics were comparable between the groups (Table 1). All ³²P microparticle implantation was successful, with an average volume of 1.6+0.1mL and an estimated 100Gy activity applied to the tumour. The median highest dose of SBRT therapy was 35Gy (IQR 35-40Gy) delivered over 5 fractions. Median overall survival from the date of chemotherapy commencement was significant better with ³²P implantation than SBRT (hazard ratio [HR] 1.98; p=0.004). Compared to SBRT, ³²P implantation was associated with superior local and distant PFS (HR 1.61; p=0.034 and HR 1.71; p=0.019 respectively). Both therapies resulted in significant reduction in serum Ca19.9. Tumour downstaging (15/58 vs. 5/61, P<0.001) and surgery (13/58 vs. 0/61, P<0.001) rates after the therapy were significant higher with ³²P implantation than SBRT. The rate of R0 resection was 77% (10/13) in the ³²P group. The rate of grade 3 adverse events was not significantly different between the groups (6/58 vs. 5/61).

Table 1. Demographics and tumour characteristics

Conclusion

When radiotherapy is used in combined with chemotherapy for LACP, EUS guided intra-tumour ³²P implantation is associated with better clinical outcomes than SBRT, including overall and progression free survival, tumour downstaging and surgical resection. Both forms of radiotherapy have demonstrated a good safety profile. These findings warrant further evaluation with a larger randomized controlled trial.

Introduction

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have demonstrated metabolic and cardiovascular benefits in patients with type 2 diabetes (T2D). However, their potential effect on pancreatic cancer (PC) risk remains unclear.

Aims & Methods

We aimed to examine the association between SGLT-2i use and PC risk in T2D patients prescribed metformin. We conducted a retrospective cohort study using a territory-wide electronic healthcare database, retrieving adult patients (≥18 years) with T2D who initiated metformin between 2015 and 2022. The index date was the first metformin prescription during the study period. Patients were observed until PC, pancreatectomy, death, or study end date (December 31, 2022). Exclusion criteria included prior history of PC, IgG4 disease, pancreatectomy, or fewer than two HbA1c measurements during follow-up. The outcome and exposure of interest was PC and SGLT-2i use (including dapagliflozin, empagliflozin, canagliflozin and ertugliflozin), respectively. SGLT-2i exposure was defined as continuous use during 90-day entry period following the index date. Cox proportional hazards model with propensity score (PS) matching (1:2) on 28 covariates – age, sex, smoking, alcohol use, body mass index (BMI), diabetes duration and complications, glycemic control (in terms of time-weighted mean HbA1c), history of pancreatitis and cholangitis, comorbidities, and concomitant medication use (aspirin, statins, and other antidiabetic medications) – were used to estimate hazard ratios (HRs). Sensitivity analysis by treating medication use as time-varying variable was conducted to address immortal time bias.

Results

Among 144,468 matched patients (mean age:59.3±11.2 years; male:58.3%; 48,156 SGLT-2i users and 96,312 SGLT-2i non-users), 441 (0.31%) developed PC during a mean follow-up of 6.6±2.0years. The mean duration of SGLT-2i use was 2.1±1.6 years. SGLT-2i use was associated with lowered PC risk (aHR:0.43; 95% CI:0.34-0.55), irrespective of empagliflozin (aHR0.43; 95%CI: 0.33-0.57) or dapagliflozin use (aHR:0.33; 95% CI:0.22-0.49). When drug use was modelled as time-varying variables, the protective effect remained significant (aHR:0.35; 95% CI:0.15-0.78). Furthermore, a dose- and duration-dependent relationship was observed. The aHR was 0.88 (95% CI:0.84-0.92) per 100-cumulative defined daily dose (cDDD) increase in use, and 0.66 (95% CI:0.59-0.75) per 1-year increase in use. Subgroup analysis showed beneficial effects persistent regardless of age (cutoff of 65 years), sex, BMI (cutoff of 25 kg/m²), diabetes complications, usage of other medications (aspirin, statins, and insulin).

Conclusion

SGLT-2i use was associated with a lower risk of PC in a dose- and duration-dependent manner, which was independent of glycemic control, among T2D patients treated with metformin. These findings provide insights into informing the choice of second-line anti-diabetic drug in lowering PC risk in T2D metformin users.

Introduction

The use of contrast-enhanced endoscopic ultrasound (CE-EUS) for characterizing solid pancreatic masses has improved diagnostic capabilities. We aimed to evaluate the performance of an artificial intelligence (AI)-powered system for differential diagnosis of pancreatic adenocarcinoma using CE-EUS.

Aims & Methods

The methodology integrates advanced imaging analysis and machine learning (ML) to develop an automated framework for pancreatic tumor characterization using EUS. A convolutional neural network (CNN) is first trained on labeled non-contrast EUS images to detect and segment the pancreas and tumor regions accurately. Once trained, the CNN is applied to new cases, identifying regions of interest (ROIs) in the non-contrast images, which are subsequently mapped onto the corresponding contrast-enhanced images for further analysis. Time-Intensity Curve (TIC) analysis was performed on the mapped ROIs, extracting a comprehensive set of quantitative parameters describing contrast enhancement dynamics. These parameters include temporal metrics (e.g., time to peak, rise time), intensity measures (e.g., peak intensity, wash-in intensity), slopes (e.g., wash-in and wash-out rates), area-based metrics (e.g., area under the curve), and perfusion-related characteristics (e.g., perfusion index, blood flow). The extracted TIC parameters are then used to train a feedforward neural network (FNN), which learns to differentiate diagnostic categories based on the perfusion characteristics of the lesions. In the final integrated model, the CNN detects pancreas and tumor regions, maps them to contrast-enhanced images, computes TIC parameters, and feeds these into the FNN to provide automated diagnostic predictions.

Results

Retrospective analysis was performed on a prospectively collected dataset of 120 CE-EUS videos obtained from patients with solid pancreatic masses in 3 tertiary referral centers. The dataset included 88 pancreatic adenocarcinomas, 1 lymphoma, 4 metastatic lesions, 10 neuroendocrine neoplasms (G1/G2), 15 cases of chronic pancreatitis, and 2 solid pseudopapillary neoplasms (SPNs). Diagnostic performance was evaluated by calculating sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy. Based on CNN analysis, both precision and recall were also calculated. The AI-powered CE-EUS system achieved high diagnostic performance, with an accuracy of over 95% for the diagnosis of pancreatic adenocarcinoma. Precision and recall were also excellent for differentiating adenocarcinoma from other pancreatic lesions based on CNN analysis.

Conclusion

This novel AI-based approach using CE-EUS reliably distinguished pancreatic adenocarcinoma from other solid pancreatic masses. Real-time analysis of time-intensity curve parameters enhances diagnostic accuracy and offers a promising adjunct to traditional EUS methods. Further prospective validation is warranted to confirm these findings and explore clinical applicability.

References

1. Săftoiu A, Vilmann P, Bhutani MS, Hassan H, Hawes R, Dietrich CF, et al. Enhanced endoscopic ultrasound imaging for pancreatic lesions: A review.
World J Gastrointest Endosc. 2022 Jul 16;14(7):369–84. doi:10.4253/wjge.v14.i7.369 PMID: 35967758; PMCID: PMC9367228.
2. Liang T, Zhang H, Wang Y, Sun Y, Ma K, Liu W, et al. Artificial intelligence-assisted endoscopic ultrasound for detection of pancreatic lesions: A systematic review and meta-analysis. World J Gastroenterol. 2023 Feb 21;29(7):1150–1164. doi:10.3748/wjg.v29.i7.1150 PMID: 36849883; PMCID: PMC10720860.

Introduction

Patients with suspected main-duct intraductal papillary mucinous neoplasms (MD-IPMN) are frequently referred for surgery due to the high risk of malignancy (as high as 40% to 60% in the literature). However, many present with significant comorbidities or concurrent malignancies, complicating the surgical risk-benefit assessment. In such cases, advanced endoscopic procedures may assist in guiding clinical decision-making.

Aims & Methods

This study aimed to evaluate the role of EUS-guided fine-needle biopsy (EUS-FNB) and pancreatoscopy in individualized risk stratification and management decisions for patients with suspected MD-IPMN. We retrospectively analyzed eight patients treated at our center between March 2020 and March 2025. All patients presented with significant comorbidities or active oncologic disease. Data collected included endoscopic findings, biopsy results, complications, and final management decisions.

Results

Eight patients with suspected main-duct IPMN were included (mean age: 67.6 years; 3 females, 37.5%). The mean main pancreatic duct (MPD) diameter was 9.1 mm. All patients were evaluated in a multidisciplinary setting due to clinical complexity, including comorbidities or concurrent malignancies. EUS-guided fine-needle biopsy (EUS-FNB) was performed in 3 patients, and pancreatoscopy in 5. All procedures were technically successful. Biopsy samples were diagnostic in 2 of 3 EUS-FNB cases and 5 of 5 pancreatoscopy cases and contributed directly to management decisions. In 1 EUS-FNB case, the sample was non-diagnostic. Pancreatoscopy revealed mucin extrusion in 4/5 patients, papillary or villous projections in 3/5, and a 'fish egg' appearance in 2/5. These features supported risk assessment and, in several cases, justified a conservative approach in high-risk patients. Three patients underwent surgery following multidisciplinary review. One had concordant findings (high-grade dysplasia), while two had discordant outcomes: one with low-risk pancreatoscopy findings had invasive adenocarcinoma, and one with EUS-FNB showing low-grade atypia had high-grade dysplasia on final pathology. Five patients were managed with active surveillance. One case of mild post-ERCP pancreatitis occurred; no other complications were reported. Endoscopic findings influenced management in 5 of 8 patients (62.5%).

Conclusion

In this real-world case series, EUS-FNB and pancreatoscopy contributed meaningfully to individualized decision-making in patients with suspected MD-IPMN. However, discordance between endoscopic impressions and final pathology in two cases highlights the limitations of visual and cytologic assessment. These findings reinforce the need for integrating endoscopic data with imaging, clinical context, and multidisciplinary input when evaluating main-duct IPMN.

References

1. Salvia R, Fernández-del Castillo C, Bassi C, Thayer SP, Falconi M, Mantovani W, Pederzoli P, Warshaw AL. Main-duct intraductal papillary mucinous neoplasms of the pancreas: clinical predictors of malignancy and long-term survival following resection. Ann Surg. 2004 May;239(5):678-85; discussion 685-7. doi: 10.1097/01.sla.0000124386.54496.15. PMID: 15082972; PMCID: PMC1356276.
2. Sohn TA, Yeo CJ, Cameron JL, Hruban RH, Fukushima N, Campbell KA, Lillemoe KD. Intraductal papillary mucinous neoplasms of the pancreas: an updated experience. Ann Surg. 2004 Jun;239(6):788-97; discussion 797-9. doi: 10.1097/01.sla.0000128306.90650.aa. PMID: 15166958; PMCID: PMC1356287.

Introduction

Pancreatic calcification is the most frequent structural change in chronic pancreatitis (CP), but the factors associated with its development are not well understood.

Aims & Methods

We aimed to investigate the risk factors of calcification development in patients with chronic pancreatitis. The study protocol was registered on PROSPERO (CRD42024591837). On September 18, 2024, we conducted a systematic search across three databases (PubMed, EMBASE, and CENTRAL) for studies reporting factors associated with calcification in chronic pancreatitis (CP). Pooled proportions and odds ratios (OR) with 95% confidence intervals (CI) were calculated using a random effects model.

Results

The systematic search resulted in 10,893 articles, from which 85 eligible studies were identified, covering a total of 34568 participants. The odds of calcification were 45% higher in alcoholic compared to idiopathic CP (OR=1.45, CI: 1.00–2.11). Alcohol consumption (OR=2.31, CI: 1.8–2.98) and smoking (OR=2.22, CI: 1.61–3.06) were associated with a two times higher risk of calcification in CP, when compared to non-smokers and non-drinkers. In contrast, the presence of CFTR mutations did not increase the risk of calcification in CP (OR=0.43, CI: 0.11–1.66) compared to patients without CFTR mutations.

Conclusion

Alcohol consumption and smoking were significantly associated with the presence of calcification in CP, making it essential to identify these risk factors and incorporate smoking cessation and alcohol reduction programs into standard care.

Introduction

Alcohol-induced acute pancreatitis (AP) is a common form of AP, while alcoholic hepatitis (AH) is a severe complication of alcoholic liver disease. Maléth et al. demonstrated that ethanol and fatty acids reduce cystic fibrosis transmembrane conductance regulator (CFTR) expression and activity, worsening alcohol-induced AP. Previously, we showed that ethanol and fatty acids disturb the CFTR-PMCA interaction, leading to disruped intracellular Ca²⁺ balance, exacerbating pancreatitis and potentially hepatitis. Previously Berrocal et al. described that MB reverses the inhibitory effect of Tau on PMCA, suggesting that its beneficial effect is based on the preservation of endogenous Ca²⁺-ATPase activity. Methylene blue (MB) is known for its antioxidant and mitochondrial protective properties, which can also influence intracellular Ca²⁺ regulation. Here we hypothesize that potentiating PMCA with methylene blue could have a protective effect in alcohol-induced AP and AH.

Aims & Methods

This study investigates MB’s effect on alcohol-induced AP severity and its underlying protective mechanisms in alcohol-related diseases. The effects of MB were assessed in mouse pancreatic (MPO), mouse liver (MLO), and human pancreatic ductal organoid (HPO) cultures. Microfluorimetric measurements were performed using an inverted fluorescence microscope. The polarized expression of ion channels was analyzed via immunofluorescence (IF). Gene expression changes were examined using qPCR, while mitochondrial membrane potential was assessed with TMRM and JC-10 staining. Cytotoxicity was evaluated using the CellTiter-Glo® 3D assay. Alcohol-induced AP and AH were modeled in wild-type FVB/N mice. AP was induced by repeated ethanol (EtOH) and palmitoleic acid (POA) injections, while AH was provoked using a 5% ethanol-fed Lieber-DeCarli diet.

Results

Fluorescent Ca²⁺ measurements showed that MB significantly potentiated PMCA activity following EtOH and PA exposure in MPOs, MLOs, and HPOs compared to EtOH-PA-treated groups. Mitochondrial membrane potential measurements confirmed MB’s protective effect. Gene expression analysis revealed no significant differences in CFTR, PMCA4, or ORAI1 expression between EtOH-PA and MB-treated groups. IF staining of PMCA4 demonstrated a defined apical localization in EtOH-PA + MB-treated groups. In experimental AH, MB’s effects were evaluated using Oil Red O and Trichrome staining, along with serum ALAT, ASAT, and triglyceride (TG) levels. In alcohol-induced AP, MB treatment significantly reduced serum amylase levels, oedema, leukocyte infiltration, and necrosis scores compared to the EtOH-POA group.

Conclusion

MB treatment mitigates the harmful effects of EtOH and PA exposure by enhancing PMCA activity, preserving mitochondrial function, and promoting PMCA4’s apical localization. Although no significant changes were observed in CFTR, PMCA4, or ORAI1 gene expression, histological and biochemical analyses highlight MB’s potential in alleviating alcohol-induced AP, as evidenced by reduced oedema, leukocyte infiltration, necrosis scores, and serum amylase levels. These findings suggest MB as a promising therapeutic candidate for protecting cellular and mitochondrial integrity in alcohol-related diseases.

Disclosure

I declare no conflict of interest

Introduction

Pancreatic fistulas (PFs) represent a remarkable clinical challenge after abdominal surgery, pancreatitis, or abdominal trauma, with significant morbidity and non-negligeable mortality. Pancreatic endoscopy plays a pivotal role in the setting of recent trend toward aggressive yet minimally invasive surgery-sparing PFs management. Mutignani et al. recently proposed a morpho-functional pancreatographic classification of PFs aimed at targeting the best suited endoscopic treatment option for each PF type.

Aims & Methods

The primary aim of this study is to evaluate efficacy and safety of endoscopic PFs treatment, according to the Mutignani et al. classification; the secondary aim is the identification of independent variables significantly associated with different treatment clinical success rate.
Monocentric data prospectively collected between March 2011 and July 2024 on patients referred to the Interventional Endoscopic Unit of ASST Grande Ospedale Metropolitano Niguarda who underwent endoscopic treatment of a PF was retrospectively analysed.

Results

A total of 110 patients were included (M 75.5%, median age 61 years [IQR 46-72]). 75/110 (68.2%) were post-surgical (33 after pancreaticoduodectomy, 23 distal pancreatectomy, and 19 other abdominal surgery), 27/110 (24.5%) developed after pancreatitis, and 8/110 (7.3%) were post-traumatic. 17/110 (15.5%) were type I PF [9 (53%) T, 5 (29.4%) H, 3 (17.6%) B], 38 (34.5%) type II [27 (71.1%) O, 11 (28.9%) C], and 55 (50%) type III [35 (63.6%) D, 20 (36.4%) P]. Median treatment delay was 9 days [IQR 5-22]. ERCP was first endoscopic approach in 92 cases (83.6% - of which 6.5% after rendez-vous), EUS-guided in 14 (12.7%), and combined in 4 (3.6%). Mutignani et al classification adherence was 98.2%. Technical success rate was 100% (91.8% at first approach), clinical success rate was 97/105 (92.4%). Early AEs occurred in 15 cases (14.3% - 33.3% of them infections), late AEs occurred in 8 (7.6% - 100% new pancreatic strictures). 9/105 (8.6%) patients died due to fistula-related causes during follow-up, PF recurrence occurred in 2 cases (2.1%). At univariate analysis, older age, presence of heart diseases, presence of sepsis at clinical presentation, class C ISGPF fistula, and high-volume PF proved to be significantly more frequent among patients without clinical success compared to those with clinical success (median 72.5 [IQR 54.3-82.7] VS 59 [IQR 46-70.1], p=0.0312; 37.5% VS 2.3%, p=0.0038; 87.5% VS 39.8%, p=0.0199; 57.1% VS 14.3%, p=0.0182; 87.5% VS 42.7%, p=0.0230, respectively). At multivariate analysis, only the presence of heart diseases confirmed to be significantly associated to the absence of clinical success (OR 2.65, 95%CI: 1.5-3.8, p=0.0217).

Conclusion

High adherence to the Mutignani et al classification system for PFs endoscopic treatment proved to high clinical success and low rate of AEs. Targeted management of PF is not only feasible but also highly effective, basically regardless of patient’s and PF’s baseline characteristics. Further large-scale prospective multicentric studies are warranted to confirm these findings and refine the optimal treatment strategies.

References

M. Mutignani et al., “Pancreatic Leaks and Fistulae: An Endoscopy-Oriented Classification,” Dig Dis Sci, vol. 62, no. 10, pp. 2648–2657, Oct. 2017, doi: 10.1007/S10620-017-4697-5.
C. Bassi et al., “The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 Years After,” Surgery, vol. 161, no. 3, pp. 584–591, Mar. 2017, doi: 10.1016/J.SURG.2016.11.014.
G. Malleo, A. Pulvirenti, G. Marchegiani, G. Butturini, R. Salvia, and C. Bassi, “Diagnosis and management of postoperative pancreatic fistula,” Langenbecks Arch Surg, vol. 399, no. 7, pp. 801–810, Oct. 2014, doi: 10.1007/S00423-014-1242-2.

Disclosure

Authors have nothing to declare.