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.

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

Autoimmune pancreatitis (AIP) is a rare, immune-mediated form of chronic pancreatitis, classified into three subtypes. Type 1 AIP, the pancreatic manifestation of IgG4-related disease, often presents with multisystem involvement and frequent relapse (1,2). Type 2 AIP is pancreas-limited, tends to affect younger individuals, and is commonly associated with inflammatory bowel disease (IBD) (2,3). A third form—checkpoint inhibitor-related pancreatitis (CIP or Type 3 AIP)—has been recently described in patients receiving immune checkpoint inhibitors, typically asymptomatic but may result in pancreatic atrophy (4).
Precise subtyping is critical due to differences in clinical behavior, relapse risk, and treatment response (1,2,3). We present a single-center series comparing clinical, radiologic, and histopathologic characteristics of Type 1 and Type 2 AIP.

Aims & Methods

We retrospectively reviewed 20 patients diagnosed with AIP between 2020–2024 at a tertiary center. Classification followed International Consensus Diagnostic Criteria (1). Diagnostic evaluation included endoscopic ultrasound (EUS), serum IgG4 levels, and contrast-enhanced CT/MRI/MRCP (1,2). EUS-guided fine-needle biopsy (FNB) was performed where malignancy could not be excluded. Histopathology differentiated lymphoplasmacytic sclerosing pancreatitis (LPSP, Type 1) from idiopathic duct-centric pancreatitis (IDCP, Type 2) (2). Data on extra-pancreatic involvement, steroid response, and relapse were collected.

Results

Fifteen patients were diagnosed with Type 1 AIP and five with Type 2. Type 1 patients had a mean age of 63 years and were predominantly male (80%). Obstructive jaundice was the most common presentation. All had elevated serum IgG4. EUS revealed diffusely hyperechoic parenchyma and long-segment ductal narrowing. Histology confirmed LPSP. Extra-pancreatic involvement was observed in 60%, most commonly IgG4 cholangitis. All responded to corticosteroids; 40% relapsed within one year and received rituximab (5).
Type 2 patients had a mean age of 38, with equal gender distribution. Presenting symptoms included abdominal pain and acute pancreatitis. Serum IgG4 was normal in all cases. EUS revealed focal hypoechoic lesions with short-segment narrowing. Histology confirmed IDCP. Two patients (40%) had ulcerative colitis. All achieved remission with steroids, and no relapses were observed (2,3).

Conclusion

This series emphasizes the distinct clinical courses of AIP subtypes. Type 1 AIP represents a systemic IgG4-related disease with high relapse risk, often requiring long-term immunosuppression (5). Type 2 AIP affects younger patients, remains confined to the pancreas, and shows sustained remission after steroid therapy (2,3). Accurate classification using EUS, MRCP, IgG4, and histology is crucial for appropriate management and long-term outcomes (1,2).

References

1. Hart PA, Zen Y, Chari ST. Recent Advances in Autoimmune Pancreatitis. Gastroenterology. 2015;149(1):39–51.

2. de Pretis N, Crinò SF, Amodio A, et al. Type 2 autoimmune pancreatitis: Clinical features and long-term follow-up in an Italian cohort. United European Gastroenterol J. 2024;12(1):50–59.
   

3. Lohr JM, Dominguez-Munoz E, Rosendahl J, et al. United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU). United European Gastroenterol J.2017;5(2):153–199.

4. Lamarca A, Dhani N, Hubner RA, et al. Immune checkpoint inhibitor-induced autoimmune pancreatitis (Type 3 AIP): Emerging entity with distinct features. Ann Oncol. 2023;34(3):385–393.
   

5. Ghazale A, Chari ST, Zhang L, et al. Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: The Mayo Clinic experience. Clin Gastroenterol Hepatol. 2012;10(6):640–646.