Introduction

Early onset pancreatic cancer (EOPC) arises in patients aged ≤50 years or, and accounts between 5%-10% of all the cases of pancreatic ductal adenocarcinoma (PDAC). Compared to late-onset pancreatic cancer (>50 years, LOPC), EOPC has been described as holding not only peculiar biology, but also poorer outcomes. However, data on the topic is scarce and controversial.

Aims & Methods

Our aim is to investigate risk factors and outcomes of EOPC compared to LOPC. This is a single-center prospective study on a cohort of consecutive histologically diagnosed PDAC patients enrolled between April 2016 and September 2024, in the context of a biobank/exposome observational registry study (NCT06552078), at Pancreas Translational and Clinical Research Centre of San Raffaele Hospital in Milan (Italy). Data on environmental and genetic risk factors, clinical and pathological information were recorded in a dedicated clinical report form (CRF) at time of diagnosis, and treatment and survival outcomes were prospectively collected during follow-up. Variables were compared using Mann-Whitney U test or Chi-square test as appropriate. Multivariable logistic regression analysis was employed to investigate factors associated with risk of EOPC. Overall survival (OS) probability was calculated with the Kaplan-Meier curve and Cox regression, adjusted for confounders.

Results

A total of 840 PDAC patients were included, of which 798 (95%) LOPC and 42 (5%) EOPC. Overall, 406 patients (48.3%) deceased after a median follow-up of 14 months (95% CI: 13-15 months). Staging at diagnosis did not significantly differ between the two groups, and 540 patients (64.2%) underwent intensive polychemotherapy, with no significant difference among the two groups. Median age was 46.5 years (95% CI: 46-48 years) for EOPC patients and 69 years (95% CI: 69-70 years) for LOPC patients.
Current smoking (p<0.0001), ever smoking habit (p=0.008), smoking intensity (pack/years) (p=0.03), alcohol consumption (p=0.007) and history of chronic pancreatitis (p=0.02) were significantly more frequent in EOPC vs LOPC patients. No significant differences were observed among the two groups regarding gender, body mass index (BMI), CA19.9, 1^st degree family history of any cancer, familial pancreatic cancer (FPC), previous cholecystectomy, genetic syndromes or history of diabetes.
The only significant risk factor for the diagnosis of EOPC at the multivariable analysis resulted to be current smoking, with an OR of 6.3 (95% CI: 2-19, p=0.001).
Median OS was significantly higher in the EOPC patients compared to LOPC (35 vs 17 months, p=0.02), and EOPC resulted as a significant prognostic factor for better OS at Cox proportional hazard regression adjusted for gender, stage and polychemotherapy (HR 0.61; 95% CI: 0.37-1.01; p=0.05).

Conclusion

EOPC seems related to active smoking, but not to familial syndromes. Younger patients display better outcomes compared to older ones. Whether this is due to different molecular behavior requires further investigation.

Introduction

Gene therapy holds great promise for the treatment of various diseases. AAVpan mediated SPINK1 overexpression has shown considerable promise in alleviating pancreatitis ^[1]. However, in the case of severe pancreatitis induced by high-dose caerulein administration, the protective effect was not markedly evident possibly due to the insufficient expression of SPINK1. To ensure therapeutic levels of hSPINK1 expression within the safe dosage range of AAV, we introduced the short intron 1 (mini intron1) sequence of hSPINK1 gene to explore whether mini-intron could enhance hSPINK1 expression, and validated the therapeutic efficacy of the AAVpan-hSPINK1-mini intron1 in pancreatitis models.

Aims & Methods

The first intron of human SPINK1 (1.8 kb) conforms to significantly enhance gene expression ^[2]. Considering limited packaging capacity of AAV (4.7 kb), we introduce the first and last 50 base pairs (which do not affect splicing) into hSPINK1 cDNA to construct hSPINK1-mini intron1. First, we investigated whether mini intron could enhance hSPINK1 overexpression: the hSPINK1 expression levels in AAVpan-hSPINK1 and AAVpan-hSPINK1-mini intron1 group were compared using qRT-PCR, Western blot, and trypsin-inhibition assays. The stability of hSPINK1 mRNA in both groups were evaluated following in vitro transcriptional inhibition with actinomycin D. Then, we evaluated the safety of mini intron-mediated hSPINK1 overexpression by detecting hepatic and renal function as well as pancreatic histology. Further, we constructed cerulein-induced severe acute pancreatitis model (250 μg/kg/h) to determine the protective effectiveness of mini intron-mediated overexpression.

Results

The AAVpan-hSPINK1-mini intron1 demonstrated substantially enhanced hSPINK1 expression compared to the AAVpan-hSPINK1. Quantitative analysis revealed a remarkable 30-fold increase in hSPINK1 mRNA levels, 7-fold elevation in protein expression, and 1.5-fold improvement in trypsin-inhibition activity in the AAVpan-hSPINK1-mini intron1 group than those in AAVpan-hSPINK1 group. The addition of actinomycin D resulted in continuous decay of hSPINK1 mRNA in AAVpan-hSPINK1 group, whereas the hSPINK1 mRNA levels in AAVpan-hSPINK1-mini intron1 group remained stable, indicating that mini intron1 effectively stabilized hSPINK1 mRNA. In safety analysis, the histological analysis of liver and pancreas, hepatic and renal function, as well as serum amylase remained within normal levels in both groups for up to 8 weeks post-injection. In the AAVpan-hSPINK1 group, mice with high-dose caerulein-induced SAP exhibited typical pancreatitis phenotypes. In contrast, the AAVpan-hSPINK1-mini intron1 attenuated SAP, implying a dose-dependently protective effect of hSPINK1 overexpression.

Conclusion

The enhanced mini intron could safely enhanced hSPINK1 expression level and trypsin-inhibition activity by improving mRNA stability, representing a promising strategy for optimizing transgene expression and opening up new possibilities for the treatment of severe pancreatitis and potentially other diseases in the field of gene therapy.

References

[1] Wang YC, Mao XT, Sun C, et al. Pancreas-directed AAV8-hSPINK1 gene therapy safely and effectively protects against pancreatitis in mice [J]. Gut, 2024, 73(7): 1142-55.
[2] Kereszturi E, Király O, Sahin-Tóth M. Minigene analysis of intronic variants in common SPINK1 haplotypes associated with chronic pancreatitis [J]. Gut, 2009, 58(4):545-9.

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.

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.

Introduction

Acute pancreatitis (AP) is closely intricately linked to electrolyte disturbances. Such imbalances can exacerbate the instability of the intracellular environment, subsequently accelerating the progression of AP. This study aimed primarily to develop a simplified electrolyte scoring system (CC score) to determine AP exacerbation.

Aims & Methods

A new CC score was established in this study using the Medical Information Mart for Intensive Care IV (MIMIC-IV) v3.1 database, and it was validated using the digestive department database of the First Affiliated Hospital of Nanchang University. The primary endpoint considered was the exacerbation of the disease post-admission in AP patients. Receiver operating characteristic (ROC) curves and decision curve analysis (DCA) plots were used to assess the predictive value and clinical applicability of the new CC score. Improvements were implemented on the acute physiology and chronic health evaluation II (APACHE II) and systemic inflammatory response syndrome (SIRS) scoring systems, and their performance was compared with that of traditional predictive scoring systems.

Results

This study incorporates data from 1413 AP patients drawn from the MIMIC-IV database, supplemented by a further 1040 AP patients in an external validation group. Of these, 178 and 70 AP patients were respectively transferred to the Intensive Care Unit (ICU). The multivariate adjustment model indicates that a significant negative correlation between serum Ca²⁺ levels and severe progression in AP patients, while serum Cl^- levels showed a J-shaped association with severe progression. Through node analysis of the restricted cubic splines (RCS) model, combined with the clinical grading standards for hyperchloremia and hypocalcemia, the critical values for Cl^- and Ca²⁺ were determined to be 110 mmol/L and 1.77 and 2.1 mmol/L, respectively. Based on these findings, we established a new CC score and optimized the APACHE II and SIRS scoring systems. The results indicated that the predictive power of the optimized APACHE II score (AUC=0.83) and SIRS score (AUC=0.87) for severe progression in AP patients surpassed that of the original APACHE II score (AUC=0.74) and SIRS score (AUC=0.71).

Conclusion

The new CC score not only effectively predicts the risk of severe progression in AP patients but also enhances the predictive performance of both SIRS and APACHE II scores for assessing severe progression risk in these patients.

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.