Vinciane Rebours

Background: Pancreatic exocrine insufficiency (PEI) is a maldigestion syndrome leading to symptoms and nutritional deficiencies. Prospective real‐world data on pancreatic enzyme replacement therapy (PERT) dose requirements across aetiologies are limited. Objective: To define PERT dose requirements and treatment outcomes across PEI aetiologies in specialist European practice. Methods: EURO‐PEI was a multicentre observational registry with predominantly prospective data collection conducted at eight pancreatic centres in five European countries between June 2021 and September 2025. Adults with clinician‐established PEI in whom PERT was initiated or actively optimised were included. The primary outcome was the optimised PERT dose associated with the achievement of a clinician‐assessed therapeutic goal: improvement or resolution of PEI‐related symptoms with normalisation or clinically relevant improvement of nutritional abnormalities. Results: Among 1015 patients, PEI was secondary to chronic pancreatitis in 496 (48.9%), pancreatectomy in 185 (18.2%), pancreatic cancer in 174 (17.1%), and acute pancreatitis in 95 (9.4%). Median total daily optimised doses were highest after pancreatectomy (240,000 PhU, IQR 175,000–375,000) and in pancreatic cancer (210,000 PhU, 175,000–325,000), compared with chronic pancreatitis (175,000 PhU, 120,000–210,000) and acute pancreatitis (100,000 PhU, 75,000–200,000). After optimisation, the therapeutic goal was achieved in 951 patients (93.7%); of these, 446 (46.9%) required enzyme doses exceeding commonly recommended starting doses. Related adverse events occurred in 38 patients (3.7%). Conclusions: PERT dose requirements vary substantially by PEI aetiology, supporting aetiology‐aware starting doses, early reassessment, and individualised optimisation in high‐risk groups.

This international, multidisciplinary consensus report represents the first effort to systematically define and characterize fatty pancreas. A key outcome of this endeavor was the recommendation to adopt “fatty pancreas” as the standardized and inclusive term to describe all forms of fat accumulation in the pancreas. This terminological consensus provides a critical foundation for unified reporting and clinical communication. Another major contribution of the report is the consensus on diagnostic imaging findings, which was based on radiological and endoscopic modalities. The proposed criteria aim to enhance consistency in clinical assessment and support the development of standardized research protocols. In addition to establishing terminology and diagnostic frameworks, the report also synthesizes current knowledge across a wide range of relevant domains. These include the etiology and epidemiology of fatty pancreas, as well as its associations with alcohol consumption, smoking, acute and chronic pancreatitis, pancreatic exocrine insufficiency, type 2 diabetes mellitus, and surgical outcomes. The potential links between fatty pancreas and neoplastic conditions such as intraductal papillary mucinous neoplasms and pancreatic cancer are also addressed, alongside the current understanding of its metabolic implications (beta‐cell function and glucose homeostasis) and treatment strategies. Throughout the consensus process, a consistent theme emerged: the limited availability of high‐quality, prospective clinical data. Therefore, many of the recommendations in this report are based on expert consensus rather than strong empirical evidence. As such, the statements require rigorous prospective validation before they can be adopted into routine clinical practice. This underscores a critical need for further research, particularly studies aimed at clarifying causal relationships, validating diagnostic tools, and determining the clinical relevance of fatty pancreas across diverse patient populations. This report serves as both a summary of our current understanding and a roadmap for future investigations, aiming to close existing knowledge gaps and guide evidence‐based clinical practice in this emerging field.

Background: In non-metastatic pancreatic adenocarcinoma (PDAC), the appropriate evaluation of tumor response to neoadjuvant treatment (NAT) has a substantial prognostic impact, but the tools used to assess it are imperfect and sometimes discordant. Objectives: We aimed to explore the prognostic impact of morphological and pathological evaluations of tumor response to NAT. Design: Single-center retrospective observational study. Methods: We retrospectively studied all patients with borderline or locally advanced PDAC who underwent surgery after neoadjuvant chemotherapy (NAC) with FOLFIRINOX, ±additional chemoradiation (NACR) between 2016 and 2022 in a tertiary center. Morphological response was evaluated according to RECIST 1.1, and pathological response was assessed according to the CAP score and proportion of viable tumor cells (VTC). The primary endpoint was recurrence-free survival (RFS), and the secondary endpoint was overall survival (OS). Factors associated with the risk of recurrence were analyzed using ROC curves and multivariable Cox proportional hazard models. Results: We included 91 patients (52% male, median age 66, 83% with borderline PDAC) who underwent surgery following NAC with additional NACR in 85% of patients. Overall, 38% of patients had an objective morphological response according to RECIST 1.1, which was not associated with prolonged RFS HR 1.16, 95% CI (0.62–2.10), p = 0.64). Conversely, poor pathological response was associated with shorter RFS on multivariable analysis, notably VTC ⩾ 30% (HR 2.28, 95% CI [1.08–5.13], p = 0.037). Median OS was 62.2 months with VTC ⩾ 30% versus 45.1 months with VTC < 30% ( p = 0.025). Identifying PDAC with VTC < or ⩾30% had a strong reproducibility (kappa 0.86). Conclusion: Morphological response per RECIST should not be the aim of NAT in patients with PDAC. Conversely, the proportion of VTC could be a reproducible, simple, and effective prognostic tool. Should this marker be further confirmed as valuable, it may help inform the adaptation of adjuvant treatment and follow-up in this setting.

Background/Objectives: While complete loss-of-function (LoF) SPINK1 variants in the simple heterozygous state cause chronic pancreatitis, biallelic complete LoF variants result in a rare pediatric disorder termed severe infantile isolated exocrine pancreatic insufficiency (SIIEPI). To date, only two individuals with a null SPINK1 genotype have been reported—one homozygous for a whole-gene deletion and the other for an Alu insertion in the 3′ untranslated region. Here, we report the genetic basis of a third SIIEPI case, presenting in early infancy with severe exocrine pancreatic insufficiency and diffuse pancreatic lipomatosis. Methods: Targeted next-generation sequencing (NGS) was used to analyze the entire coding region and exon–intron boundaries of the SPINK1 gene. Copy number variant (CNV) analysis was performed with SeqNext, based on normalized amplicon coverage. Results: The proband harbored compound heterozygous complete LoF SPINK1 variants. One was the known NM_001379610.1:c.180_181del (p.(Cys61PhefsTer2)), inherited from the father. The second, initially detected as an exon 2 deletion and confirmed by quantitative fluorescent multiplex PCR (QFM-PCR), was further characterized by long-range PCR as a complex rearrangement comprising a 1185 bp deletion removing exon 2, a 118 bp templated insertion followed by a non-templated nucleotide, and an 8 bp deletion. The mutational signature is consistent with serial replication slippage or template switching involving translesion synthesis. This maternally inherited variant has not been previously reported. Conclusions: This study expands the mutational spectrum of SPINK1-related SIIEPI and suggests that this distinct pediatric disorder may be under recognized in clinical practice.

Introduction: United European Gastroenterology (UEG) Guidelines on immunoglobulin G4 (IgG4)‐related digestive disease provides evidence‐based recommendations for the diagnosis and management of IgG4‐related digestive disease. The aim of this study is to evaluate the adherence to recommendations of this IgG4 guideline across centers in Europe.Patients and methods: Questionnaire‐based data related to organ involvement, diagnosis, treatment and follow‐up of newly diagnosed patients with IgG4‐related digestive diseases over a 3‐year period, were collected from 14 centers in 11 European countries.Results: One hundred and ninety‐nine patients (76% males) were included. Median age at diagnosis was 64 years. Most of the patients had concomitant pancreatic and biliary tree involvement (46%), followed by isolated pancreatic involvement (33.5%), isolated biliary tree involvement (18.5%), esophageal involvement (1.5%) or bowel (0.5%) involvement. Most of the patients (64%) underwent a combination of computed tomography and magnetic resonance imaging at diagnosis. Among the 158 autoimmune pancreatitis patients with or without concomitant bile duct involvement, treatment was performed according to guidelines in 115 patients (73%; moderate adherence). Follow‐up assessment was performed between 2 and 4 weeks in 75 patients (47%, partial adherence). Among 37 patients with liver‐ or biliary tree involvement, 29 patients were treated according to guidelines (78%; full adherence). In the follow‐up of patients with isolated liver‐ or biliary tree involvement, we observed moderate adherence in 21 (57%). Disease monitoring for activity and damage using the IgG4 responder activity index was utilized in only 3/14 centers (poor adherence).Conclusions: IgG4‐related digestive disease is restricted to the pancreas and bile ducts in the majority of patients. Even in specialist centers with an interest in IgG4‐related digestive disease, UEG guideline treatment adherence was moderate, follow‐up at 2–4 weeks was only partial, and monitoring for disease activity was poor. These findings highlight the need for ongoing education and improved adherence to monitoring among healthcare providers.

While complete loss-of-function (LoF) SPINK1 variants in the simple heterozygous state predispose to or cause chronic pancreatitis, biallelic complete LoF variants result in severe infantile isolated exocrine pancreatic insufficiency (SIIEPI). To date, only two individuals with a null SPINK1 genotype have been reported—one homozygous for a full-gene deletion and the other for an Alu insertion in the 3′ untranslated region. Here, we report a third case of SIIEPI, presenting in early infancy with severe exocrine pancreatic insufficiency and diffuse pancreatic lipomatosis, without extra-pancreatic involvement. Targeted next-generation sequencing (NGS) identified compound heterozygous complete LoF SPINK1 variants. One was the known c.180_181delAT variant, inherited from the father. The second, initially detected as an exon 2 deletion and confirmed by quantitative fluorescent multiplex PCR (QFM-PCR), was further characterized by long-range PCR as a complex rearrangement. This variant includes a 1,185 bp deletion removing exon 2, a 118 bp templated insertion followed by a non-templated nucleotide, and an 8 bp deletion—consistent with serial replication slippage or template switching involving translesion synthesis. This maternally inherited variant has not been previously reported. Our findings expand the mutational spectrum of SPINK1-related SIIEPI and suggest that this distinct pediatric disorder may be underrecognized in clinical practice.

Background: Intraductal papillary mucinous neoplasms (IPMNs) are clinically detectable precursors of pancreatic adenocarcinoma, yet the mechanisms initiating their development remain poorly defined. Although KRAS mutations are highly frequent in human IPMNs, KRAS activation in pancreatic ductal cells alone fails to recapitulate IPMN development in murine models, indicating that additional tumor-suppressive mechanisms must be overcome. Objective: The objective was to determine whether loss of the transcription factor HNF1B predisposes to initiation of IPMN. Design: We assessed HNF1B nuclear expression and promoter methylation in resected human IPMN specimens. To model IPMN initiation, we generated mice with ductal-specific inactivation of Hnf1b , alone or combined with KRAS ^G12D . Ductal organoids and RNA-sequencing were used to investigate molecular mechanisms. Transcriptomic analyses were also performed on human IPMN surgical specimens. MRI from germline HNF1B mutation/deletion carriers was re-evaluated for IPMN prevalence. Results: Human IPMNs showed loss of HNF1B by immunochemistry, with enrichment to promoter methylation that increased with dysplasia grade. The KHC model recapitulated the key features of IPMN development including ductal dilation, high proliferation, papillary architecture and mucin production. Loss of Hnf1b together with Kras activation induced loss of primary cilia, cellular reprogramming and engaged oncogenic YAP and Wnt/β-catenin signaling, similar to human IPMNs. Moreover, germline HNF1B carriers exhibited a markedly increased prevalence of branch-duct IPMN. Conclusion: HNF1B functions as a tumor-suppressive gatekeeper of pancreatic ductal cells. These findings highlight HNF1B inactivation as a potential biomarker and therapeutic entry point for early interception of IPMN-driven pancreatic cancer. They also have implications for the surveillance of HNF1B-syndrome.

Obesity has been associated with several pancreatic disorders and is an important risk factor for pancreatic cancer. Nevertheless, the role of lipids in the early steps of carcinogenesis is unknown. Although we previously identified two types of pancreatic fatty infiltration with different lipid compositions that were associated with precancerous lesions and fibrosis, their mechanisms of action have not been clarified. We hypothesized that saturated palmitic acid and mono-unsaturated oleic acid (OA and PA) could play diverse roles in the activation of pancreatic stellate cells (PSCs) during the genesis of pancreatic fibrosis and the promotion of precancerous lesions. This study explored the lipotoxic effect of OA and PA on PSCs and exocrine pancreatic tissue (acinar cells). We also explored PA-induced pyroptosis in PSCs. A three-dimensional culture system of organotypic slices from human pancreatic tissues was used as well as a two-dimensional culture of hTERT immortalized PSCs. The results show that PA could induce the secretion of collagens and inflammatory cytokines (IL18) in PSCs (p < 0.05). We defined a standardized protocol of precision-cut pancreas slices cultured from human non-tumoral pancreatic tissue (n = 9). Both OA and PA are involved in the initiation of acinar cell transformation into ductal cells. OA was found to have a protective effect against PA-induced fibrosis (p < 0.05). These results highlight the antagonistic roles of oleic and palmitic acids in the initiation of pancreatic fibrosis and show that palmitic acid has a profibrotic role.