Introduction

Pancreatic steatosis (PS) has been increasingly recognized and associated with some relevant metabolic implications. However, data on its correlation with exocrine pancreatic function remain limited. We conducted a systematic review and meta-analysis to evaluate whether PS is associated with exocrine pancreatic insufficiency (EPI).

Aims & Methods

This study aimed to investigate whether imaging-detected PS is related to exocrine pancreatic dysfunction, assessed by fecal elastase-1 (FE-1) levels. We searched PubMed, EMBASE, and Cochrane Central for studies including adults with and without PS identified on imaging, and reporting FE-1 concentrations. Data were pooled using random-effects models.

Results

Three studies evaluating a total of 1,864 patients were included. Fecal elastase levels were significantly lower in patients with PS compared to controls, indicating worse exocrine pancreatic function in this group (MD -199.78; 95% CI -303.66 to -95.91; p < 0.05; I² = 97%). Moreover, PS was associated with a significantly increased risk of exocrine pancreatic insufficiency (RR 3.13; 95% CI 1.17–8.40; p = 0.023; I² = 81%), reinforcing the link between fat accumulation in the pancreas and impaired exocrine function.

Conclusion

This meta-analysis demonstrates a significant association between PS and impaired pancreatic exocrine function, compared to individuals without known pancreas disease. These findings underscore the importance of a comprehensive metabolic assessment in patients with PS, given its potential role in pancreatic dysfunction.

Introduction

Recurrent abdominal pain is the predominant symptom of chronic pancreatitis (CP), contributing to significant morbidity and reduced quality of life. Medical management includes analgesics, antioxidants, neuromodulators, and pancreatic enzyme replacement therapy (PERT). While PERT is used for pancreatic exocrine insufficiency (PEI), it is also thought to reduce pain by suppressing pancreatic secretion via negative feedback. However, previous meta-analysis did not show pain reduction, though subgroup analysis suggested potential pain relief with non-enteric (NE) coated enzymes1. Unlike currently available enteric-coated formulations, high in lipase but low in proteas, non-enteric coated enzymes with high protease content dissolve rapidly and may more effectively suppress cholecystokinin-mediated pancreatic stimulation, potentially improving pain outcomes.

Aims & Methods

To primarily assess the effect of a high-protease, non-enteric-coated pancreatic enzyme preparation on pain in patients with painful chronic pancreatitis. The study was registered under ClinicalTrials.gov (NCT05042284).
We conducted a randomized, double-blind, placebo-controlled trial where we randomly assigned participants to a high protease (30,000 U)-containing, non-enteric-coated enzyme preparation (n=54) and a placebo (n=53) group. The study duration was 24 weeks. Patients with painful CP (per Mayo Clinic criteria) with chronic pain were enrolled. The primary outcome was to see a difference in mean Izbicki pain score at 12 and 24 weeks and a change in pain scores (VAS 0-10) using pain diaries. Secondary outcomes were changes in the number of painful days, analgesic requirements, patient’s global impression of change (PGIC), quality of life, and adverse effects. Weekly pain data were collated. Repeated measures, linear, and mixed-effects models were used to analyze the primary outcome. Analysis was intention-to-treat.

Results

107 out of 256 screened patients fulfilled enrollment criteria. The mean age was comparable between groups (35.1±10.6 vs. 33.6±12.3 years; p=0.51), and baseline characteristics were similar. The primary outcome using mixed model analysis showed no significant differences in the change in Izbicki pain scores between the two groups at 12 and 24 weeks (Table: Results). The mean difference in VAS pain score was -3.7(95%CI: -4.3to-3.1) in enzyme group vs. -3.5(95%CI: -4.2to-2.9) in placebo group (p=0.64) at 12 weeks. The changes were -4.2(95%CI: -4.7to-3.6) vs. -4.1(95%CI: -4.7to-3.5), respectively (p=0.79), at 24 weeks indicating no significant difference. The median number of painful days was also similar, at 12 weeks, 16 (IQR: 9–35) in the enzyme group vs. 16 (IQR: 4–36.5) in placebo (p=0.31); at 24 weeks, 3(IQR: 0–8.5) vs. 3(IQR: 0–7)(p=0.30) respectively. Analgesic use was higher in the enzyme group at 12 weeks (45(83.3%) vs. 37(69.8%); p=0.11) and 24 weeks (42(77.8%) vs. 35(66%); p=0.20). Differences in the change in global health status, quality of life, PGIC, and adverse effects at both time points were also non-significant.

Conclusion

Despite the high protease content, Non-enteric coated enzyme preparations did not improve pain and quality of life in patients with painful chronic pancreatitis. Further RCTs are needed to evaluate benefits in distinct subgroups.

References

1. Yaghoobi, Mohammad, Julia McNabb-Baltar, Raheleh Bijarchi, and Peter B. Cotton. “Pancreatic Enzyme Supplements Are Not Effective for Relieving Abdominal Pain in Patients with Chronic Pancreatitis: Meta-Analysis and Systematic Review of Randomized Controlled Trials.” Canadian Journal of Gastroenterology and Hepatology. Doi: https://doi.org/10.1155/2016/8541839

Clinical Case Summary

A 71-year-old female presented to the gastroenterology clinic following a two year history of dysphagia and sensation of food sticking in the oesophagus. Her dysphagia was limited to solid foods, and symptoms were not exacerbated by positional change. Pain was mostly localised around the sternal notch where she would have the sensation of a food bolus. Over the preceding 2 years, she had experienced about 7.5kg of weight loss with no constitutional symptoms of fevers or fatigue. Her past medical history included hypertension, dyslipidaemia, lower back pain, cold agglutinin disease, monoclonal B lymphocytosis and peripheral arterial disease. On examination, there were no signs of malnourishment or palpable lymph nodes in the axilla, neck or supraclavicular region. Her abdomen was soft and non-tender. Given largely non-illuminating blood results, an oesophageal-gastroduedonoscopy was performed. However, no findings were noted, specifically no oesophageal webs, Zenker diverticulum, gastroparesis, trachealisation of the oesophagus or corrosive pathology. H. pylori was also not isolated on histopathology. A barium swallow was then performed which showed extensive external compression of the proximal third of the oesophagus at the level of the arch of the aorta, most indicative of dysphagia lusoria (Fig 1). Computed tomography angiography (CTA) showed retroesophageal aberrant right subclavian artery bifurcating from the ascending aorta independent of a brachiocephalic artery and causing external oesophageal compression (Fig 2 & 3). Given this definitive diagnosis, the patient was then seen in clinic where management of dysphagia lusoria was explained. Despite ongoing symptoms, the patient decided to continue with conservative management and lifestyle modifications, which included eating smaller bites and increase in fluid intake. Although an extensive compression typically requires surgical intervention, our patient was stable at two-year follow-up (Fig 4 A-B).

References

Figure 1: Barium swallow examination showing extrinsic compression of the proximal third of the oesophagus at the level of the aortic arch (white arrow).
Figure 2: Axial view of computed tomography angiography (CTA) showing the posterior course of the retroesophageal aberrant right subclavian artery.
Figure 3: Axial view of computed tomography angiography (CTA) showing compression of oesophagus (white arrow) by the retroesophageal aberrant right subclavian artery (white arrowhead).
Figure 4: Computed tomography angiography (CTA) multi-planar reconstruction (MPR) showing the posterior course of the right subclavian artery (white arrow), crossing the mediastinum and compressing the oesophagus. A. coronal view B. Sagittal view

Disclosure

None.

Introduction

Besides stage, age and CA19-9 there is limited knowledge on “patient-related factors” associated with chemotherapy response for Pancreatic Ductal Adenocarcinoma (PDAC) patients. Smoking worsens chemotherapy response in other tumours and seems to promote tumor progression in PDAC preclinical models, but data in human PDAC are scanty.

Aims & Methods

PDAC patients were prospectively enrolled at diagnosis with exposome and clinical data registered, and tumors sampled for research purpose during Endoscopic Ultrasound (EUS). Patients were then followed-up to register chemotherapy treatment [whether Folfirinox (F), Abraxane-gemcitabine (AG) or a combination of cisplatin, abraxane, capecitabine and gemcitabine (PAXG)] and evaluate disease control rate (DCR) at 6-months (DCR-6), Progression-Free-Survival (PFS) and Overall-Survival (OS). We also explored transcriptomic signatures associated with smoking on a subset of EUS-acquired PDAC samples undergoing RNA-sequencing, with differential gene expression (DGE) analysis and pathways analysis performed. Furthermore, in vitro analyses with PDAC cell lines CAPAN-1 were treated with Folfirinox or gemcitabine with/without the nicotine compound 4-(Methylnitrosoamino)-1-(3-pyridinyl)-1-butanone to evaluate in vitro effects.

Results

326 patients treated with chemotherapy of interest were analyzed. Median age was 65, with 51.5% being males. Disease’s resectability at diagnosis was 10.4% resectable, 37.7% borderline-resectable, 26.9.% locally-advanced, 24.8% metastatic. AG was used in 42.3% of patients, PAXG in 25.7%, Folfirinox in 31.9%. DCR-6 was 57.9% in current smokers vs 70.4% in never-/ex-smokers (p=0.05). Current smoking was associated with a lack of DCR-6 at adjusted multivariable analysis (OR=1.99; 95%CI:1.1-3.5; p=0.01). At subgroup analysis, this was confirmed only for Folfirinox patients, with DCR-6 being 46.2% for current smokers vs 75.6% for non-current smokers(p=0.007). Current smokers had a significantly shorter PFS (5 vs 13 months; HR:1.79; 95%CI:1.13-3.21; p=0.01) and OS (24 vs 34; HR 1.93; 95%CI: 1-3.67; p=0.04) compared to non-smokers at adjusted multivariable analysis.
At transcriptomic analysis on a subset of 84 patients, current smokers were more prevalent in patients developing the more aggressive basal-like subtype (50% vs 15%; p=0.03), had lower expression of the classical marker GATA6 (3.27 vs 3.92; p=0.03) as also different activated pathways such as activated MAPK signalling, Axon guidance, Hypoxia and epithelial-mesenchymal-transition signalling among the others.
At in vitro experiments, for cell survival analysis, CAPAN-1 PDAC cells showed a significant reduced response to Folfirinox treatment when treated in combination with nicotin compounds, which was not observed for gemcitabine alone or in combination.

Conclusion

Collectively, our results consistently point towards a deleterious effect of smoking on response to Folfirinox regimen. Clinical data show that current smoking is a predictive factor for lower DCR-6, shorter PFS and OS; transcriptomic analyses show different gene expressions between smokers and non-smokers, with a transition toward reduced expression of classical phenotype and activation of inflammatory and pro-mesenchimal pathways. In vitro experiments support the negative effect of smoking on the response to Folfirinox. Smoking should be considered as a covariate to be investigated when choosing chemotherapy regimens in patients with PDAC, and patients should be discouraged to continue smoking.

Introduction

Incidental inflammation of the terminal ileum is not uncommon in individuals who are submitted to screening colonoscopy. It is mostly mild and considered to have a benign course without the need for immunosuppressive therapy used for moderate Crohn’s disease. In the light of recent literature highlighting the effectiveness of early treatment of Crohn’s Disease we sought to determine the natural course of asymptomatic terminal ileitis in our pool of individuals who underwent screening (ileo)colonoscopy, and in particular which patients ended up being treated with biologics in real life , as well as any baseline factors.

Aims & Methods

We included individuals from the endoscopic database with asymptomatic terminal (Crohn’s) ileitis in the last 5 years: we only included those with recorded endoscopic images available for endoscopic assessment with the SES-CD score and biopsies compatible with Inflammatory Bowel Disease (IBD) without a history of significant NSAID consumption. We recorded baseline characteristics (age, gender, smoking status, IBD family history, extra-intestinal autoimmunity), endoscopic severity, degree of histologic inflammation and biomarkers of inflammation (C-RP, Fecal Calprotectin). Finally we went through the Greek Prescription Database to find out the ones that were prescribed with biologics, steroids or had IBD-related surgery or hospitalization. We used point-biserial correlation, Pearson correlation, chi-square test to establish any variable correlations.

Results

We included 46 individuals : 28 women, 18 men with a median age of 55.8 years and a median follow up of 46.8 months. Nine of them were smokers (19.5%) and 10 (21.7%) had elevated C-RP (>0.5 mg/dL) and/or Fecal Calprotectin (>250 μg/mg). Steroids were used in 11 patients (23.9%) and only 1 had IBD-related surgery. Patients that received biologic therapy at some time-point amounted to 15 (32.6%): 9 with adalimumab (60%), 5 with ustekinumab (33.3%) and 1 patient received upadacitinib (concomitant rheumatoid arthritis). No factor other than an initial SES-CD score > 4 displayed statistically significant correlation with the future use of biologic therapy (p-bc=0,4214, p=0,0032). Interestingly enough most of the patients to eventually receive biologic therapy showed some kind of endoscopically visible ileocecal valve inflammation.

Conclusion

In this carefully selected but with a real life follow up group of patients with incidental asymptomatic terminal (Crohn’s) ileitis a rather surprising one third of patients was eventually treated with biologic therapy during a median period of a 4-year follow up. Only baseline endoscopic severity (SES CD score >4) predicted the use of biologic therapy (mostly adalimumab or ustekinumab). All those patients had moderate disease and uneventful disease course. We need more studies to determine the (endoscopic?) threshold for biologic therapy or the right non-invasive tool (intestinal ultrasound?) to monitor these individuals in order to prevent over (or under)treatment.

References

Jellyana Peraza, Marco Emilio Kaper, Andre Bargas, Iris Kim, Manasi Agrawal, Lone Larsen, Henrik Albaek Jacobsen, Tine Jess, Jean-Frederic Colombel, Joana Torres, Ryan C. Ungaro, Ashwin N. Ananthakrishnan. A Simple Endoscopic Score for Crohn's Disease (SES-CD) ≥ 7 Predicts Disease Progression. Alimentary Pharmacology and Therapeutics 2025. Mar;61(6):1011-1018. doi: 10.1111/apt.18492. Epub 2025 Jan 5.PMID: 39757503.

Introduction

Autoimmune pancreatitis (AiP) is a rare form of chronic pancreatitis. Studies from Japan and Germany suggest that AiP patients may have a higher incidence of malignancies compared to the general population. However, reliable data in this regard are still lacking.

Aims & Methods

We initiated a retrospective, multicenter observational study within the Pancreas 2000 framework to investigate the incidence of malignancy in AiP Patients.In our global multicenter retrospective observational trial, we are currently collecting data from patients with AiP diagnosed after 2005, including type 1, type 2, and not-otherwise-specified (NOS) AIP, regardless of the diagnostic criteria used. Patients with less than 12 months of follow-up after AIP diagnosis and those with immune checkpoint inhibitor-induced pancreatitis are excluded. Our primary outcome is to determine the occurrence of the first invasive cancer in AiP patients. The secondary outcome is to evaluate the characteristics of AiP patients with distinct pancreatic and/or extrapancreatic cancers and the prevalence of all cancer diagnoses within 12 months prior to AiP diagnosis. The standardized incidence ratio of any first invasive cancer after AiP diagnosis will be compared to age-grouped and gender-matched controls in the general population. The expected number of cancers in the general population will be determined using the Cancer Incidence in Five Continents Volume XI (CI5XI) registry.

Results

We will present the current status of recruitment and preliminary data. To date, 16 centers from Europe and America have entered 321 cases. Ethics submissions have already been applied for in an additional 45 centers across four continents (Europe, Asia, America, and Oceania).

Conclusion

To the best of our knowledge, this is the first global observational trial analyzing the risk of developing cancer in patients with AiP.