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

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.

Clinical Case Summary

Case: A 23-year-old female patient presented with non-bloody diarrhea, abdominal pain, flatulence, postprandial fullness, bloating, nausea, anal pain and itching, and low back pain. Three years prior, a minor trauma led to an X-ray revealing a compression fracture of two lumbar vertebrae. A densitometric exam of bone tissue showed osteopenia (T-score = -1.2). The patient reported no harmful habits and no relevant family medical history. Physical exam revealed abdominal tenderness in the right and left pelvic regions. Laboratory abnormalities included CRP at 6.78 mg/L, fecal calprotectin >1000 µg/g, total IgA at 1.91 g/L, and Anti-tTG IgA at 406.1 RU/mL. Tests for intestinal infections were negative. An abdominal CT scan revealed terminal ileitis with mesenteric lymphadenopathy. Endoscopy showed multiple erosive lesions in the stomach (Helicobacter pylori negative), as well as multiple erosive lesions with fibrin coating in the ileum. Isolated erosive lesions were also noted in the transverse, descending, and sigmoid colons, and the lower ampullary section of the rectum. Histological patterns were consistent with both Crohn's disease (Montreal classification: A2, L3 + L4, B1p) and Celiac disease (Marsh classification: III B). The therapeutic approach was tailored to the patient’s condition: biological therapy (Infliximab), a gluten-free diet, bisphosphonates, calcium, and vitamin D supplementation.
Conclusion: Both Crohn’s and Celiac disease are primarily considered gastrointestinal (GI) disorders, but they are systemic conditions that may present with a broad range of extraintestinal manifestations. These may develop earlier than, or in the absence of, classic GI symptoms and may be the only indication of the underlying condition. Patients presenting with osteopenia, osteoporosis, or fractures may initially be evaluated for metabolic bone disorders, while underlying Crohn’s or Celiac disease remains undiagnosed and/or alters both diagnostic and therapeutic pathways.

References

1. Chong, K. W., & Ananthakrishnan, A. N. (2018). Extraintestinal manifestations of inflammatory bowel disease. World Journal of Gastroenterology, 24(42), 4757-4767.
2. Lebwohl, B., Sanders, D. S., & Green, P. H. (2018). Celiac disease. The Lancet, 391(10115), 70-81.
3. Aro, P., & Mustalahti, K. (2010). Extra-intestinal manifestations of celiac disease. Celiac Disease: From Pathogenesis to Treatment, 11-27.
4. O’Mahony, S., et al. (2012). Extra-intestinal manifestations of Crohn’s disease. World Journal of Gastroenterology, 18(32), 4091-4098.

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

The rising number of patients with intraductal papillary mucinous neoplasms (IPMNs) in countries with aging populations in the near future is predictable considering that the incidence of pancreatic cystic tumors is positively correlated with patient age and that IPMNs occur most frequently among multifocal pancreatic cystic tumors. Although the majority of IPMNs detected incidentally through various imaging tests have a tumor diameter ≤10 mm and are thus deemed low-risk for carcinogenesis, the possibility of malignant transformation persists. Thus, such IPMNs are subject to periodic follow-up diagnostic imaging. Therefore, an appropriate surveillance system must be established to effectively and efficiently identify cases of IPMN-related malignant transformation, which develops only in few IPMN cases, under the constraints of limited national healthcare funding.

Aims & Methods

In the current study, we analyzed the clinical background observed at initial patient presentation that affect long-term prognosis and tried to narrow the population for whom continued evaluation is inevitable. The study included 1645 patients with IPMNs (776 men and 869 women) treated at our hospital since 2010. We examined the types and timing of medical intervention (surgical resection or pancreatic carcinogenesis) selected mainly in terms of worrisome features (WF) as advocated by the international guidelines (Pancreatology, 2024:24;255–70) for IPMN treatment. Statistical analysis was performed using the chi-square test, log-rank test, and Cox proportional hazards model, with statistical significance set at α = 0.05.

Results

During the entire observation period, 123 patients (7.5%) had IPMN-derived carcinoma (IPMN-DC), whereas 41 patients (2.5%) had concomitant pancreatic ductal adenocarcinoma (PDAC), which required medical intervention. The proportion of cases with c-Stage I, II, III, and IV (UICC 8th edition) at the time of diagnosis were 52.0%, 43.9%, 0.8%, and 3.3%, respectively, for IPMN-DC and 39.0%, 31.7%, 9.8%, and 19.5%, respectively for PDAC. A significantly higher proportion of PDAC cases were diagnosed with an advanced disease stage that developed earlier in time. Factors with significantly shorter time for IPMN-DC medical intervention were: maximum cyst diameter ≥30 mm, non-branched type, main pancreatic duct diameter ≥5 mm, and septal nodal structure for IPMN-DC. For PDAC, these factors were maximum cyst diameter ≥30 mm, main duct type, main pancreatic duct diameter ≥5 mm, septal nodal structure, cyst enlargement (≥2.5 mm/year), and abnormally high levels of CA19-9. Both groups could be significantly stratified by the number of WFs. However, the difference was more distinct in IPMN-DC, whereas <1% (9/1190) medical intervention from the group with 0 WFs was noted in PDAC. Relative risk (hazard ratio, HR) analysis of WF in which proportional hazard was maintained revealed that the presence of septal nodular structure (HR 5.2), maximum cyst diameter ≥30 mm (HR 3.3), and main pancreatic duct diameter ≥5 mm (HR 2.6) were significant factors for IPMN-DC, whereas abnormally high CA19-9 levels (HR 5.0) and septal nodular structure (HR 4.8) were significant for PDAC. Conversely, a significantly higher percentage of patients who exhibited these factors at initial presentation also later developed IPMN-DC or PDAC.

Conclusion

Ten percent of IPMN cases will develop IPMN-DC or PDAC, thereby requiring careful follow-up, especially in cases with septal nodules, abnormally high CA19-9 levels, and cysts with a maximum diameter of ≥30 mm.