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

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.

Introduction

The rise in obesity rates has triggered a surge in associated health issues, with metabolic syndrome (MS) affecting approximately 25% of populations in Western countries. Severe acute pancreatitis (AP) is associated with mortality rates as high as 50%. Prior research has linked components of MS to heightened complications and mortality in cases of AP.

Aims & Methods

This meta-analysis aims to elucidate potential risk factors and their combined effects on the outcomes of AP. We performed a systematic search of PubMed, Embase, and the Cochrane Library until November 1, 2023, identifying studies based on specified criteria. We investigated the influence of MS and its components (obesity, hypertension, diabetes mellitus, and hypertriglyceridemia) on AP outcomes, calculating pooled odds ratios (OR) with 95% confidence intervals (CIs). The study protocol was registered with PROSPERO under the identifier CRD42023471092.

Results

From an initial 15,904 records, 93 studies were included in the analysis. Overweight and obesity emerged as significant risk factors for complications (local OR: 2.677, 95%CI: 1.421-5.044; systemic OR: 2.404, 95%CI: 1.481-3.901) and the severity of AP (BMI≥30 kg/m², OR: 3.058, 95%CI: 1.369-6.829). Elevated triglyceride levels were linked to ICU admissions (OR: 2.546, 95%CI: 1.529-4.237) and severe AP (OR: 2.372, 95%CI: 1.275-4.413); hypertension correlated with increased mortality (OR: 2.135, 95%CI: 1.870-2.437), while diabetes was associated with higher odds of ICU admission (OR: 1.645, 95%CI: 1.358-1.992) and severe AP (OR: 1.49, 95%CI: 1.09-2.03). Our findings suggest that MS may elevate the likelihood of severe AP (OR=1.398, 95%CI: 0.918-2.129).

Conclusion

The individual components of metabolic syndrome are significant risk factors for complications, severity, and mortality related to acute pancreatitis. It is imperative to prioritize lifestyle counseling, education, and effective management for patients dealing with obesity.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is characterized by very poor 5-year survival of only 8-12% due to a late diagnosis and a highly desmoplastic environment, limiting therapeutic options [1]. Current treatment options for PDAC patients are mostly restricted to chemotherapy followed by surgery or palliative care [2]. These treatments have limited efficacy and are accompanied by severe side effects, strongly affecting the quality of life of these patients. Recent advances in nanotechnology have optimized targeted drug delivery in tumors with high stromal density by improving intratumoral drug retention, enhancing local drug concentrations, and thereby boosting treatment efficacy and potentially reducing side effects [3-6]. This would enable an efficient endoscopic delivery of a local depot of concentrated chemotherapy.

Aims & Methods

Here we investigated the preclinical efficacy and tolerability of a novel thermosensitive hydrogel, ChemoGell (CG), loaded with gemcitabine in preclinical human and mouse PDAC models. To evaluate the efficacy of CG, in vitro experiments using patient-derived organoids and PDAC explants were performed. This was further explored in vivo by using a human patient-derived xenograft (PDX) and the syngeneic KPC3 mouse model. Two intratumoral injections with saline, CG and gemcitabine-loaded CG (CG-Gem) were performed in both PDX and KPC3 models and compared to systemic gemcitabine administration. To evaluate potential off-target effect, other vital organs and haematological toxicity related to gemcitabine were evaluated.

Results

Both CG and CG-Gem were safe and well-tolerated in vivo. Upon CG-Gem, both in vitro and in vivo models showed strongly increased cytotoxicity compared to unloaded CG and control groups. Remarkably, we were able to inject a much higher dose (~125x) intratumorally compared to systemic gemcitabine dose. By increasing gemcitabine cytotoxicity, locally treated mice showed a significant improved survival. In a human PDX model, complete survival of mice (100%) was observed compared to control groups in which all reached humane endpoint. Given the enhanced treatment efficacy, we are currently investigating the role of the tumor microenvironment, particularly looking at stromal and immune cell dynamics. Interestingly, preliminary data shows that CG-Gem depots are surrounded and/or infiltrated with fibroblasts, macrophages, and other immune cells. To reveal the mechanism behind, further experiments looking at the different cell subtypes are undergoing.

Conclusion

Our findings represent a potential strategy for integrating localized (endoscopic) and systemic treatment modalities, addressing critical challenges in hard-to-treat PDAC management, and improving patient prognosis through more effective and targeted therapeutic strategies.

References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3): 229-263.
2. Conroy T, Pfeiffer P, Vilgrain V, Lamarca A, Seufferlein T, O’Reilly EM, et al. Pancreatic cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Annals of Oncology. 2023/11/01;34(11).
3. Ramazani F, Nostrum CFv, Storm G, Kiessling F, Lammers T, Hennink WE, et al. Locoregional cancer therapy using polymer-based drug depots. Drug Discovery Today. 2016/04/01;21(4).
4. Luo W, Zhang T. The new era of pancreatic cancer treatment: Application of nanotechnology breaking through bottlenecks. Cancer Letters. 2024/07/10;594.
5. Jiang Z, Fu Y, Shen H. Development of Intratumoral Drug Delivery Based Strategies for Antitumor Therapy. Drug Design, Development and Therapy. 2024 Dec 31:2189-202.
6. Rossi SM, Ryan BK, Kelly HM. Evaluation of the activity of a chemo-ablative, thermoresponsive hydrogel in a murine xenograft model of lung cancer. British Journal of Cancer 2020 123:3. 2020-05-27;123(3).

Disclosure

Helena Kelly is a named inventor on granted patent US20230126053 ‘Thermo-responsive hydrogel for intratumoral administration as a treatment in solid tumor cancers’ and is also co-founder and CSO of OncoLize LLC. Mike de Leeuw is co-founder and CEO of OncoLize LLC. Tushar Tomar is drug development director of OncoLize LLC. This work was supported by a research grant from OncoLize to LH.

Introduction

Intraductal papillary mucinous neoplasms (IPMNs) are a common type of mucinous pancreatic cystic lesions and represent a precursor of pancreatic cancer. The WHO classification distinguishes three grades of IPMN — low-grade/high-grade intraepithelial neoplasia and IPMN-associated invasive carcinoma—with distinct clinical management. The correct estimation of IPMN biology in clinical practice is often challenging and relies particularly on the assessment of lesion morphology, as histological confirmation is seldom possible. Therefore, improved biomarkers are needed to guide personalized management of IPMN patients.
In our preliminary analysis of public RNA-seq datasets (healthy controls n=7; LGD IPMN n=6; HGD IPMN n=6; invasive IPMN n=3), DLGAP5 expression increased significantly with IPMN grade (ANOVA p=5.48×10⁻⁶). DLGAP5 is a microtubule-associated protein essential for mitosis and vesicular trafficking—processes implicated in pancreatic cancer progression.

Aims & Methods

We aimed to assess the utility of DLGAP5 as a marker of IPMN progression as well as identify potential surrogate cystic-fluid biomarkers. Because of the intracellular localization of DLGAP5, we did not expect it to be present in the cyst fluid. However, given the role of microtubules in protein secretion, we hypothesized that DLGAP5 regulates the secretion of distinct set of proteins, which are highly correlated with its expression.
Protein expression of DLGAP5 was evaluated by immunohistochemistry (Santa Cruz Biotechnology, sc-377044) on retrospective cohort of patients who underwent pancreatic resection for IPMN at our institution (n=45). Functional studies were conducted in vitro by modulating DLGAP5 expression in pancreatic cancer cell lines (PaTu 8902, MiaPaCa2) and IPMN precursor cell line (ASAN-PaCa). Mass spectrometry-based secretome analysis of IPMN precursor cells was performed to identify DLGAP5-associated secreted proteins with potential for clinical testing in cyst fluid.

Results

DLGAP5 staining density and intensity differed significantly among LGD, HGD, and carcinoma (Fisher–Freeman–Halton p<0.0001 for both). Post-hoc Fisher’s exact tests showed LGD vs HGD (density p<0.001; intensity p<0.001) and LGD vs carcinoma (density p<0.001; intensity p<0.001) to be significant; HGD vs carcinoma was not (density p=0.673; intensity p=0.414). Functional assays demonstrated that DLGAP5 knockdown in pancreatic cancer cells decreased proliferation, while its overexpression in IPMN precursor cells increased proliferation. Secretome profiling revealed eight proteins whose secretion was significantly increased in IPMN precursor cells overexpressing DLGAP5 compared to empty vector expressing cells. Among them, PRDX1, PRDX2, FABP5, and SCGB1D2 (p=0.03, 0.038, 0.035 and 0.009 respectively) have previously been identified in cyst fluid or serum of IPMN patients, indicating translational relevance.

Conclusion

In conclusion, we validated DLGAP5 as a marker for IPMN progression and identified several DLGAP5-dependent secreted proteins that may serve as surrogate biomarkers for stratification of the patients with IPMN. Prospective validation in cystic fluid samples is ongoing.

Introduction

​Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths, with a five-year survival rate under 10% [1]. Its lethality stems from its aggressive progression and strong chemotherapy resistance, both closely linked to epithelial-mesenchymal transition (EMT). EMT enables epithelial cells to gain migratory mesenchymal traits and is regulated by transcription factors such as SNAIL, SLUG, ZEB1/2, and TWIST [2]. Among these, SNAIL plays a major role in metastasis [3], while ZEB1 is associated with poor prognosis [4]. EMT is tightly modulated by networks including ELAVL1, which encodes the RNA-binding protein HuR. HuR stabilizes mRNAs by binding AU-rich elements (AREs) in their 3′ untranslated regions (3′UTRs), promoting their expression [5].

Aims & Methods

This study aimed to identify post-transcriptional interactions between ELAVL1 and EMT-related genes and assess their prognostic value in PDAC. mRNA was extracted from cancerous and adjacent normal tissues (n=65), converted to cDNA, and analyzed by RT-PCR. BxPC-3, MiaPaCa-2, and Su.86.86 cell lines were cultured under standard conditions. Immunoprecipitation was performed on 1–2×10⁷ cells using a mouse monoclonal anti-HuR antibody, with IgG as control. qRT-PCR assessed mRNA enrichment. Binding sites were annotated using CISBP-RNA, considering only RNAdirect-confirmed 3′UTR motifs. Target 3′UTR sequences were retrieved from GENCODE V47. Statistical analysis was performed using GraphPad Prism, applying the Wilcoxon signed-rank test, Kruskal-Wallis test with Dunn’s correction, and Spearman correlation. Data were presented as median ± interquartile range, with p<0.05 considered significant.

Results

​Expression levels of EMT-related genes and ELAVL1 varied according to survival outcomes. In short-term survivors (1–12 months), SNAIL and SLUG were significantly upregulated (2.19- and 1.92-fold), while ZEB2 was downregulated (0.65-fold). Medium-term survivors (13–35 months) showed reduced ZEB1 (0.53), SNAIL (0.30), SLUG (0.35), and TWIST (0.68). Long-term survivors (36–125 months) had the lowest levels of ZEB1 (0.24), ZEB2 (0.50), SLUG (0.24), TWIST (0.35), and ELAVL1 (0.72). ELAVL1 showed strong positive correlations with ZEB1, SNAIL, and SLUG (r = 0.74–0.76), whereas overall survival was weakly negatively correlated with the expression of ZEB1, SNAIL, SLUG, and TWIST (r = -0.25 to -0.32). Although ZEB1, SNAIL, and TWIST did not show significant survival differences individually, low SLUG predicted better early survival (36 vs. 15 months, p = 0.0278). ELAVL1 expression was stratified as high and low. High ELAVL1 corresponded to a 71.65-fold increase in ZEB1, whereas high ZEB1 reduced ELAVL1 by 96.1%. High ELAVL1 also led to a 312.35-fold increase in SNAIL, while low ELAVL1 still supported elevated SNAIL expression (8.45-fold). High SNAIL expression reduced ELAVL1 by 90%, though simultaneous high expression of both resulted in a 3.71-fold ELAVL1 increase. High SLUG reduced ELAVL1 by 93%, whereas low SLUG led to a 198.11-fold increase. Binding site analysis revealed ELAVL1 targets within 3′UTRs: 34 in ZEB1, 1 in SNAIL, and 9 in SLUG.

Conclusion

ELAVL1 (HuR) likely plays a central role in regulating EMT in PDAC through stabilization of key transcription factor mRNAs. High levels of ELAVL1, SNAIL, SLUG, and ZEB1 were associated with worse outcomes, particularly in short-term survivors. Conversely, low expression of SLUG was linked to improved survival. The strong correlations and validated binding sites suggest ELAVL1 as a promising prognostic biomarker and potential therapeutic target in PDAC.

References

1. Nakaoka K, Ohno E, Kawabe N, Kuzuya T, Funasaka K, Nakagawa Y, et al. Current status of the diagnosis of early-stage pancreatic ductal adenocarcinoma. Diagnostics (Basel). 2023;13(2).
2. Kaşıkcı E, Aydemir E, Bayrak ÖF, Şahin F. Inhibition of migration, invasion and drug resistance of pancreatic adenocarcinoma cells - role of Snail, Slug and Twist and small molecule inhibitors. Onco Targets Ther. 2020;13:5763-77.
3. Tang X, Sui X, Weng L, Liu Y. SNAIL1: Linking tumor metastasis to immune evasion. Front Immunol. 2021;12:724200.
4. Liu M, Zhang Y, Yang J, Zhan H, Zhou Z, Jiang Y, et al. Zinc-dependent regulation of ZEB1 and YAP1 coactivation promotes epithelial-mesenchymal transition plasticity and metastasis in pancreatic cancer. Gastroenterology. 2021;160(5):1771-1783.e1.
5. Majumder M, Chakraborty P, Mohan S, Mehrotra S, Palanisamy V. HuR as a molecular target for cancer therapeutics and immune-related disorders. Adv Drug Deliv Rev. 2022;188(114442):114442.