Declan McDonnell

Background Early detection of pancreatic ductal adenocarcinoma (PDAC) is critical. While faecal elastase-1 (FE-1) is a standard clinical marker for pancreatic function, its diagnostic accuracy for malignancy is limited. We sought to identify plasma metabolites that enhance FE-1 performance in symptomatic patients with suspected pancreatic pathology. Methods Using the DEPEND cohort (CRUK C45617/A29908), plasma metabolomics was performed on patients with resectable PDAC (n=23) and healthy volunteers (n=24). Diagnostic modelling included feature selection and cross-validation, with further validation in an independent external cohort (PDAC n=15, healthy controls n=10). Results Citrulline was identified as significantly depleted in PDAC patients across discovery and validation cohorts. In isolation, Citrulline achieved an AUC of 0.86 (95% CI: 0.84-0.90) internally and 0.88 (95% CI: 0.71-1.00) on external validation. Standalone FE-1 demonstrated an AUC of 0.67. However, combining Citrulline and FE-1 significantly improved diagnostic performance, achieving a combined AUC of 0.96 (95% CI: 0.94 – 0.98). Stratification revealed distinct metabolomic signatures associated with poorly differentiated tumours, suggesting a link to histological grade. Conclusions Integrating Citrulline with FE-1 testing substantially improves PDAC detection in symptomatic patients. This non-invasive panel offers high diagnostic potential, though prospective validation is required to establish clinical cut-offs for routine practice.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is insidious, with only 15–20% of those diagnosed suitable for surgical resection as it is either too advanced and has invaded local structures or has already spread to distant sites. The associated tumor microenvironment provides a protective shield which limits the efficacy of chemotherapeutic agents, but also impairs the delivery of nutrients required for the PDAC cells. To compensate for this, metabolic adaptions occur to provide alternative sources of fuel. The aim of this study is to explore metabolomic differences between participants with resectable PDAC compared to healthy volunteers (HV). The objectives were to use nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) to determine if resectable PDAC induces sufficient metabolic adaptations and variations which could be used to discriminate between the two groups. Methods: Plasma samples were collected from fasted individuals with resectable PDAC (n = 23, median age 68 [IQR 56–75], 69.6% male) and HV (n = 24, median age 63 [IQR 58–71], 54.2% male). Samples were analyzed using NMR and the Biocrates MxP Quant 500 kit at University Hospital Southampton. Results: NMR spectroscopy identified six independent metabolites that significantly discriminated between the PDAC and HV groups, including elevated plasma concentrations of 3-hydroxybutyrate and citrate, with decreased amounts of glutamine and histidine. MS analysis identified 84 metabolites with a significant difference between the PDAC and HV cohorts. The metabolites with a fold change (FC) > 1.5 in the PDAC population were conjugated bile acids (taurocholic acid, glycocholic acid, and glycochenodexoycholic acid). Discussion: In conclusion, using metabolomics, biochemical differences between resectable PDAC and HV were detected. These differences indicate metabolic plasticity and utilization of alternative fuel sources.

Background and Aims: The impact of metabolic syndrome (MetS) traits on chronic kidney disease (CKD) risk in metabolic dysfunction‐associated steatotic liver disease (MASLD) is unknown. We investigated the impact of type and number of MetS traits and liver fibrosis on prevalent CKD and incident end‐stage renal disease (ESRD) risk in SLD. Methods: 234 488 UK Biobank participants' were analysed. Hepatic steatosis index (> 36 for SLD, < 30 for no SLD) and MRI‐proton density fat fraction (≥ 5.56%) were used to identify SLD. MetS traits were identified using MASLD criteria. Advanced fibrosis (FIB‐4 score > 2.67) was determined using FIB‐4 scores. eGFR < 60 mL/min/1.73 m ² or albuminuria > 3 mg/mmol identified prevalent CKD. A validated algorithm identified incident ESRD. Binary logistic and Cox regressions were used to test associations with prevalent CKD ([adjusted odds ratios (ORs)]) and incident ESRD (adjusted hazard ratios [HRs]) respectively. Results: 102 410 participants (41.2%) had SLD. 64.4% had MetS. 1.3% had FIB‐4 score > 2.67. With SLD and only one MetS trait, hypertension (OR 1.35, 95% CI 1.35–1.72) or type 2 diabetes (T2D) (OR 1.89, 95% CI 1.06–3.38) increased risk of prevalent CKD. MetS (≥ 3 traits) increased prevalent CKD risk (OR 1.94, 95% CI 1.75–2.15), which was further increased by advanced liver fibrosis (OR 4.29, 95% CI 3.36–5.47). CKD prevalence increased with increasing MetS traits. Over 13.6 years (median follow‐up), MetS was associated with increased risk of developing ESRD (HR 1.70, 95% CI 1.19–2.43). Conclusions: In MASLD, hypertension, and T2D, number of MetS traits and liver fibrosis increased risk of prevalent CKD and presence of MetS increased the risk of incident ESRD.

Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed late, leading to a high mortality rate. Early detection facilitates better treatment options. The aim of this UK-based case–control study was to determine whether two validated tests for pancreatic exocrine insufficiency (PEI), namely, the ¹³C-mixed triglyceride breath test (¹³C-MTGBT) and a faecal elastase (FE-1) test, can discriminate between patients with resectable PDAC versus healthy volunteers (HVs) along with a comparison group with chronic pancreatitis (CP). Discrimination between disease states and HVs was tested with receiver operator characteristic (ROC) curves. In total, 59 participants (23 PDAC (16 men), 24 HVs (13 men) and 12 CP (10 men)) were recruited, with a similar age in each population, and a combined median (IQR) age of 66 (57–71). The areas under the ROC curve for discriminating between PDAC and HVs were 0.83 (95% CI: 0.70–0.96) for the ¹³C-MTGBT, and 0.85 (95% CI: 0.75–0.95) for the FE-1 test. These were similar to CP vs. HV. In conclusion, PEI occurs in resectable PDAC to a similar extent as in CP; further large-scale, prospective studies using these tests in the primary care setting on high-risk groups are warranted.

Background: The role of dysglycaemia as a risk marker for Pancreatic Ductal Adenocarcinoma (PDAC) is uncertain. We investigated the relationship between glycated haemoglobin (HbA1c) and incident PDAC using a retrospective cohort study within the UK Biobank. Methods: A study involving 499,804 participants from the UK Biobank study was undertaken. Participants were stratified by diabetes mellitus (DM) status, and then by HbA1c values < 42 mmol/mol, 42–47 mmol/mol, or ≥48 mmol/mol. Cox proportional hazard models were used to describe the association between HbA1c category (with time-varying interactions) and incident PDAC. Results: PDAC occurred in 1157 participants during 11.6 (10.9–12.3) years follow up [(median (interquartile range)]. In subjects without known DM at baseline, 12 months after recruitment, the adjusted hazard ratios (aHR, 95% CI) for incident PDAC for HbA1c 42–47 mmol/mol compared to HbA1c < 42 mmol/mol (reference group) was 2.10 (1.31–3.37, p = 0.002); and was 8.55 (4.58–15.99, p < 0.001) for HbA1c ≥ 48 mmol/mol. The association between baseline HbA1c and incident PDAC attenuated with increasing duration of time of follow-up to PDAC diagnosis. Conclusions: Dysglycaemia detected by elevated HbA1c is associated with an increased risk of PDAC. The strength of the association between elevated HbA1c and incident PDAC is inversely proportional to the time from detecting dysglycaemia but remains significant for at least 60 months following HbA1c testing.

Introduction: Pancreatic cancer (PC) is the fifth leading cause of cancer-related death in the UK. The incidence of PC is increasing, with little or no improvement in overall survival and the best chance for long-term survival in patients with PC relies on early detection and surgical resection. In this study, we propose the use of a diagnostic algorithm that combines tests of pancreatic exocrine function (faecal elastase-1 (FE-1) test and the ¹³ C-mixed triglyceride ( ¹³ C-MTG) breath test) to identify patients with PC that urgently needs imaging studies. Methods and analysis: This prospective pilot (proof of concept) study will be carried out on 25 patients with resectable PC, 10 patients with chronic pancreatitis and 25 healthy volunteers. This study will construct a predictive algorithm for PC, using two tests of pancreatic exocrine function, FE-1 test and the ¹³ C-MTG breath test. Continuous flow isotope ratio mass spectrometry in the ¹³ C-MTG breath test will be used to analyse enriched ¹³ CO ₂ in exhaled breath samples. The additional predictive benefit of other potential biomarkers of PC will also be considered. Potential biomarkers of PC showing abilities to discriminate between patients with PC from healthy subjects or patients with chronic pancreatitis will be selected by metabolomic analysis. Ethics and dissemination: The study was approved by the North of Scotland Research and Ethics Committee on 1 October 2020 (reference: 20/NS/0105, favourable opinion granted). The results will be disseminated in presentations at academic national/international conferences and publication in peer-review journals.