Background/Objectives: Individuals with type 2 diabetes have an increased risk of pancreatic cancer (PC), yet early detection markers remain limited. We examined associations between routinely measured serum biomarkers and subsequent PC risk in this population. Methods: Using the Swedish AMORIS cohort, 101,051 individuals aged ≥50 years at diabetes diagnosis with newly diagnosed type 2 diabetes (1969-2019) were analysed. Ten biomarkers, including liver enzymes, inflammatory markers, renal function, and lipid profiles, were assessed. The primary analysis focused on measurements within ±1 year of the diabetes diagnosis (n = 13,190; Cohort 1). Sensitivity analyses considered broader windows: -3, -5, and -10 years before diagnosis to +1 year after, and from the diagnosis to the end of the follow-up (Cohorts 2-5). Multivariable Cox models adjusted for age and sex were applied. Results: During a mean follow-up of 15.9 years, 192 individuals developed PC. In primary analysis, higher alkaline phosphatase was associated with increased PC risk (HR: 1.16, 95% CI: 1.09-1.24 per 1 SD increase). Higher creatinine was associated with reduced PC risk (HR: 0.55, 95% CI: 0.36-0.83 per 1 SD increase), while haptoglobin (HR: 1.20, 95% CI: 0.97-1.49 per 1 SD increase) suggested a modest positive association. Patterns were consistent across sensitivity analyses. Conclusions: In individuals ≥ 50 years with newly diagnosed type 2 diabetes, higher ALP and lower creatinine were independently associated with increased PC risk before and after diabetes diagnosis, while haptoglobin showed a modest positive association. As these biomarkers are routine laboratory panels, their potential to support risk stratification in primary care requires further evaluation within established risk-prediction frameworks.

High-fat diet (HFD) and obesity are increasingly recognized as risk factors of pancreatic ductal adenocarcinoma (PDAC), yet the mechanisms by which dietary fat contribute to oncogenic transformation remain elusive. Using an inducible acinar-specific KrasG12V / Trp53 -loss genetically-engineered mouse model of PDAC, we established early- and late-onset protocols to assess age-dependent susceptibility to HFD. Specifically, HFD accelerated tumorigenesis with poorer prognosis in early-onset mice and, strikingly, enabled full PDAC development in late-onset adult mice otherwise resistant to oncogenic transformation. Tumors arising under HFD activated a distinct transcriptional and epigenetic state enriched in pathways or genes related to stemness, plasticity, and metastatic competence, which was maintained even in tumor-derived cell lines. Mechanistically, fatty acid-educated macrophages secreted the cathelicidin antimicrobial peptide (CAMP), activating P2X purinoceptor 7 (P2RX7) signaling in tumor cells to drive a highly plastic, immune-evasive phenotype reinforced by the expression of the peptidoglycan recognition protein 1 (PGLYRP1), further shielding tumor cells from macrophage phagocytosis. Functionally, HFD-induced tumors displayed enhanced metastatic potential independent of host context. Analysis of 164 human PDAC samples revealed that elevated body-mass index (BMI) was associated to a conserved CAMP-P2RX7-CXCR4 signature, maintained despite weight loss during disease progression. Together, these findings uncover a diet-imprinted macrophage-tumor cell circuit that promotes transformation and accelerates PDAC progression, positioning it as a therapeutic vulnerability in obesity-associated pancreatic cancer. ### Competing Interest Statement The authors have declared no competing interest. Asociación Española Contra el Cáncer, https://ror.org/00gxct719, PRDMA246123GALV, POSTD258037LÓPE, LABAE223389SANC Asociación Cancer de Pancreas, IX Carmen Delgado/Miguel Pérez-Mateo grant European Research Council, ERC-AG/695566-THERACAN Centro de Investigación Biomédica en Red de Cáncer, CB21/12/00121 AIRC, IG 26201, IG 32351 PNRR Program, PNRR-MCNT2-2023-12377229 NEXTGENERATION-EU, CN00000013 European Regional Development Fund, PID2024-159192OB-I00 Pancreatic Cancer UK, 06/Q0512/106 Instituto de Salud Carlos III, PT20/0045, PT23/00098

Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis as early-stage asymptomaticity leads to late-stage diagnoses. Strategies to detect PDAC earlier or identify high-risk individuals are therefore paramount. Here, we report results from genetically engineered mice and PDAC patients that identify serum proteins associated with pancreatic intraepithelial neoplasms (PanINs), the most common PDAC precursor, and early-stage PDAC. Initially, we screened previously described PanIN-abundant mice, harbouring pancreatic and duodenal homeobox 1 (Pdx1)-Cre, Lox-STOP-Lox-KrasG12D/+ and floxed alleles of essential autophagy genes autophagy-related 7 (Atg7) or autophagy-related 5 (Atg5). Sera from these mice were assessed by proteomics and hits were compared to those in Lox-STOP-Lox-KrasG12D/+ Lox-STOP-Lox-Trp53R172H/+ Pdx1-Cre (KPC) mice, which closely recapitulate human disease, and early-stage (I-II) PDAC patients. Levels of inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) were significantly elevated in all three screens, with complement C5, complement factors B and H (CFB/CFH), and monocyte differentiation antigen CD14 increased in KPC mice and PDAC patients; and all were significantly increased co-ordinately in PDAC according to disease stage. Serum levels of C5, CFH and CD14 together constitute a novel panel for identifying PanINs and early-stage PDAC with confidence, and when combined with additional screening, could help increase survival from this dismal disease.

Background and Aims:Cholangiocarcinoma (CCA) displays remarkable anatomical and histological heterogeneity. Besides diagnosis confirmation, histology currently does not have a major role in the management of CCA. We aimed to study the clinical relevance of histological heterogeneity of CCA and putative tissue biomarkers by creating a multicentric digitalized European CCA Histology Registry.Approach and Results:Nine referral centers, participating in the International Cholangiocarcinoma Clinical Registry, shared samples and data from 293 patients. Histological and immunohistochemistry stains (n=10) were performed. Computed tomography (CT) scans (n=112 cases) were analyzed by morphological and radiomics techniques. A selection of cases (n=18) was processed for spatial transcriptomics analysis. No significant differences in 5-year overall survival (OS) were found in perihilar CCA versus intrahepatic (i) CCA, and in small bile duct (SBD) versus large bile duct (LBD) iCCA. When cases were classified by Periodic acid of Schiff (PAS) positivity (mucin content), PASHIGH LBD iCCA showed a significantly worse 5-year OS compared to PASLOW iCCA. Multivariate Cox regression identified PASHIGH LBD iCCA phenotype as an independent predictor of worse OS. PASHIGH LBD iCCA subtype showed specific molecular characteristics at spatial transcriptomics and immunohistochemistry; CT scans and serology could distinguish PASHIGH LBD iCCA phenotype with excellent accuracy.Conclusions:Our data underline the importance of identifying morphological subclasses with a significant prevalence in CCA as a tool for risk stratification and prognosis. The European CCA Histology Registry represents a valuable platform for integrating digital pathology with clinical, radiological, and molecular information as a framework for digital twin advancement.

Pancreatic cancer is a highly lethal malignancy and is predicted to become the second leading cause of cancer-related deaths by 2030. Early detection significantly improves outcomes, but general population screening remains infeasible due to the low prevalence of the disease and lack of specific biomarkers. This review evaluates current recommendations for pancreatic cancer surveillance in high-risk individuals, synthesises evidence from recent studies and explores the sustainability of current imaging-based surveillance programmes. Challenges such as overdiagnosis, economic feasibility and disparities in access highlight the need for targeted, cost-effective strategies. Collaborative initiatives and consortia are needed to advance biomarker research and refine risk stratification. By integrating evidence-based recommendations with sustainable approaches, this review outlines pathways to improve early detection and reduce mortality from pancreatic cancer.

Abstract Introduction Pancreatic cancer is the deadliest common cancer. Its poor prognosis is associated with its complex biology and lack of early detection strategies. Although much progress has been made in finding more effective therapeutic strategies, pancreatic tumours remain difficult to treat. A major reason why chemotherapy is relatively ineffective against this type of cancer is inefficient delivery of drugs to their target sites combined with multidrug resistance. Our aim is to use the technique called Photochemical Internalisation (PCI), a light-triggered intracellular drug delivery method which combines low dose Photodynamic Therapy (PDT) with chemotherapy, to induce efficient cytosolic delivery of therapeutic compounds to their specific subcellular targets. Methodology Treatment outcomes using saporin (a type I ribosome-inactivating protein) and gemcitabine as monotherapies, or in combination with a light-activated photosensitizer (the porphyrin TPPS2a), were thoroughly analysed in both established pancreatic cancer cell lines and patient-derived xenograft (PDX) models. The efficacy of these treatments was assessed in both 2D and 3D tumour models through various cell viability assays, including MTT, crystal violet staining, and neutral red staining. Additionally, molecular techniques such as western blotting, protein arrays, and flow cytometry were employed to determine the effects on cell viability and to elucidate changes in signalling pathways leading to the therapeutic response. Results In this study, we observed minimal cytotoxicity induced by saporin, gemcitabine or TPPS2a + light monotherapies. However, PCI synergistically enhanced saporin and gemcitabine cytotoxicity (p<0.001) using very low concentrations in all tumour models. Moreover, we determined the mechanism of cell death triggered by these protocols. PCI induced endosomal disruption following light excitation and apoptosis leading to caspases 3/7 activation, in a time dependent manner. Conclusions Overall, our findings demonstrate the potential of PCI to enhance the efficacy of cancer chemotherapy for pancreatic cancer using lower doses than in monotherapy and open a new window for future translational studies. By using low doses of light therapy, we have found a promising avenue for future studies that could eventually lead to better treatments for this challenging disease. Citation Format: Maria Rosado, Ismahan Mahamed, Andres Garcia-Sampedro, Sandy MacRoberts, Pål Selbo, Stephen Pereira, Pilar Acedo. Enhancing pancreatic cancer chemotherapy through photochemical internalisation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A027.

Abstract Pancreatic cancer is associated with late-stage diagnosis and poor patient prognosis. The disease is characterised by chronic dysregulated immunity and inflammation. Moreover, chronic pancreatitis is linked with an increased risk of pancreatic cancer. Tissue remodelling during disease progression involves a complex network of cells and a crosstalk between cancer cells, stromal components and immune cells, but it remains poorly explored. Thus, to improve the outcome of patients, there is a need for better understanding of biological changes associated with the initiation and progression of pancreatic cancer at the molecular and spatial levels. Using samples obtained from our Accelerated Diagnosis of neuroEndocrine and Pancreatic TumourS (ADEPTS) biobank, we have evaluated blood samples for the discovery of non- invasive biomarkers to discriminate patients with pancreatic cancer from symptomatic patients without cancer. In this pilot study, the transcriptome of peripheral blood mononuclear cells (PBMCs), isolated using a ficoll gradient was explored to identify PDAC-associated mRNA signatures. Moreover, the Olink® Explore Inflammation and Oncology panels were performed in a cohort of 40 patients with early stage (I-II) PDAC, 40 chronic pancreatitis samples and 40 control patients with benign symptomatic upper GI diseases. To validate and enrich these results, a panel of inflammatory and immune markers including immunoglobulins, cytokines and chemokines was also run using multiplex techniques. Symptoms observed in our cohort were also analysed together with clinical (e.g diabetic status, biochemistry profile) and demographic data (age, sex, ethnicity, post code etc). We have identified mRNA transcriptome signatures and differentially expressed proteins associated with inflammatory and immunological processes in PDAC compared to benign symptomatic samples. Our results offer potential diagnostic utility for early-stage disease. Additionally, our unique cohort of patient samples comprising of those with confirmed PDAC and those presenting to clinic with benign disease and similar non-specific symptoms, allows for the development of non-invasive diagnostic tests with better translational applicability. Future work will involve the validation of these findings in a larger patient cohort and the use of NanoString GeoMx® Digital Spatial Profiler to perform whole transcriptome and proteome profiling in human chronic pancreatic and pancreatic cancer tissue samples. Citation Format: Kyra Fraser, Maria Rosado, Stephen P Pereira, Pilar Acedo. Unravelling fibroinflammatory and immune signatures for pancreatic cancer early detection [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B023.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide, mainly due to its high heterogeneity, resistance to therapy and late diagnosis, with a 5-year survival rate of less than 10%. This dismal prognosis has promoted strategies to develop more effective treatments. Nanoparticle-based strategies have emerged, in the last decades, as a great opportunity because they can enhance drug delivery and promote controlled release, presenting lower side effects than conventional therapeutic regimens. Moreover, nanoparticles can often be modified to target specific cells or to achieve a sustained release of the drugs into the tumor. However, very few nanoparticle-based therapies are clinically approved. Concretely for pancreatic cancer treatment only two nanoformulations have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) so far. Clinical translation of nanoparticles remains a challenge for modern medicine, and in particular for pancreatic cancer therapy, because of the complexity of the disease, and a lack of studies been performed in clinically relevant in vitro and in vivo models. In this review, we have summarized the most recent clinical trials using nanoparticle-based formulations in PDAC, giving a small context of the diverse types of nanoparticles employed and the most recent advancements in the field.

Establishing and nurturing strong patient relations stands as an essential pillar in the framework of UEG. Within Europe's diverse healthcare landscape, fostering strong relations and collaboration among the digestive health community will not only optimize healthcare outcomes but also establish solidarity and mutual understanding between healthcare professionals, patients, and patient advocates. By prioritizing patient-centered approaches in our advocacy efforts, and recognizing patient advocates as active partners, we ensure that healthcare services are tailored to meet individual needs and preferences. With these considerations in mind, at UEG Week 2023 in Copenhagen, UEG launched the Digestive Health Roundtable, a new format of dialog between experts in digestive health and dedicated patient advocates. This event marked the first in a series of multidisciplinary meetings, all driven by a shared purpose—to address challenges, identify opportunities and reach consensus on joint actions aimed at improving digestive health across Europe. We were pleased to be joined by representatives from the Association of European Coeliac Societies, Digestive Cancers Europe, the European Federation of Crohn's & Ulcerative Colitis Associations (EFCCA), the European Liver Patient Association, the Danish Celiac Association, the Danish Colitis-Crohn Association, and the Danish Liver Association. The meeting was also joined remotely by Dr Kremlin Wickramasinghe—Regional Adviser for Nutrition, Physical Activity and Obesity at WHO/Europe. He reported that, according to WHO data (WHO Global Health Estimates 2020), the burden of noncommunicable diseases has increased continuously over recent years worldwide, and in 2021 they caused 90% of deaths and 85% of years lived with disability in the WHO European Region. Digestive diseases were reported as the fourth cause of death among all NCD-related deaths in 2019. Moreover, Dr Wickramasinghe reported alarming data on obesity and overweight, notably in children, where the findings show that 29% of children in Europe, aged 7–9 years old, are overweight or obese (WHO European Childhood Obesity Surveillance Initiative [or COSI], Report on the fifth round of data collection, 2018–2020 [https://apps.who.int/iris/handle/10665/363950]). The roundtable attendees discussed recommendations across three core topics crucial to shaping a healthier future: prevention, early diagnosis, and quality of life (Figure 1). Visual representation of the group discussions involving medical experts and patient advocates on three key topics: prevention, early diagnosis, and quality of life. Prevention was identified as a core priority for the digestive health community. Among the challenges identified were low health literacy at societal levels, exacerbated by inadequate awareness and/or tools for early diagnosis for some conditions, and the persistent lack of incentives at the societal level for addressing addictions and/or implementing measures to improve digestive health. Furthermore, the erosion of trust in medical information and healthcare professionals following the COVID pandemic underscored the urgent need for intervention. It was recognized that current measures targeting risk factors often place undue emphasis on individual responsibility, neglecting systemic changes and lack of basic living conditions (like unemployment, poor housing, unsafe neighborhoods, pollution etc.). In response to these challenges, the group rallied around a series of proactive measures aimed at effecting positive change. These included a commitment to investing more in education across all social groups to enhance health literacy and community awareness, particularly regarding early signs of diseases, healthy habits, and the critical role of healthy nutrition. Additionally, there was consensus on the necessity of enhancing healthcare professionals' training, particularly in areas such as nutrition. The group also advocated for addressing physical inactivity in the workplace through the implementation of designated exercise time and the provision of on-site facilities to support employees. Furthermore, there was a resounding call for increased governmental and international investment in combating misinformation and disseminating credible, well-targeted information to rebuild trust in scientific evidence. This will improve the uptake of national vaccination and screening programs, and thereby improve health outcomes. Underlining the need for collaboration across various sectors, the group identified key stakeholders for engagement. These include actors of change such as parents and educators, who play pivotal roles in shaping health behaviors and attitudes from an early age. Additionally, actors of power such as local policymakers, the WHO, and EU institutions were highlighted as crucial collaborators in driving policy changes and implementing systemic interventions. Furthermore, the group underscored the importance of engaging with the food and agriculture industry, particularly in advising on topics of mutual interest, such as dietary requirements for coeliac patients. However, it was also noted that aligning with industries contributing to health harms, such as alcohol and tobacco, would be contrary to the group's mission, emphasizing the need for ethical partnerships in pursuit of improved digestive health outcomes. The group who discussed challenges related to diagnosis identified persistent barriers to accessing primary care, characterized by a lack of specific knowledge among healthcare providers and the burden of repeated examinations. Additionally, the group emphasized the widespread difficulty in accessing timely diagnoses across many countries, highlighting the detrimental impact of misdiagnosis on patients' quality of life and mental well-being. Furthermore, concerns were raised regarding the risk of overdiagnosis, particularly in cases where treatments may impact on patients' quality of life, as observed in certain cancer diagnoses. Knowledge of age-related signs and symptoms affects the efficiency of timely diagnosis, especially in the younger patients. In response to these challenges, the group presented a series of best practice examples aimed at improving healthcare delivery and patient outcomes. These included prioritizing prevention as the most cost-effective investment, increasing awareness of early disease signs within healthcare settings, and championing patient-centered care by involving patients as partners in their illness experiences. The group also underscored the importance of anti-stigma training for healthcare providers and the prioritization of transitional care services. Looking ahead, the group emphasized the critical importance of collaboration between healthcare professionals and patient representatives in developing evidence-based guidelines, which should be translated at national levels and made accessible to non-specialists. Furthermore, joint advocacy projects were deemed essential involving key stakeholders such as patient representatives, healthcare professionals, and policymakers. Collaboration with educational institutions and representatives from the school system was also highlighted as a vital avenue for promoting health literacy and early intervention initiatives within communities. When discussing quality of care, the biggest reported challenge faced by the patient community was the prevalent stigma experienced by patients, which takes a heavy toll on their well-being, particularly among those diagnosed with liver diseases and inflammatory bowel diseases. The group also highlighted the detrimental effects of a lack of knowledge, which often manifests in patients experiencing feelings of guilt and shame. Additionally, the strain placed on healthcare systems was identified as a significant factor impacting both the quality of life of healthcare professionals and their ability to deliver personalized and compassionate care, and the well-being of family members caring for patients. In response to these pressing issues, the group formulated a set of recommendations aimed at tackling these challenges head-on. These recommendations included prioritizing self-management education for patients, fostering effective communication between healthcare professionals and patients, and ensuring the active involvement of patients in setting standards of care. Furthermore, the group advocated for the implementation of holistic care approaches and the reduction of logistical and bureaucratic barriers within healthcare systems. Moreover, the identification and implementation of transitions of care interventions were deemed crucial steps toward improving the quality of life among patients and alleviating the burden on healthcare systems and caregivers alike. Through concerted action on these recommendations, the group endeavors to address the multifaceted challenges faced by individuals within the digestive health community, fostering improved outcomes and well-being for all stakeholders involved. In conclusion, the collaborative efforts initiated by the first Digestive Health Roundtable mark a significant step forward in enhancing patient relations within the digestive healthcare landscape. As we navigate the complexities of modern healthcare, it is imperative that we continue to prioritize the voices and experiences of patients, recognizing them as invaluable partners in the pursuit of improved health outcomes and quality of care. Moving forward, we remain committed to nurturing these relationships, advocating for the integration of joint recommendations into policy-making and clinical practice, and ensuring that every individual receives optimal care. The authors have no conflicts of interest to declare. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Background Endoscopic retrograde cholangiopancreatography (ERCP) still has a relatively high complication rate, underscoring the importance of high-quality training. Despite existing guidelines, real-world data on training conditions remain limited. This pan-European survey aims to systematically explore the perceptions surrounding ERCP training. Methods A survey was distributed through the friends of United European Gastroenterology (UEG) Young Talent Group network to physicians working in a UEG member or associated states who regularly performed ERCPs. Results Of 1035 respondents from 35 countries, 649 were eligible for analysis: 228 trainees, 225 trainers, and 196 individuals who regularly performed ERCP but were neither trainees nor trainers. The mean age was 43 years, with 72.1% identifying as male, 27.6% as female, and 0.3% as non-binary. The majority (80.1%) agreed that a structured training regimen is desirable. However, only 13.7% of trainees and 28.4% of trainers reported having such a structured program in their institutions. Most respondents (79.7%) supported the concept of concentrating training in centers meeting specific quality metrics, with 64.1% suggesting a threshold of 200 annual ERCPs as a prerequisite. This threshold revealed that 36.4% of trainees pursued training in lower-volume centers performing <200 ERCPs annually. As many as 70.1% of trainees performed <50 annual ERCPs, whereas only 5.0% of trainers performed <50 ERCPs annually. A low individual trainee caseload (<50 ERCPs annually) was more common in lower-volume centers than in higher-volume centers (82.9% vs. 63.4%). Conclusions The first pan-European survey investigating ERCP training conditions reveals strong support for structured training and the concentration of training efforts within centers meeting specific quality metrics. Furthermore, this survey exposes the low availability of structured training programs with many trainees practicing at lower-volume centers and 71% of all trainees having little hands-on exposure. These data should motivate to standardize ERCP training conditions further and ultimately improve patient care throughout Europe.

Pancreaticobiliary cancers (pancreatic ductal adenocarcinoma, cholangiocarcinoma and gallbladder) are relatively uncommon tumors with a rising incidence. The 5-year survival rates for patients with this group of tumors are poor as the majority are diagnosed at a locally advanced or metastatic disease stage, when potentially curative surgical resection is no longer optional. Early-stage detection is therefore key for improving survival yet due to their rarity, the non-specific clinical course preceding diagnosis and the sub-optimal performance of current diagnostics, screening of low-risk (asymptomatic) populations is not recommended. Efforts have therefore shifted toward risk modification, identification, and monitoring of high-risk individuals and development of more accurate and minimally invasive tests for early cancer detection. In this chapter we review risk factors and high-risk groups, strategies for their screening and surveillance as well as key developments in predictive, diagnostic and prognostic biomarker discovery for pancreatic and biliary tract cancers.

Background The grim (<10% 5-year) survival rates for pancreatic ductal adenocarcinoma (PDAC) are attributed to its complex intrinsic biology and most often late-stage detection. The overlap of symptoms with benign gastrointestinal conditions in early stage further complicates timely detection. The suboptimal diagnostic performance of carbohydrate antigen (CA) 19-9 and elevation in benign hyperbilirubinaemia undermine its reliability, leaving a notable absence of accurate diagnostic biomarkers. Using a selected patient cohort with benign pancreatic and biliary tract conditions we aimed to develop a data analysis protocol leading to a biomarker signature capable of distinguishing patients with non-specific yet concerning clinical presentations, from those with PDAC. Methods 539 patient serum samples collected under the Accelerated Diagnosis of neuro Endocrine and Pancreatic TumourS (ADEPTS) study (benign disease controls and PDACs) and the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS, healthy controls) were screened using the Olink Oncology II panel, supplemented with five in-house markers. 16 specialized base-learner classifiers were stacked to select and enhance biomarker performances and robustness in blinded samples. Each base-learner was constructed through cross-validation and recursive feature elimination in a discovery set comprising approximately two thirds of the ADEPTS and UKCTOCS samples and contrasted specific diagnosis with PDAC. Results The signature which was developed using diagnosis-specific ensemble learning demonstrated predictive capabilities outperforming CA19-9, the only biomarker currently accepted by the FDA and the National Comprehensive Cancer Network guidelines for pancreatic cancer, and other individual biomarkers and combinations in both discovery and held-out validation sets. An AUC of 0.98 (95% CI 0.98-0.99) and sensitivity of 0.99 (95% CI 0.98-1) at 90% specificity was achieved with the ensemble method, which was significantly larger than the AUC of 0.79 (95% CI 0.66-0.91) and sensitivity 0.67 (95% CI 0.50-0.83), also at 90% specificity, for CA19-9, in the discovery set (p = 0.0016 and p = 0.00050, respectively). During ensemble signature validation in the held-out set, an AUC of 0.95 (95% CI 0.91-0.99), sensitivity 0.86 (95% CI 0.68-1), was attained compared to an AUC of 0.80 (95% CI 0.66-0.93), sensitivity 0.65 (95% CI 0.48-0.56) at 90% specificity for CA19-9 alone (p = 0.0082 and p = 0.024, respectively). When validated only on the benign disease controls and PDACs collected from ADEPTS, the diagnostic-specific signature achieved an AUC of 0.96 (95% CI 0.92-0.99), sensitivity 0.82 (95% CI 0.64-0.95) at 90% specificity, which was still significantly higher than the performance for CA19-9 taken as a single predictor, AUC of 0.79 (95% CI 0.64-0.93) and sensitivity of 0.18 (95% CI 0.03-0.69) (p = 0.013 and p = 0.0055, respectively). Conclusion Our ensemble modelling technique outperformed CA19-9, individual biomarkers and indices developed with prevailing algorithms in distinguishing patients with non-specific but concerning symptoms from those with PDAC, with implications for improving its early detection in individuals at risk.