Metabolic syndrome (MetS) is defined by the presence of at least three of five clinical parameters including abdominal obesity, insulin resistance, elevated triglycerides, reduced high-density lipoprotein (HDL) and hypertension. Major features describing MetS have been recognized risk factors for cancer onset, with an alarming impact on gastrointestinal (GI) tumors. Intriguingly, therapeutic administration of drugs to improve glycemic control and dyslipidemia (including metformin, statins) has been shown to have a preventive role in the development and in prognosis improvement of several cancer types. Overall, these observations highlight the key role of altered metabolism prevalently in cancer risk development and unveil anti-MetS agent repurposing potential beyond their conventional pharmacological action. The objective of this review is to summarize the current knowledge about the antitumor activity of anti-diabetic and anti-lipemic agents in GI cancer onset and progression. Here, pre-clinical evidence of their therapeutic potential and of their integration in novel compelling therapeutic strategies will be discussed. Possible clinical outcomes of these novel therapeutic combined protocols specifically dedicated to GI cancer patients will be put under the spotlight. In the future, these novel therapeutic options should be considered to improve conventional chemotherapy response and prognosis of this group of patients.

Pancreatic cancer, an aggressive cancer that presents with few or unspecific symptoms, has a poor prognosis. Thus, diagnosis at an early stage is vital for survival and a chance for curative treatment. Therefore, surveillance programmes for high-risk individuals are of the utmost importance. However, data on the psychological burden among participants in these programmes are limited.

This study aimed to investigate the psychological burden for participants in a pancreatic cancer surveillance programme and explore whether the psychological burden was related to the individual's risk level for pancreatic cancer.

This single-centre cross-sectional study investigated cancer worry, anxiety, coping and perceived physical and mental health using a digital questionnaire, including the following instruments: Cancer Worry Scale (CWS), State-Trait Anxiety Inventory (STAI), 13-Item Sense of Coherence and 12-Item Short-Form Survey. The invited participants (n=413) were healthy individuals with an increased risk of pancreatic cancer enrolled in a pancreatic cancer surveillance programme.

The results indicated high cancer worry among respondents (n=78) with high scores on CWS (mean, 16.45). The majority (69.3%) had scores indicating high cancer worry (≥14). Anxiety was not equally high among respondents (mean STAI-T, 35.13; STAI-S, 35.9). Female sex and younger age were significantly correlated with higher cancer worry and anxiety (p < 0.001). Outcomes in coping and perceived health were similar to those of the normal population.

Cancer worry is particularly high among participants. No correlation was found between the risk level and psychological burden.

Gastroesophageal reflux disease (GERD) is increasingly recognized for its associations with extragastric diseases, yet its potential role in pancreatic cancer (PC) etiology remains underexplored. This study investigates the genetic causal relationship between GERD and PC using Mendelian randomization (MR), a method designed to reduce confounding factors.

A two-sample MR analysis was conducted using genome-wide association studies (GWAS) data. The inverse variance weighted (IVW) method was applied, with additional sensitivity analyses performed to evaluate pleiotropy and heterogeneity.

The IVW analysis demonstrated a significant genetic association between the genetic signature predisposing to GERD and an increased risk of PC (OR: 1.36, 95% CI: 1.04-1.80, P = 0.03). There was no evidence of pleiotropy (P = 0.71) or heterogeneity (P = 0.94).

Our study provides robust genetic evidence supporting that the genetic predisposition to GERD is associated with an increased risk of PC. These findings emphasize the necessity of integrating GERD into PC risk assessments and encourage further research to elucidate the underlying biological mechanisms. This insight holds potential to inform strategies for early detection, prevention, and personalized management of PC in GERD patients.

Rationale: Siglec-15 (S15) is a membrane-associated antigen overexpressed across various cancer types, and also induces immunosuppression. We believe this makes S15 a promising target for cellular immunotherapy of solid tumors characterized by an immunosuppressive tumor microenvironment, but this remains underexplored to date. Method: We engineered a bispecific antibody that simultaneously binds S15 on tumor cells and CD3 on T cells in the popular IgG-scFv format; we termed this molecule STAB. Results: In vitro, STAB induced marked proliferation of CD3+ T cells in human PBMCs, and mediated effective killing of Panc-1 pancreatic ductal adenocarcinoma (PDAC) and H460 non-small cell lung cancer (NSCLC) cells in co-culture studies with PBMCs or CD3+ T cells. In NSG mice with human PDAC and NSCLC tumors, STAB effectively suppressed tumor growth and prolonged survival, in sharp contrast to mice receiving either anti-S15 or anti-CD3 mAbs alone. STAB increased activated T cells in both tumor and circulation, as well as reduced the stromal barrier-a key hallmark of PDAC. Conclusion: Our results underscore STAb as a promising therapeutic molecule to be investigated further for PDAC and NSCLC, and potentially other S15-positive solid tumors.

Pancreatic cancer is a malignant tumor with one of the worst prognoses among solid tumors, characterized by resistance to treatment. Therefore, there is an urgent need for new methods of targeted therapy. Previous studies have shown that the overexpression of receptor tyrosine kinases such as c-KIT or PDGFR can increase proliferation, migration, and invasion of cancer cells. The aim of our study was to analyze aggregates between a supramolecular carrier (Congo red, CR) and a tyrosine kinase inhibitor (BLU-258) as well as to investigate the effect of the free inhibitor and its aggregate with Congo red (CR-BLU-258) on selected properties of pancreatic cells, including these cells' viability and three-dimensional cell spheroid cultures. To better understand the interactions between Congo red and BLU-258, we used molecular modeling in addition to biophysical methods. These attempts allowed us to determine the optimal molar ratio, which we used for in vitro studies on pancreatic cancer cell lines. A significantly greater decrease in the viability of the tested 3D cultures was observed after 48 h of incubation with CR-BLU-258, which resulted in a lower IC50 value for the tested co-aggregate compared with BLU-258 alone. Moreover, a higher resistance of PANC-1 and BxPC3 spheroid cells to the tested compounds was noted compared with the 2D culture model. A significantly lower response was observed in 3D cell cultures (BxPC3 and PANC-1) treated with BLU-258 alone compared with the 2D culture. Thus, our results showed that both BLU-258 (alone) and in its co-aggregate with Congo red exhibit anticancer activity, inhibiting the growth of pancreatic cancer cells and reducing their viability, survival, and migration. Both tested compounds also affected the phosphorylation of the selected signaling proteins. We conclude that the selected tyrosine kinase inhibitor (alone) and in its co-aggregate with Congo red exhibit anticancer activity and should be considered as a novel effective therapy against pancreatic cancer.

Extrachromosomal circular DNA (eccDNA) is crucial for carcinogenesis and bile has direct contact with malignant biliary strictures, yet eccDNA features in bile and its function in malignant biliary strictures remain underexplored.

We observed the widespread presence of eccDNA in bile and systematically profiled the landscape of bile cell-free eccDNA (bcf-eccDNA). For functional exploration, a simple and efficient workflow was designed to synthesize large eccDNA particularly containing multiple regions. Compared with the noncancer group, bcf-eccDNAs in the cancer group had different origins and larger sizes with six characteristic peaks. These peaks were also identified in the validation cohort (100%). There were more bcf-eccDNA carrying LINC00598 or CELF2 in malignant biliary strictures, showing potential diagnostic performance in training and validation cohorts (all AUCs > 0.9). Bcf-eccDNAs carried cancer-related mutations, which could guide treatment. EccDNA carrying miR-106a/363 cluster or miR-374b/421 cluster were proven to regulate cancer gene expression, accelerate tumor proliferation, and inhibit tumor apoptosis.

This study profiles a comprehensive bcf-eccDNA landscape in patients with biliary strictures and offers valuable insights into eccDNA's role in bile liquid biopsy and carcinogenesis.

In recent years, it has been discovered that the expression of long non-coding RNAs is highly deregulated in several types of cancer and contributes to its progression and development. Recently, it has been described that in tumors of the digestive system, such as colorectal cancer, pancreatic cancer, and gastric cancer, DNA damage-activated lncRNA (NORAD) was frequently up-regulated. The purpose of this review is to elucidate the functions of NORAD in tumors of the digestive system, emphasizing its involvement in important cellular processes such as invasion, metastasis, proliferation, and apoptosis. NORAD acts as a ceRNA (competitive endogenous RNA) that sponges microRNAs and regulates the expression of target genes involved in tumorigenesis. Thus, the mechanisms underlying the effects of NORAD are complex and involve multiple signaling pathways. This review consolidates current knowledge on the role of NORAD in digestive cancers and highlights the need for further research to explore its potential as a therapeutic target. Understanding the intricate functions of NORAD could elucidate the way for innovative approaches to cancer treatment.

Oncolytic virus (OV) mediated immunotherapy is one of the recent techniques used to treat higher grade cancers where conventional therapies like chemotherapy, radiation fail. OVs as a therapeutic tool show high efficacy and fewer side effects than conventional methods as supported by multiple preclinical and clinical studies since they are engineered to target tumours. In this chapter, we discuss the modifications in viruses to make them oncolytic, types of strains commonly administered, mechanisms employed by viruses to specifically target and eradicate malignancy and progress achieved as reported in case studies (preclinical and clinical trials). OVs also face some unique challenges with respect to the malignancy being treated and the varied pathogen exposure of the patients, which is also highlighted here. Since pathogen exposure varies according to population dynamics worldwide, chances of generating a non-specific recall response to an OV cannot be negated. Lastly, the future perspectives and ongoing practises of combination therapies are discussed as they provide a leading edge over monotherapies in terms of tumour clearance, blocking metastasis and enhancing patient survival. Efforts undertaken to overcome current challenges are also highlighted.

Pancreatic cancer and prediabetes pose significant public health challenges. Given the lack of strong evidence we performed a meta-analysis to assess the risk of pancreatic cancer in prediabetes.

We performed a thorough search of the major databases over the last 10 years to identify relevant articles. The pooled odds ratio (OR) and hazard ratio (HR) were combined to calculate the effect size (ES).

We analyzed 5 studies including 5,425,111 prediabetic individuals and 16,096,467 normoglycemic population across 5 countries with a median follow-up of 8.5 years. We identified a noteworthy association between prediabetes and pancreatic cancer, reporting an unadjusted ES of 1.36 (95% confidence interval [CI] 1.05-1.77, P = 0.02) and an adjusted ES of 1.40 (1.23-1.59, P < 0.01). Subgroup analyses by age revealed variations in risk, with studies involving participants aged 60 and above exhibiting a higher ES (ES 1.83, 95% CI 1.28-2.62, P < 0.01). Geographical differences were also observed, with Japanese studies reporting a higher risk (ES 1.89, 95% CI 1.15-3.10, P < 0.01) compared with those from the United States (ES 1.32, 95% CI 1.13-1.53, P < 0.01).

We identified 40% higher risk of pancreatic cancer in patients with prediabetes than those with normal blood glucose necessitating urgent attention for further research and policy change.

Background The relationship between physical activity and incident pancreatic cancer is poorly defined, and the evidence to date is inconsistent, largely due to small sample sizes and insufficient incident outcomes. Using the UK Biobank cohort dataset, the association between physical activity levels at recruitment and incident pancreatic ductal adenocarcinoma (PDAC) at follow-up was analysed. Method Physical activity, the key exposure, was quantified using Metabolic Equivalent Task (MET) values and categorised into walking, moderate, and vigorous activity. These categories were each analysed in quartiles. Summed activity was analysed both in quartiles and using International Physical Activity Questionnaire (IPAQ) activity levels (low, moderate, high). Univariate hazard ratios (HRs) and multivariable-adjusted HRs (aHRs) with 95% confidence intervals (CIs) were calculated using Cox regression analyses. Results A total of 542 incident PDAC cases and 2,139 controls (1:4 matching for age and sex) with a median (IQR) follow-up of 6.8 (1.7) years were analysed. No significant association was found in walking, moderate, and vigorous activities. In summed activity, only the 3rd quartile showed a statistically significant inverse association with PDAC risk (aHR 0.67, 95% CI 0.52-0.86, p<0.01). For IPAQ activity, the moderate and high activity groups showed borderline statistically significant associations with incident PDAC (aHR 0.80, 95% CI 0.63-1.00, p=0.05, and aHR 0.80, 95% CI 0.64-1.01, p=0.06, respectively). Conclusion The large UK Biobank cohort study did not show a strong association between physical activity levels and the development of incident PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterised by poor survival rates and an increasing global incidence. Advances in the staging and categorization of pancreatic tumours, along with the discovery of functional mutations, have made precision treatments possible, which may lead to better clinical results. To further improve customized treatment approaches, in vitro models that can be used for functional drug sensitivity testing and precisely mimic the disease at the organ level are required. In this study, we present a workflow for creating a personalized PDAC chip utilising primary tumour-derived human pancreatic organoids (hPOs) and Human Umbilical Vein Endothelial Cells (HUVECs) to simulate the vascular barrier and tumour interactions within a PDMS-free organ-on-a-chip system. The patient PDAC tissue, expanded as tumour hPOs, could be cultured as adherent cells on the chip for more than 50 days, allowing continuous monitoring of cell viability through outflows from tumour and endothelial channels. Our findings demonstrate a gradual increase in cell density and cell turnover in the pancreatic tumor channel. Tumour-specific biomarkers, including CA-19.9, TIMP-1, Osteopontin, MIC-1, ICAM-1 and sAXL were consistently detected in the PDAC chip outflows. Comparative analyses between tissue culture plates and microfluidic conditions revealed significant differences in biomarker secretion patterns, highlighting the advantages of the microfluidics approach. This PDAC chip provides a stable, reproducible tumour model system with a functional endothelial cell barrier, suitable for drug sensitivity and secretory biomarker studies, thus serving as a platform for functional precision medicine application and multi-organ chip development.

This review explores the progression of pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma through a dual lens of intrinsic molecular alterations and extrinsic microenvironmental influences. PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations driving PanIN initiation. Key additional mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and mothers against decapentaplegic homolog 4 (SMAD4) disrupt cell cycle control and genomic stability, crucial for PanIN progression from low-grade to high-grade dysplasia. Additional molecular alterations in neoplastic cells, including epigenetic modifications and chromosomal alterations, can further contribute to neoplastic progression. In parallel with these alterations in neoplastic cells, the microenvironment, including fibroblast activation, extracellular matrix remodeling, and immune modulation, plays a pivotal role in PanIN initiation and progression. Crosstalk between neoplastic and stromal cells influences nutrient support and immune evasion, contributing to tumor development, growth, and survival. This review underscores the intricate interplay between cell-intrinsic molecular drivers and cell-extrinsic microenvironmental factors, shaping PanIN predisposition, initiation, and progression. Future research aims to unravel these interactions to develop targeted therapeutic strategies and early detection techniques, aiming to alleviate the severe impact of pancreatic cancer by addressing both genetic predispositions and environmental influences.

Pancreatic cancer is one of the most aggressive and lethal forms of cancer, with a five-year survival rate of less than 10%. Despite advances in treatment modalities, the prognosis for pancreatic cancer patients remains poor, highlighting the urgent need for innovative approaches for early diagnosis and targeted therapies. In recent years, there has been significant progress in understanding the molecular mechanisms underlying pancreatic cancer development and progression. This paper reviews the current knowledge of molecular targets for the diagnosis and treatment of pancreatic cancer.

Pancreatic adenocarcinoma (PDAC) is becoming a public health issue with a 5-years survival rate around 10%. Patients with PDAC are often sarcopenic, which impacts postoperative outcome. At the same time, overweight population is increasing and adipose tissue promotes tumor related-inflammation. With several studies supporting independently these data, we aimed to assess if they held an impact on survival when combined.

We included 232 patients from two university hospitals (CHU de Lille, Institut Paoli Calmette), from January 2011 to December 2018, who underwent Pancreaticoduodenectomy (PD) for resectable PDAC. Preoperative CT scan was used to measure sarcopenia and visceral fat according to international cut-offs. Neutrophil to lymphocyte (NLR) and platelet to lymphocyte ratios (PLR) were used to measure inflammation. For univariate and multivariate analyses, the Cox proportional-hazard model was used. P-values below 0.05 were considered significant.

Sarcopenic patients with visceral obesity were less likely to survive than the others in multivariate analysis (OS, HR 1.65, p= 0.043). Cutaneous obesity did not influence survival. We also observed an influence on survival when we studied sarcopenia with visceral obesity (OS, p= 0.056; PFS, p = 0.014), sarcopenia with cutaneous obesity (PFS, p= 0.005) and sarcopenia with PLR (PFS, p= 0.043). This poor prognosis was also found in sarcopenic obese patients with high PLR (OS, p= 0.05; PFS, p= 0.01).

Sarcopenic obesity was associated with poor prognosis after PD for PDAC, especially in patients with systemic inflammation. Pre operative management of these factors should be addressed in pancreatic cancer patients.

BACKGROUND & OBJECTIVES: Screening for pancreatic cancer is recommended for individuals with a strong family history, certain genetic syndromes, or a neoplastic cyst of the pancreas. However, limited data supports a survival benefit attributable to screening these higher-risk individuals.

All patients enrolled in screening at a High-Risk Pancreatic Cancer Clinic (HRC) from July 2013 to June 2020 were identified from a prospectively maintained institutional database and compared to patients evaluated at a Surgical Oncology Clinic (SOC) at the same institution during the same period. Clinical outcomes of patients selected for surgical resection, particularly clinicopathologic stage and overall survival, were compared.

Among 826 HRC patients followed for a median (IQR) of 2.3 (0.8-4.2) years, 128 were selected for surgical resection and compared to 402 SOC patients selected for resection. Overall survival was significantly longer among HRC patients (median survival: not reached vs. 2.6 years, p < 0.001). Among 31 HRC and 217 SOC patients with a diagnosis of pancreatic ductal adenocarcinoma (PDAC), the majority of HRC patients were diagnosed with stage 0 disease (carcinoma in situ), while the majority of SOC patients were diagnosed with stage II disease (p < 0.001). Overall survival after resection of invasive PDAC was also significantly longer among HRC patients compared to SOC patients (median survival 5.5 vs. 1.6 years, p = 0.002).

Patients at increased risk for PDAC and followed with guideline-based screening exhibited downstaging of disease and improved survival from PDAC in comparison to patients who were not screened.

Diabetes and cancer are two prevalent disorders, pose significant public health challenges and contribute substantially to global mortality rates, with solely 10 million reported cancer-related deaths in 2020. This review explores the pathological association between diabetes and diverse cancer progressions, examining molecular mechanisms and potential therapeutic intersections. From altered metabolic landscapes to dysregulated signaling pathways, the intricate links are delineated, offering a comprehensive understanding of diabetes as a modulator of tumorigenesis. Cancer cells develop drug resistance through mechanisms like enhanced drug efflux, genetic mutations, and altered drug metabolism, allowing them to survive despite chemotherapeutic agent. Glucose emerges as a pivotal player in diabetes progression, and serving as a crucial energy source for cancer cells, supporting their biosynthetic needs and adaptation to diverse microenvironments. Glycation, a non-enzymatic process that produces advanced glycation end products (AGEs), has been linked to the etiology of cancer and has been shown in a number of tumor forms, such as leiomyosarcomas, adenocarcinomas, and squamous cell carcinomas. Furthermore, in aggressive and metastatic breast cancer, the receptor for AGEs (RAGE) is increased, which may increase the malignancy of the tumor. Reprogramming glucose metabolism manifests as hallmark cancer features, including accelerated cell proliferation, angiogenesis, metastasis, and evasion of apoptosis. This manuscript encapsulates the dual narrative of diabetes as a driver of cancer progression and the potential of repurposed antidiabetic drugs as formidable countermeasures. The amalgamation of mechanistic understanding and clinical trial outcomes establishes a robust foundation for further translational research and therapeutic advancements in the dynamic intersection of diabetes and cancer.

Pancreatic adenocarcinoma is one of the most lethal types of gastrointestinal cancer despite the latest medical advances. Its incidence has continuously increased in recent years in developed countries. The location of the pancreas can result in the initial symptoms of neoplasia being overlooked, which can lead to a delayed diagnosis and a subsequent reduction in the spectrum of available therapeutic options. The role of modifiable risk factors in pancreatic cancer has been extensively studied in recent years, with smoking and alcohol consumption identified as key contributors. However, the few screening programs that have been developed focus exclusively on genetic factors, without considering the potential impact of modifiable factors on disease occurrence. Thus, fully understanding and detecting the risk factors for pancreatic cancer represents an important step in the prevention and early diagnosis of this type of neoplasia. This review reports the available evidence on different risk factors and identifies the areas that could benefit the most from additional studies.

Cancer cells can leave their primary sites and travel through the circulation to distant sites, where they lodge as disseminated cancer cells (DCCs), even during the early and asymptomatic stages of tumor progression. In experimental models and clinical samples, DCCs can be detected in a non-proliferative state, defined as cellular dormancy. This state can persist for extended periods until DCCs reawaken, usually in response to niche-derived reactivation signals. Therefore, their clinical detection in sites like lymph nodes and bone marrow is linked to poor survival. Current cancer therapy designs are based on the biology of the primary tumor and do not target the biology of the dormant DCC population and thus fail to eradicate the initial or subsequent waves of metastasis. In this brief review, we discuss the current methods for detecting DCCs and highlight new strategies that aim to target DCCs that constitute minimal residual disease to reduce or prevent metastasis formation. Furthermore, we present current evidence on the relevance of DCCs derived from early stages of tumor progression in metastatic disease and describe the animal models available for their study. We also discuss our current understanding of the dissemination mechanisms utilized by genetically less- and more-advanced cancer cells, which include the functional analysis of intermediate or hybrid states of epithelial-mesenchymal transition (EMT). Finally, we raise some intriguing questions regarding the clinical impact of studying the crosstalk between evolutionary waves of DCCs and the initiation of metastatic disease.

Oncolytic viruses (OVs) are increasingly recognized as potent tools in cancer therapy, effectively targeting and eradicating oncogenic conditions while sparing healthy cells. They enhance antitumor immunity by triggering various immune responses throughout the cancer cycle. Genetically engineered OVs swiftly destroy cancerous tissues and activate the immune system by releasing soluble antigens like danger signals and interferons. Their ability to stimulate both innate and adaptive immunity makes them particularly attractive in cancer immunotherapy. Recent advancements involve combining OVs with other immune therapies, yielding promising results. Transgenic OVs, designed to enhance immunostimulation and specifically target cancer cells, further improve immune responses. This review highlights the intrinsic mechanisms of OVs and underscores their synergistic potential with other immunotherapies. It also proposes strategies for optimizing armed OVs to bolster immunity against tumors.

With the lack of specific signs and symptoms, pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at late metastatic stages, resulting in poor survival outcomes. Among various biomarkers, microRNA-21 (miR-21), a small non-coding RNA, is highly expressed in PDAC. By inhibiting regulatory proteins at the 3' untranslated regions (UTR), miR-21 holds significant roles in PDAC cell proliferation, epithelial-mesenchymal transition, angiogenesis, as well as cancer invasion, metastasis, and resistance therapy. We conducted a systematic search across major databases for articles on miR-21 and pancreatic cancer mainly published within the last decade, focusing on their diagnostic, prognostic, therapeutic, and biological roles. This rigorous approach ensured a comprehensive review of miR-21's multifaceted role in pancreatic cancers. In this review, we explore the current understandings and future directions regarding the regulation, diagnostic, prognostic, and therapeutic potential of targeting miR-21 in PDAC. This exhaustive review discusses the involvement of miR-21 in proliferation, epithelial-mesenchymal transition (EMT), apoptosis modulation, angiogenesis, and its role in therapy resistance. Also discussed in the review is the interplay between various molecular pathways that contribute to tumor progression, with specific reference to pancreatic ductal adenocarcinoma.

Active smoking and the A blood group are associated with pancreatic adenocarcinoma (PC) risk. However, potential interactions between those risk factors and the role of passive smoking have been little investigated. We aimed to explore specific and joint associations of passive and active smoking, and effect modification by the ABO blood group in French women.

The study included 96,594 women from the E3N prospective cohort, mean age: 49 years (SD 6.7). Information on active and passive smoking was reported at inclusion and throughout follow-up. Cases were classified according to the International Classification of Diseases 10. Associations with passive and active smoking and effect modification by the ABO blood group were investigated with multivariable Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI).

During a 24-year median follow-up, 346 incident PC cases were identified. Current smoking compared with never and former smoking (HR 1.51 [95% CI 1.08-2.10]), and passive smoking in childhood compared with no childhood exposure (HR 1.47 [95% CI 1.08-2.00]) were associated with increased PC risk, but not passive exposure in adulthood (HR 1.16 [95% CI 0.91-1.47]). Exposure to both passive smoking in childhood and current smoking was associated with a stronger risk (HR 2.80 [95% CI 1.42-5.52]) than exposure to both current smoking and passive smoking only in adulthood (HR 1.68 [95% CI 1.10-2.57]) compared with neither passive nor active smoking. Associations between active smoking and PC risk were strongest in the O or B groups, while associations with passive smoking were strongest in the A or AB blood groups, but the interaction terms were not statistically significant.

Both current smoking and passive smoking in childhood were associated with PC risk, with a maximal risk of current smokers exposed to passive smoking during childhood. Possible interactions between blood groups and active or passive smoking must be investigated in a larger series.

Pancreatic cancer is one of the most lethal malignancies. Even though many substantial improvements in the survival rates for other major cancer forms were made, pancreatic cancer survival rates have remained relatively unchanged since the 1960s. Even more, no standard classification system for pancreatic cancer is based on cellular biomarkers. This review will discuss and provide updates about the role of stem cells in the progression of PC, the genetic changes associated with it, and the promising biomarkers for diagnosis.

The search process used PubMed, Cochrane Library, and Scopus databases to identify the relevant and related articles. Articles had to be published in English to be considered.

The increasing number of studies in recent years has revealed that the diversity of cancer-associated fibroblasts is far greater than previously acknowledged, which highlights the need for further research to better understand the various cancer-associated fibroblast subpopulations. Despite the huge diversity in pancreatic cancer, some common features can be noted to be shared among patients. Mutations involving CDKN2, P53, and K-RAS can be seen in a big number of patients, for example. Similarly, some patterns of genes and biomarkers expression and the level of their expression can help in predicting cancer behavior such as metastasis and drug resistance. The current trend in cancer research, especially with the advancement in technology, is to sequence everything in hopes of finding disease-related mutations.

Optimizing pancreatic cancer treatment requires clear classification, understanding CAF roles, and exploring stroma reshaping approaches.

Pancreatic ductal adenocarcinoma (PDAC) cancer cells specifically produce abnormal oncogenic collagen to bind with integrin α3β1 receptor and activate the downstream focal adhesion kinase (FAK), protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) signaling pathway. Collectively, this promotes immunosuppression and tumor proliferation and restricts the response rate of clinical cancer immunotherapies.

Here, by leveraging the hypoxia tropism and excellent motility of the probiotic Escherichia coli strain Nissle 1917 (ECN), we developed nanodrug-bacteria conjugates to penetrate the extracellular matrix (ECM) and shuttle the surface-conjugated protein cages composed of collagenases and anti-programmed death-ligand 1 (PD-L1) antibodies to PDAC tumor parenchyma.

We found the oncogenic collagen expression in human pancreatic cancer patients and demonstrated its interaction with integrin α3β1. We proved that reactive oxygen species (ROS) in the microenvironment of PDAC triggered collagenase release to degrade oncogenic collagen and block integrin α3β1-FAK signaling pathway, thus overcoming the immunosuppression and synergizing with anti-PD-L1 immunotherapy.

Collectively, our study highlights the significance of oncogenic collagen in PDAC immunotherapy, and consequently, we developed a therapeutic strategy that can deplete oncogenic collagen to synergize with immune checkpoint blockade for enhanced PDAC treatment efficacy.

This work was supported by the University of Wisconsin Carbone Cancer Center Research Collaborative and Pancreas Cancer Research Task Force, UWCCC Transdisciplinary Cancer Immunology-Immunotherapy Pilot Project, and the start-up package from the University of Wisconsin-Madison (to Q.H.).

This comprehensive review explores the complexities surrounding pancreatic head cancer, a highly fatal and challenging-to-treat illness with a survival rate of less than five years. Despite being a major contributor to cancer-related deaths, pancreatic head malignancy often eludes early detection due to its posterior location and high metastatic potential. The review delves into the associated symptoms, including gastric outlet obstruction and obstructive jaundice, highlighting the impact on the patient's eligibility for surgery. Examining recent advancements, the article discusses fast-track surgery recovery programs and emerging immunotherapeutic approaches, acknowledging the unique challenges posed by the immunosuppressive environment of pancreatic head cancer. Additionally, the review elucidates the intricate relationship between pancreatic cancer and glucose levels, emphasizing the role of islets of Langerhans in insulin production. The pathogenesis section explores lifestyle and genetic factors contributing to pancreatic head carcinoma, shedding light on risk factors such as smoking, obesity, diabetes, and hereditary predispositions. The extensive analysis of pancreatic cancer diagnosis methods encompasses imaging techniques, biopsies, and biomarkers, emphasizing the challenges posed by late-stage diagnoses. Addressing treatment modalities, the review emphasizes the significance of surgery, chemotherapy, radiotherapy, and targeted therapy. The intricate details of neoadjuvant, immunotherapy, and microbial therapy provide a comprehensive understanding of evolving treatment strategies. The review concludes by highlighting promising areas of research, including oncolytic viral therapy and gene editing technology, aiming to enhance the limited treatment options for this devastating disease.

The key challenge of cell-free tumor DNA (cftDNA) analysis in pancreatic ductal adenocarcinoma (PDAC) is overcoming its low detection rate, which is mainly explained by the overall scarcity of this biomarker in plasma. Obstructive jaundice is a frequent event in PDAC, which enables bile collection as a part of routine treatment. The aim of this study was to evaluate the performance of KRAS-mutated cftDNA detection-based liquid biopsy of plasma and bile in patients with pancreatic neoplasms using digital droplet PCR. The study included healthy volunteers (n = 38), patients with PDAC (n = 95, of which 20 had obstructive jaundice) and other pancreatic neoplasms (OPN) (n = 18). The sensitivity and specificity compared to the control group were 61% and 100% (AUC-ROC-0.805), and compared to the OPN group, they were 61% and 94% (AUC-ROC-0.794), respectively. Bile exhibited higher cftDNA levels than plasma (248.6 [6.743; 1068] vs. 3.26 [0; 19.225] copies/mL) and a two-fold higher detection rate (p < 0.01). Plasma cftDNA levels were associated with distant metastases, tumor size, and CA 19-9 (p < 0.05). The probability of survival was worse in patients with higher levels of cftDNA in plasma (hazard ratio-2.4; 95% CI: 1.3-4.6; p = 0.005) but not in bile (p > 0.05). Bile is a promising alternative to plasma in patients with obstructive jaundice, at least for the diagnostic purposes of liquid biopsy.

Radiomics allows the extraction of quantitative imaging features from clinical magnetic resonance imaging (MRI) and computerized tomography (CT) studies. The advantages of radiomics have primarily been exploited in oncological applications, including better characterization and staging of oncological lesions and prediction of patient outcomes and treatment response. The potential introduction of radiomics in the clinical setting requires the establishment of a standardized radiomics pipeline and a quality assurance program. Radiomics and texture analysis of the liver have improved the differentiation of hypervascular lesions such as adenomas, focal nodular hyperplasia, and hepatocellular carcinoma (HCC) during the arterial phase, and in the pretreatment determination of HCC prognostic factors (e.g., tumor grade, microvascular invasion, Ki-67 proliferation index). Radiomics of pancreatic CT and MR images has enhanced pancreatic ductal adenocarcinoma detection and its differentiation from pancreatic neuroendocrine tumors, mass-forming chronic pancreatitis, or autoimmune pancreatitis. Radiomics can further help to better characterize incidental pancreatic cystic lesions, accurately discriminating benign from malignant intrapancreatic mucinous neoplasms. Nonetheless, despite their encouraging results and exciting potential, these tools have yet to be implemented in the clinical setting. This non-systematic review will describe the essential steps in the implementation of the radiomics and feature extraction workflow from liver and pancreas CT and MRI studies for their potential clinical application. A succinct overview of reported radiomics applications in the liver and pancreas and the challenges and limitations of their implementation in the clinical setting is also discussed, concluding with a brief exploration of the future perspectives of radiomics in the gastroenterology field.

Obesity is a prominent health issue worldwide and directly impacts pancreatic health, with obese individuals exhibiting a significant risk for increasing pancreatic ductal adenocarcinoma (PDAC). Several factors potentially explain the increased risk for the development of PDAC, including obesity-induced chronic inflammation within and outside of the pancreas, development of insulin resistance and metabolic dysfunction, promotion of immune suppression within the pancreas during inflammation, pre- and malignant stages, variations in hormones levels (adiponectin, ghrelin, and leptin) produced from the adipose tissue, and acquisition of somatic mutations in tumor once- and suppressor proteins critical for pancreatic tumorigenesis. In this manuscript, we will explore the broad impact of these obesity-induced risk factors on the development and progression of PDAC, focusing on changes within the tumor microenvironment (TME) as they pertain to prevention, current therapeutic strategies, and future directions for targeting obesity management as they relate to the prevention of pancreatic tumorigenesis.

There has been increasing interest into the role of germline BRCA1/2 pathogenic variants (gBRCA PV) and gATM PV and likely PV (PV and LPV; PV + LPV) in the carcinogenesis and treatment of pancreatic cancer (PC), but the clinical features have not been well described.

Patients with confirmed gBRCA PV and gATM PV + LPV PC treated at our hospital between April 2016 and December 2021, were retrospectively evaluated for clinical characteristics and outcomes.

Twenty-two patients harbored gBRCA PV and three patients harbored gATM PV + LPV. Of the gBRCA PV patients, 81.8 % received platinum-based chemotherapy with favorable treatment outcomes with an objective response rate of 50.0 % (95 % CI: 23.0-77.0), median progression free survival (PFS) of 334 days, and median overall survival (OS) of 926 days from the initiation of first-line chemotherapy. The annual number of patients with gBRCA PV was two patients per year before January 2021 (when BRACAnalysis became available in Japan), and ten patients during the 10 months thereafter. Four patients (20 %) with gBRCA PV developed soft-tissue metastasis with progression. Two patients with gATM PV + LPV received platinum-based chemotherapy and the best response of those patients was partial response and stable disease and their OS from the initiation of first-line chemotherapy was 1192 and 989 days, and PFS was 579 and 140 days, respectively.

The diagnosis of gBRCA PV-positive PC has increased revealed in recent years. These tumors appear to be sensitive to platinum-based chemotherapy, with long term survival observed in gATM PV + LPV-positive patients.

Pancreatic ductal adenocarcinoma (PDAC) has an overall 5-year survival rate of just 12.5% and thus is among the leading causes of cancer deaths. When detected at early stages, PDAC survival rates improve substantially. Testing high-risk patients can increase early-stage cancer detection; however, currently available liquid biopsy approaches lack high sensitivity and may not be easily accessible.

Extracellular vesicles (EVs) were isolated from blood plasma that was collected from a training set of 650 patients (105 PDAC stages I and II, 545 controls). EV proteins were analyzed using a machine learning approach to determine which were the most informative to develop a classifier for early-stage PDAC. The classifier was tested on a validation cohort of 113 patients (30 PDAC stages I and II, 83 controls).

The training set demonstrates an AUC of 0.971 (95% CI = 0.953-0.986) with 93.3% sensitivity (95% CI: 86.9-96.7) at 91.0% specificity (95% CI: 88.3-93.1). The trained classifier is validated using an independent cohort (30 stage I and II cases, 83 controls) and achieves a sensitivity of 90.0% and a specificity of 92.8%.

Liquid biopsy using EVs may provide unique or complementary information that improves early PDAC and other cancer detection. EV protein determinations herein demonstrate that the AC Electrokinetics (ACE) method of EV enrichment provides early-stage detection of cancer distinct from normal or pancreatitis controls.

Pancreatic cancer (PC) is usually diagnosed at an advanced stage of its development, which results in lower overall survival (OS). Prognosis is also poor even with curative-intent surgery. Approximately 80% of patients with localized PDAC have micrometastases at the time of diagnosis, which leads to a worse prognosis than in other cancers. The objective of this study is to present the progress in the treatment of metastatic pancreatic cancer based on the recommendations of oncological scientific societies, such as ESMO, NCCN, ASCO, NICE and SEOM, over the last 5 years. Combined FOLFIRINOX therapy is mostly a recommended therapy among patients with good performance statuses, while gemcitabine is recommended for more fragile patients as a first-line treatment. The newest guidelines suggest that molecular profiling of the tumor should be the first step in determining the course of treatment. The use of modern molecular therapies in patients with specific gene mutations should extend the survival of patients with this disease.

Pancreatic ductal adenocarcinoma (PDAC) is expected to soon surpass colorectal cancer as a leading cause of cancer mortality in both males and females in the US, only lagging behind lung cancer. The lethality of PDAC is driven by late diagnosis and inefficient therapies. The complex biology of PDAC involves various cellular components, including exosomes that carry molecular information between cells. Thus, recipient cells can be reprogrammed, impacting tumorigenesis. Rab27a is a GTPase responsible for the last step of exosomes biogenesis. Hence, dissecting the mechanisms that regulate the expression of Rab27a and that control exosomes biogenesis can provide fundamental insights into the molecular underpinnings regulating PDAC progression.

To assess the mechanism that regulates Rab27a expression in PDAC, we used PDAC cell lines. The biological significance of these findings was validated in PDAC genetically engineered mouse models (GEMMs) and human samples.

In this work we demonstrate in human PDAC samples and GEMMs that Rab27a expression decreases throughout the development of the disease, and that Rab27a knockout promotes disease progression. What is more, we demonstrate that Rab27a expression is epigenetically regulated in PDAC. Treatment with demethylating agents increases Rab27a expression specifically in human PDAC cell lines. We found that SMC3, a component of the cohesin complex, regulates Rab27a expression in PDAC. SMC3 methylation is present in human PDAC specimens and treatment with demethylating agents increases SMC3 expression in human PDAC cell lines. Most importantly, high levels of SMC3 methylation are associated with a worse prognosis in PDAC. Mechanistically, we identified an enhancer region within the Rab27a gene that recruits SMC3, and modulates Rab27a expression.

Overall, we dissected a mechanism that regulates Rab27a expression during PDAC progression and impacts disease prognosis.

The single risk factors of pancreatic cancer (PC) has been extensively studied. We aimed to synthesize results from such studies to identify and estimate multiple independent risk factors of PC.

Articles published up to Feb 28, 2020 in English or Chinese reporting risk factors of PC were reviewed. The fixed-effects model with 95% confidence interval (CI) were used to calculate the pooled Odds Ratio (OR). Data were analyzed using RevMan 5.3.

PC was significantly associated with smoking (OR: 1.76, 95% CI: 1.61-1.92, P < 0.00001, I2 = 6%), diabetes (OR: 2.69, 95% CI: 2.52-2.88, P < 0.00001, I2 = 0%), family history of PC (OR: 2.58, 95% CI: 2.13-3.11, P < 0.00001, I2 = 0%), and chronic pancreatitis (OR: 5.84, 95% CI: 3.63-9.41, P < 0.00001, I2 = 0%).

Smoking, diabetes, family history of PC, and chronic pancreatitis were independent risk factors for PC. These independent risk factors have an important role in identifying high-risk groups, which is of great significance to reduce the incidence of PC and improve the quality of life and prognosis of patients.

Pancreatic cancer is one of the deadliest forms of cancer with one of the lowest 5-year survival rates of all cancer types. A defining characteristic of pancreatic cancer is the existence of dense desmoplastic stroma that, when exposed to stimuli such as cytokines, growth factors, and chemokines, generate a tumor-promoting environment. Cancer-associated fibroblasts (CAFs) are activated during the progression of pancreatic cancer and are a crucial component of the tumor microenvironment (TME). CAFs are primarily pro-tumorigenic in their activated state and function as promoters of cancer invasion, proliferation, metastasis, and immune modulation. Aided by many signaling pathways, cytokines, and chemokines in the tumor microenvironment, CAFs can originate from many cell types including resident fibroblasts, mesenchymal stem cells, pancreatic stellate cells, adipocytes, epithelial cells, endothelial cells, and other cell types. CAFs are a highly heterogeneous cell type expressing a variety of surface markers and performing a wide range of tumor promoting and inhibiting functions. Single-cell transcriptomic analyses have revealed a high degree of specialization among CAFs. Some examples of CAF subpopulations include myofibrotic CAFs (myCAFs), which exhibit a matrix-producing contractile phenotype; inflammatory CAFs (iCAF) that are classified by their immunomodulating, secretory phenotype; and antigen-presenting CAFs (apCAFs), which have antigen-presenting capabilities and express Major Histocompatibility Complex II (MHC II). Over the last several years, various attempts have been undertaken to describe the mechanisms of CAF-tumor cell interaction, as well as CAF-immune cell interaction, that contribute to tumor proliferation, invasion, and metastasis. Although our understanding of CAF biology in cancer has steadily increased, the extent of CAFs heterogeneity and their role in the pathobiology of pancreatic cancer remains elusive. In this regard, it becomes increasingly evident that further research on CAFs in pancreatic cancer is necessary.

Pancreatic cancer is the seventh most common cause of death in the group of oncological diseases. Due to the asymptomatic course, early diagnosis is difficult. Currently, early detection methods are only used in high-risk groups. A literature review based on the available results of observational studies on patients with pancreatic cancer and people from high-risk groups was used to summarize the knowledge on risk factors. The GLOBOCAN 2020 data were used to assess the epidemiological situation in Europe. A summary of screening recommendations was prepared based on the available documents from medical organizations and associations. Pancreatic cancer risk factors are divided into two main groups: non-modifiable factors, e.g., hereditary factors and age, which increase the risk of developing this disease, and modifiable factors-BMI, smoking, and alcohol consumption. Hereditary factors account for 10% of pancreatic cancer cases. The highly specialized methods of early detection, (MRI, CT, or EUS) are used for screening high-risk populations. Of all the imaging methods, EUS is considered the most sensitive for pancreatic cancer and allows an accurate assessment of the size of even small lesions (<30 mm) and the extent of tumour infiltration into blood vessels. The available studies vary on the level of sensitivity and specificity of these methods for the diagnosis of pancreatic cancer. EUS, MRI, and CT are also expensive procedures and in some patients can be invasive, which is one of the arguments against the introduction of population screening programs based on imaging methods. Therefore, it is important to look for viable solutions that would improve early detection. This is important from the point of view of healthcare systems in Europe, where almost 29% of all global pancreatic cancer cases are reported.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is developing into the 2nd leading cause of cancer-related death. Often, the clinical and radiological presentation of PDAC may be mirrored by other inflammatory pancreatic masses, such as autoimmune pancreatitis (AIP) and mass-forming chronic pancreatitis (MFCP), making its diagnosis challenging. Differentiating AIP and MFCP from PDAC is vital due to significant therapeutic and prognostic implications. Current diagnostic criteria and tools allow the precise differentiation of benign from malignant masses; however, the diagnostic accuracy is imperfect. Major pancreatic resections have been performed in AIP cases under initial suspicion of PDAC after a diagnostic approach failed to provide an accurate diagnosis. It is not unusual that after a thorough diagnostic evaluation, the clinician is confronted with a pancreatic mass with uncertain diagnosis. In those cases, a re-evaluation must be entertained, preferably by an experienced multispecialty team including radiologists, pathologists, gastroenterologists, and surgeons, looking for disease-specific clinical, imaging, and histological hallmarks or collateral evidence that could favor a specific diagnosis. Our aim is to describe current diagnostic limitations that hinder our ability to reach an accurate diagnosis among AIP, PDAC, and MFCP and to highlight those disease-specific clinical, radiological, serological, and histological characteristics that could support the presence of any of these three disorders when facing a pancreatic mass with uncertain diagnosis after an initial diagnostic approach has been unsuccessful.

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, currently has a dismal five-year survival rate of approximately 10% due to late diagnosis and a lack of efficient treatment options such as surgery. Furthermore, the majority of PDAC patients have surgically unresectable cancer, meaning cancer cells have either reached the surrounding blood vessels or metastasized to other organs distant from the pancreas area, resulting in low survival rates as compared to other types of cancers. In contrast, the five-year survival rate of surgically resectable PDAC patients is currently 44%. The late diagnosis of PDAC is a result of little or no symptoms in its early stage of development and a lack of specific biomarkers that may be utilized in routine examinations in the clinic. Although healthcare professionals understand the importance of early detection of PDAC, the research on the subject has lagged and no significant changes in the death toll of PDAC patients has been observed. This review is focused on understanding potential biomarkers that may increase the early diagnosis of PDAC patients at its surgically resectable stage. Here, we summarize the currently available biomarkers used in the clinic as well as those being developed with the hope of providing insight into the future of liquid biomarkers to be used in routine examinations for the early diagnosis of PDAC.

The purpose of this study was to investigate whether tumor necrosis depicted on contrast-enhanced abdominal MRI can predict tumor aggressiveness in pancreatic ductal adenocarcinoma (PDAC). In this retrospective analysis, we included 71 patients with pathology-proven PDAC who underwent contrast-enhanced MRI from 2006 to 2020. Assessment for the presence/absence of imaging detected necrosis was performed on T2-weighted and contrast-enhanced T1-weighted images. Primary tumor characteristics, regional lymphadenopathy, metastases, stage, and overall survival were analyzed. Fisher's exact and Mann-Whitney U tests were used for statistical analysis. Of the 72 primary tumors, necrosis was identified on MRI in 58.3% (42/72). Necrotic PDACs were larger (44.6 vs. 34.5 mm, p = 0.0016), had higher rates of regional lymphadenopathy (69.0% vs. 26.7%, p = 0.0007), and more frequent metastases (78.6% vs. 40.0%, p = 0.0010) than those without MRI-evident necrosis. A non-statistically significant reduction in median overall survival was observed in patients with versus without MRI-evident necrosis (15.8 vs. 38.0 months, p = 0.23). PDAC tumor necrosis depicted on MRI was associated with larger tumors and higher frequency of regional lymphadenopathy and metastases.

Pancreatic ductal adenocarcinoma (PDAC) is the most common (∼90% cases) pancreatic neoplasm and one of the most lethal cancer among all malignances. PDAC harbor aberrant oncogenic signaling that may result from the multiple genetic and epigenetic alterations such as the mutation in driver genes (KRAS, CDKN2A, p53), genomic amplification of regulatory genes (MYC, IGF2BP2, ROIK3), deregulation of chromatin-modifying proteins (HDAC, WDR5) among others. A key event is the formation of Pancreatic Intraepithelial Neoplasia (PanIN) that often results from the activating mutation in KRAS. Mutated KRAS can direct a variety of signaling pathways and modulate downstream targets including MYC, which play an important role in cancer progression. In this review, we discuss recent literature shedding light on the origins of PDAC from the perspective of major oncogenic signaling pathways. We highlight how MYC directly and indirectly, with cooperation with KRAS, affect epigenetic reprogramming and metastasis. Additionally, we summarize the recent findings from single cell genomic approaches that highlight heterogeneity in PDAC and tumor microenvironment, and provide molecular avenues for PDAC treatment in the future.

Pancreatic ductal adenocarcinoma (PDAC) is the third most lethal cancer in the United States, with a 5-year life expectancy of 11%. Most symptoms manifest at an advanced stage of the disease when surgery is no longer appropriate. The dire prognosis of PDAC warrants new strategies to improve the outcomes of patients, and early detection has garnered significant attention. However, early detection of PDAC is most often incidental, emphasizing the importance of developing new early detection screening strategies. Due to the low incidence of the disease in the general population, much of the focus for screening has turned to individuals at high risk of PDAC. This enriches the screening population and balances the risks associated with pancreas interventions. The cancers that are found in these high-risk individuals by MRI and/or EUS screening show favorable 73% 5-year overall survival. Even with the emphasis on screening in enriched high-risk populations, only a minority of incident cancers are detected this way. One strategy to improve early detection outcomes is to integrate artificial intelligence (AI) into biomarker discovery and risk models. This expert review summarizes recent publications that have developed AI algorithms for the applications of risk stratification of PDAC using radiomics and electronic health records. Furthermore, this review illustrates the current uses of radiomics and biomarkers in AI for early detection of PDAC. Finally, various challenges and potential solutions are highlighted regarding the use of AI in medicine for early detection purposes.

Three percent of patients with pancreatic ductal adenocarcinoma (PDAC) present a germline pathogenic variant (GPV) associated with an increased risk of this tumor, CDKN2A being one of the genes associated with the highest risk. There is no clear consensus on the recommendations for surveillance in CDKN2A GPV carriers, although the latest guidelines from the International Cancer of the Pancreas Screening Consortium recommend annual endoscopic ultrasound (EUS) or magnetic resonance imaging (MRI) regardless of family history. Our aim is to describe the findings of the PDAC surveillance program in a cohort of healthy CDKN2A GPV heterozygotes. This is an observational analysis of prospectively collected data from all CDKN2A carriers who underwent screening for PDAC at the high-risk digestive cancer clinic of the "Hospital Clínic de Barcelona" between 2013 and 2021. A total of 78 subjects were included. EUS or MRI was performed annually with a median follow-up of 66 months. Up to 17 pancreatic findings were described in 16 (20.5%) individuals under surveillance, although most of them were benign. No significant precursor lesions were identified, but an early PDAC was detected and treated. While better preventive strategies are developed, we believe that annual surveillance with EUS and/or MRI in CDKN2A GPV heterozygotes may be beneficial.