Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignant tumor characterized by a poor prognosis. A prominent feature of PDAC is the rich and dense stroma present in the tumor microenvironment (TME), which significantly hinders drug penetration. Cancer-associated fibroblasts (CAFs), activated fibroblasts originating from various cell sources, including pancreatic stellate cells (PSCs) and mesenchymal stem cells (MSCs), play a critical role in PDAC progression and TME formation. MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules that are frequently involved in tumorigenesis and progression, exhibiting either oncolytic or oncogenic activity. Increasing evidence suggests that aberrant expression of miRNAs can mediate interactions between cancer cells and CAFs, thereby providing novel therapeutic targets for PDAC treatment. In this review, we will focus on the potential roles of miRNAs that target CAFs or CAFs-derived exosomes in PDAC progression, highlighting the feasibility of therapeutic strategies aimed at restoring aberrantly expressed miRNAs associated with CAFs, offering new pathways for the clinical management of PDAC.

Research studies aimed at improving the outcomes of patients with pancreatic ductal adenocarcinoma (PDAC) have brought about limited progress, and in clinical practice, the optimized use of surgery, chemotherapy and supportive care have led to modest improvements in survival that have probably reached a plateau. As a result, PDAC is expected to be the second leading cause of cancer-related death in Western societies within a decade. The development of therapeutic advances in PDAC has been challenging owing to a lack of actionable molecular targets, a typically immunosuppressive microenvironment, and a disease course characterized by rapid progression and clinical deterioration. Yet, the progress in our understanding of PDAC and identification of novel therapeutic opportunities over the past few years is leading to a strong sense of optimism in the field. In this Perspective, we address the aforementioned challenges, including biological aspects of PDAC that make this malignancy particularly difficult to treat. We explore specific areas with potential for therapeutic advances, including targeting mutant KRAS, novel strategies to harness the antitumour immune response and approaches to early detection, and propose mechanisms to improve clinical trial design and to overcome various community and institutional barriers to progress.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal cancer, typically diagnosed at advanced stages due to its asymptomatic onset and challenges in early detection. To address the critical need for the early diagnosis of PDAC, we developed a laser desorption/ionization mass spectrometry (LDI-MS) platform based on mesoporous silica-modified magnetic graphene (MG@mSiO2). MG@mSiO2 exhibited exceptional ultraviolet (UV) absorption, efficient ionization, and minimal background interference, enabling high-resolution profiling of serum metabolic fingerprints (SMFs). Based on the extracted SMFs, we constructed a Random Forest (RF) model to classify PDAC patients, high-risk (HR) individuals, and healthy controls (HC), achieving an accuracy of 97.5% in the independent test set. Additionally, a six-metabolite biomarker panel was identified, showing strong diagnostic potential with sensitivity and accuracy exceeding 89.1% for distinguishing HC from PDAC. When coupled with the serological marker carbohydrate antigen 19-9 (CA19-9), the integrated strategy delivered significantly improved diagnostic performance, achieving high accuracy ranging from 95.3% to 100% in distinguishing HR and PDAC patients from HC. Furthermore, metabolic pathway analysis revealed key pathways associated with PDAC progression, providing mechanistic insights into the disease. This work provides a powerful diagnostic tool for PDAC screening, establishing a foundation for early detection and precision medicine in clinical practice.

Screening for pancreatic ductal adenocarcinoma alters the course of disease among high-risk individuals (HRIs) and is recommended by multiple societies including the International Cancer of the Pancreas Screening Consortium, American Gastroenterological Association, and American Society of Gastrointestinal Endoscopy. However, there are limited analyses on the screening rates and barriers to adherence among HRIs. This study aims to describe real-world longitudinal screening adherence of a HRI surveillance cohort and identify potential barriers to adherence.

Patients followed by Stanford's Benign Pancreas Clinic were identified as HRIs if they met screening criteria per the latest abovementioned screening guidelines, and were included in our study if they underwent at least 1 screening exam. Data on HRIs were obtained retrospectively from our hospital's electronic health record system. Patient and screening characteristics were analyzed by adherence rates.

262 HRIs undergoing recommended screening were identified. The mean follow-up time per patient was 4.9 years and the mean successful annual screening rate within the entire cohort was 67%. HRIs in the lowest quartile of adherence were more likely to have more EUS rather than MRI surveillance exams compared to those who were completely adherent (p = 0.01). HRIs who were completely adherent were also an older cohort compared to those with non-complete adherence (p = 0.02) or in the lowest quartile of adherence (p = 0.01).

It is difficult to achieve high adherence rates for annual pancreatic cancer screening of HRIs as recommended by the latest guidelines. Age and screening modality may be factors that contribute to adherence difficulty.

Pancreatic cancer, often diagnosed at advanced stages, has poor survival rates. Effective screening aims to detect the disease early, improving outcomes. Current guidelines recommend screening high-risk groups, including those with a family history or genetic predispositions, using methods like endoscopic ultrasound and MRI. The American Gastroenterological Association and other organizations advise annual surveillance for high-risk individuals, typically starting at the age of 50 or 10 years younger than the youngest affected relative. For certain genetic syndromes, such as Peutz-Jeghers syndrome or hereditary pancreatitis, screening may begin as early as the age of 35 to 40 years.

Pancreatic adenocarcinoma (PAAD) is a highly aggressive cancer with a poor prognosis, reliable markers are urgently needed for early detection and prognosis evaluation. SAPCD2, a cell cycle related gene, has been implicated in tumorigenesis and proposed as a potential therapeutic target in cancer. However, no comprehensive study has explored its expression and regulation, discussed its role in tumor prognosis and immune modulation, along with therapy response in pan-cancer until now.

SAPCD2 expression was analyzed using data from The Cancer Genome Atlas database (TCGA) and Human Protein Atlas (HPA) database. Genetic and epigenetic alterations of SAPCD2 and the immune microenvironment were explored via NCBI, TIMER2 and cBioPortal platforms. Western blot analysis and immunohistochemistry (IHC) were performed to check SAPCD2 protein expression in PAAD cells and tissues. Cell counting kit 8 (CCK8), flow cytometry, and transwell experiments were used to evaluate the role of SAPCD2 in PAAD cell lines.

Our study found that SAPCD2 is notably upregulated in various cancers, especially early-stage digestive cancers, and is linked to poor survival in most cancers like PAAD and LIHC. Gene amplification and promoter DNA hypomethylation appear to drive this upregulation. Additionally, SAPCD2 expression correlates with tumor mutation burden, microsatellite instability, and immune scores across several cancers. In PAAD, elevated SAPCD2 levels correlated with reduced immune activity, whereas in stomach cancer (STAD), its prognostic impact appeared immune-independent. In PDAC cell lines, SAPCD2 knockdown reduced proliferation and invasion, and caused reduction of G0/G1 phase. PAAD cells with high SAPCD2 expression showed increased sensitivity to DNA-PK, p38α MAPK, and Bcl-2 inhibitors.

SAPCD2 serves as both a prognostic marker and a potential therapeutic target in PAAD, where its low expression may enhance responsiveness to specific drugs. These findings underscore SAPCD2's dual role in cancer progression and therapy.

Currently, those recommended to undergo pancreatic cancer (PC) surveillance include appropriately aged individuals at high risk of PC due to an identifiable genetic susceptibility or those without identifiable genetic susceptibility who nonetheless have a strong family history of PC. With increases in identification of individuals at high risk for PC and increased use of PC surveillance in clinical practice, there has been increasing debate about who should undergo surveillance as well as how surveillance should be performed including use of imaging and blood-based testing. Furthermore, there is increasing interest in the outcomes of PC surveillance in high-risk individuals with some studies demonstrating that surveillance leads to downstaging of PC and improvements in survival. In this review, we summarize the current state of PC surveillance in high-risk individuals, providing an overview of the risk factors associated with PC, selection of high-risk individuals for PC surveillance, and the current, but non-uniform, recommendations for performing PC surveillance. Additionally, we review approaches to apply various imaging and blood-based tests to surveillance and the outcomes of PC surveillance.

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.

In the last decade there has been increasing interest in defining pancreatic steatosis (PS) and establishing its association with pancreatic ductal adenocarcinoma (PDAC). However, no consensus guidelines have yet been published on the management of PS. In this systematic review and meta-analysis performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we investigated the association between PS and PDAC.

Medical literature between 2007 and 2023 was reviewed for eligible trials investigating the prevalence of PS in patients with PDAC. Eligible studies reporting on PS, assessed via imaging or histology, were included. The primary objective was to determine the association between PDAC and PS by comparing the prevalence of PS in individuals with- and without PDAC. Secondary, an evaluation was conducted to establish whether the method of assessment correlated with the association of PDAC and PS, and the prevalence of PDAC in individuals with PS. Measures of effect size were determined using odds ratios (ORs) and corresponding 95 % confidence intervals (95 % CI).

The systematic review identified a total of 23 studies, of which seventeen studies examined PS prevalence among PDAC patients and were included in the meta-analysis. Overall, the pooled prevalence of PS in patients with PDAC was 53.6 % (95 % CI 40.9-66.2). No significant difference in PS prevalence was observed across various diagnostic methods or geographical regions. Overall, the pooled OR for PS in patients with PDAC compared to controls was 3.23 (95 % CI 1.86-5.60).

PDAC patients have a high prevalence of PS, and they are significantly more likely to have PS compared to controls. These findings emphasize the need to prioritize a standardized approach to the diagnosis, follow-up, and treatment of PS, with future studies focusing on identifying patients who would benefit from PDAC surveillance programs.

Early detection of pancreatic ductal adenocarcinoma (PDAC) can improve survival but is hampered by the absence of early disease symptoms. Imaging remains key for surveillance but is cumbersome and may lack sensitivity to detect small tumors. CA19-9, the only FDA-approved blood biomarker for PDAC, is insufficiently sensitive and specific to be recommended for surveillance. We aimed to discover a blood-based protein signature to improve PDAC detection in our main target population consisting of stage I or II PDAC patients (n = 75) and various controls including healthy controls (n = 50), individuals at high risk (genetic and familial) for PDAC (n = 47), or those under surveillance for an intraductal papillary mucinous neoplasm (n = 36). Roughly 3000 proteins were measured using Olink multiplex technology and conventional immunoassays. Machine learning combined biomarker candidates into 4- to 6-plex signatures. These signatures significantly (p < 0.001) outperformed CA19-9 with 84% sensitivity at 95% specificity, compared to CA19-9's sensitivity of 53% in the target population. Exploratory analysis was performed in new-onset diabetes (n = 81) and chronic pancreatitis (n = 50) patients. In conclusion, 41 promising biomarker candidates across multiple signatures were identified using proteomics technology and will be further tested in an independent cohort.

Pancreatic ductal adenocarcinoma continues to have a poor prognosis, although recent advances in neoadjuvant treatments (NATs) have provided some hope. Imaging assessment of suspected tumours can be challenging and requires a specific approach, with pancreas protocol CT being the primary imaging modality for staging with other modalities used as problem-solving tools to facilitate appropriate management. Imaging assessment post NAT can be particularly difficult due to a current lack of robust radiological criteria to predict response and differentiate treatment induced fibrosis/inflammation from residual tumour. This review aims to provide an update of pancreatic ductal adenocarcinoma with particular focus on three points: tumour staging pre- and post-NAT including vascular assessment, structured reporting with introduction of the PAncreatic Cancer reporting Template-UK (PACT-UK) radiology template, and the potential future role of artificial intelligence in the diagnosis and staging of pancreatic cancer.

Limited research has compared external beam radiotherapy (RT) to non-RT in patients with nonsurgical locally advanced pancreatic cancer (LAPC). Therefore, this study investigates the impact of RT on overall survival (OS) in patients with nonsurgical LAPC in a real-world context.

The authors conducted an analysis of patients with nonsurgical LAPC using data from the Surveillance, Epidemiology, and End Results (SEER) database. This analysis involved the utilization of Kaplan-Meier survival curves and multivariable Cox regression analyses.

A total of 5413 individuals with nonsurgical LAPC were included in this analysis. Among them, 2320 (42.9%) received RT, while 3093 (57.1%) underwent non-RT treatment. The median OS was 12.0 months for the RT group and 9.0 months for the non-RT group, with a statistically significant difference ( P <0.001). Multivariate analysis revealed that RT had a statistically significant impact on OS (HR, 0.86; 95% CI: 0.81-0.91; P <0.001). Propensity score matching analysis confirmed a statistically significant association of RT with improved OS (HR, 0.84, 95% CI: 0.79-0.90; P <0.001). These results remained consistent after conducting sensitivity analyses, subgroup analyses, and propensity score matching.

The study findings suggest that RT could be advantageous for patients with nonsurgical LAPC. Further investigations are warranted to explore the relationship between RT and OS.

A blood test that enables surveillance for early-stage pancreatic ductal adenocarcinoma (PDAC) is an urgent need. Independent laboratories have reported PDAC biomarkers that could improve biomarker performance over CA19-9 alone, but the performance of the previously reported biomarkers in combination is not known. Therefore, we conducted a coordinated case/control study across multiple laboratories using common sets of blinded training and validation samples (132 and 295 plasma samples, respectively) from PDAC patients and non-PDAC control subjects representing conditions under which surveillance occurs. We analyzed the training set to identify candidate biomarker combination panels using biomarkers across laboratories, and we applied the fixed panels to the validation set. The panels identified in the training set, CA19-9 with CA199.STRA, LRG1, TIMP-1, TGM2, THSP2, ANG, and MUC16.STRA, achieved consistent performance in the validation set. The panel of CA19-9 with the glycan biomarker CA199.STRA improved sensitivity from 0.44 with 0.98 specificity for CA19-9 alone to 0.71 with 0.98 specificity (p < 0.001, 1000-fold bootstrap). Similarly, CA19-9 combined with the protein biomarker LRG1 and CA199.STRA improved specificity from 0.16 with 0.94 sensitivity for CA19-9 to 0.65 with 0.89 sensitivity (p < 0.001, 1000-fold bootstrap). We further validated significantly improved performance using biomarker panels that did not include CA19-9. This study establishes the effectiveness of a coordinated study of previously discovered biomarkers and identified panels of those biomarkers that significantly increased the sensitivity and specificity of early-stage PDAC detection in a rigorous validation trial.

To evaluate the diagnostic yield of pancreatic cancer screening in individuals at risk (IAR) from familial pancreatic cancer (FPC) families with respect to the presence or absence of pathogenic germline variants predisposing to pancreatic adenocarcinoma (PDAC).

In a 20 years period, IAR from FPC families were enrolled in a prospective screening program of the national case collection for FPC of Germany, including magnet resonance imaging (MRI) and endoscopic ultrasound (EUS). The diagnostic yield was analyzed regarding significant pancreatic lesions such as PDAC, high-grade pancreatic-intraepithelial-neoplasia (PanIN3) and intraductal-papillary-mucinous-neoplasia (IPMN) with high-grade dysplasia. Screening results were compared between carriers of pathogenic variants and variant-negative IAR.

337 IAR, including 74 (22%) variant-carriers and 263 IAR of variant-negative FPC families (mean age 49; standard deviation [SD] + 8.9) were followed 64 (SD + 55) months. IAR underwent 5.1 (SD + 3.9) screening visits with 1733 MRI (5.1,SD + 3.9 per IAR) and 728 EUS (2.2,SD + 1.7 per IAR). In 12 (4%) cases, significant pancreatic lesions were detected, including 4 PDAC, 3 PanIN3 and 5 high-grade IPMN. Three of 4 IAR with PDAC died after a mean of 27 months postoperatively, and one IAR is alive without evidence of disease after 31 months. The diagnostic yield for significant lesions was 13.5% (10/74) for variant carriers compared to 0.8% (2/263) for IAR of variant-negative FPC families (p < 0.001). Logistic regression analysis revealed that a negative variant status was almost always accompanied by the absence of a significant lesion over time with a negative predictive value of 99.2% (95% CI 97.3%-99.9%).

The diagnostic yield seems to justify PDAC screening in IAR of FPC-families with pathogenic germline variants in PDAC predisposing genes, not in IAR of variant-negative families.

Pancreatic ductal adenocarcinoma (PDAC) continues to remain one of the leading causes of cancer-related death. Unlike other malignancies where universal screening is recommended, the same cannot be said for PDAC. The purpose of this study is to review which patients are at high risk of developing PDAC and therefore candidates for screening, methods/frequency of screening, and risk for these groups of patients.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality and it is often diagnosed at advanced stages due to non-specific clinical presentation. Disease detection at localized disease stage followed by surgical resection remains the only potentially curative treatment. In this era of precision medicine, a multifaceted approach to early detection of PDAC includes targeted screening in high-risk populations, serum biomarkers and "liquid biopsies", and artificial intelligence augmented tumor detection from radiologic examinations. In this review, we will review these emerging techniques in the early detection of PDAC.

Individuals with a germline CDKN2A pathogenic variant (PV) are at high risk of developing melanoma and pancreatic cancer and are therefore offered surveillance. The potential advantages and disadvantages associated with genetic testing and surveillance are discussed during medical counseling, although little is known about the associated psychosocial factors that are relevant to this population. This study sought to provide a qualitative exploration of psychosocial factors related to genetic testing and participation in skin and pancreatic surveillance in (potential) carriers of a CDKN2A PV. Fifteen individuals-both at-risk individuals and confirmed variant carriers-participated in one of the three online focus groups. Pre-defined discussion topics, including genetic testing, cancer surveillance, influence on lifestyle and family planning, were discussed. Patients reported that important reasons to engage in genetic testing included the possibility to participate in surveillance to gain control over their cancer risk and to get clarification on the potential carrier status of their children. We observed considerable differences in risk perception and experienced burden of surveillance. Knowledge of the PV has had a positive influence on lifestyle factors and altered attitudes toward life in some. Most participants were not aware of preimplantation genetic testing. This focus group study provided insight into a variety of psychosocial themes related to (potential) carriership of a CDKN2A PV. Future efforts should focus on identifying those who may benefit from additional psychosocial support, development of a centralized source of information, and assessing the knowledge, needs, and timing of counseling for family planning.

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.

Pancreatic cancer is a rare but lethal cancer due to its biologically aggressive nature, advanced stage at the time of diagnosis, and poor response to oncologic therapies. The risk of pancreatic cancer is significantly higher to 5% in certain high-risk individuals with inherited genetic susceptibility. Screening for pancreatic cancer in these individuals from high-risk groups can help with the early detection of pancreatic cancer as well as the detection of precursor lesions leading to early surgical resection and improved overall outcomes. The advancements in radiological imaging as well as advanced endoscopic procedures has made a significant impact on the early diagnosis, surveillance, and staging of pancreatic cancer. There is also a significant advancement in the development of biomarkers for the early detection of pancreatic cancer, which has also led to the development of liquid biopsy, allowing for microRNA detection in serum and circulating tumor cells. Various societies and organizations have provided guidelines for pancreatic cancer screening and surveillance in high-risk individuals. In this review, we aim to discuss the hereditary risk factors for developing pancreatic cancer, summarize the screening recommendations by different societies, and discuss the development of novel biomarkers and areas for future research in pancreatic cancer screening for high-risk individuals.

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.

As in Western countries, familial pancreatic cancer accounts for 5-7% of pancreatic cancer (PC) in Japan. Opportunities for diagnosing hereditary pancreatic cancer (HPC) are increasing owing to the coverage of companion diagnostics and cancer genomic profiling by national health insurance in patients with unresectable or recurrent PC refractory to standard chemotherapies. HPC is recognized in 7% of PCs and 15% of familial pancreatic cancer, including germline variants of BRCA1/2, ATM, PALB2, APC, and mismatch repair genes. Individuals with 5-fold or greater inherited risks of PC are recommended to undergo pancreatic surveillance according to Japanese guidelines. The imaging modalities for this surveillance include endoscopic ultrasound, magnetic resonance cholangiopancreatography, abdominal ultrasound, and enhanced computed tomography. Currently, a nationwide prospective surveillance study is ongoing in Japan. Platinum-based chemotherapy is an effective pancreatic cancer treatment in patients with variants of homologous recombination repair genes (BRCA1/2 and PALB2); however, the use of platinum regimens solely based on familial/personal cancer history remains controversial. The efficacy of olaparib maintenance therapy, as confirmed by the POLO study, has significantly impacted the clinical treatment of advanced PC patients in Japan. Since the initiation of precision cancer medicine in 2019, genetic medicine for PC patients has expanded in Japan.

In the 1990s, as prevention became a central strategy in the battle against cancer and the molecular genetics revolution uncovered the genetic basis of numerous hereditary cancer syndromes, there were no options available for patients at increased risk of developing pancreatic cancer. When surveillance efforts for those at familial and hereditary risk of pancreatic cancer emerged in the late 1990s, it was uncertain if early detection was achievable.In this introduction to the special issue, we offer an overview of the history of surveillance for pancreatic cancer, including the first reports of familial pancreatic cancer in the medical literature, the initial results of surveillance in the United States and the initiation of surveillance programs for hereditary pancreatic cancer in the Netherlands.This special issue features a collection of 18 articles written by prominent experts in the field, focusing specifically on refining surveillance methodologies with the primary objective of improving care of high-risk individuals. Several reviews in this collection highlight improved survival rates associated with pancreas surveillance, underlying the potential of early detection and improved management in the continuing fight against pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the Western world. The number of diagnosed cases and the mortality rate are almost equal as the majority of patients present with advanced disease at diagnosis. Between 4 and 10% of pancreatic cancer cases have an apparent hereditary background, known as hereditary pancreatic cancer (HPC) and familial pancreatic cancer (FPC), when the genetic basis is unknown. Surveillance of high-risk individuals (HRI) from these families by imaging aims to detect PDAC at an early stage to improve prognosis. However, the genetic basis is unknown in the majority of HRIs, with only around 10-13% of families carrying known pathogenic germline mutations. The aim of this study was to assess an individual's genetic cancer risk based on sex and personal and family history of cancer. The Best Linear Unbiased Prediction (BLUP) methodology was used to estimate an individual's predicted risk of developing cancer during their lifetime. The model uses different demographic factors in order to estimate heritability. A reliable estimation of heritability for pancreatic cancer of 0.27 on the liability scale, and 0.07 at the observed data scale as obtained, which is different from zero, indicating a polygenic inheritance pattern of PDAC. BLUP was able to correctly discriminate PDAC cases from healthy individuals and those with other cancer types. Thus, providing an additional tool to assess PDAC risk HRI with an assumed genetic predisposition in the absence of known pathogenic germline mutations.

New-onset diabetes represent a high-risk cohort to screen for pancreatic cancer.

Develop a machine model to predict pancreatic cancer among patients with new-onset diabetes.

A retrospective cohort of patients with new-onset diabetes was assembled from multiple health care networks in the United States. An XGBoost machine learning model was designed from a portion of this cohort (the training set) and tested on the remaining part of the cohort (the test set). Shapley values were used to explain the XGBoost's model features. Model performance was compared with 2 contemporary models designed to predict pancreatic cancer among patients with new-onset diabetes.

In the test set, the XGBoost model had an area under the curve of 0.80 (0.76 to 0.85) compared with 0.63 and 0.68 for other models. Using cutoffs based on the Youden index, the sensitivity of the XGBoost model was 75%, the specificity was 70%, the accuracy was 70%, the positive predictive value was 1.2%, and the negative predictive value was >99%. The XGBoost model obtained a positive predictive value of at least 2.5% with a sensitivity of 38%. The XGBoost model was the only model that detected at least 50% of patients with cancer one year after the onset of diabetes. All 3 models had similar features that predicted pancreatic cancer, including older age, weight loss, and the rapid destabilization of glucose homeostasis.

Machine learning models isolate a high-risk cohort from those with new-onset diabetes at risk for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence. The majority of PDACs are incurable at presentation, but population-based screening is not recommended. Surveillance of high-risk individuals for PDAC may lead to early detection, but the survival benefit is unproven.

To compare the survival of patients with surveillance-detected PDAC with US national data.

This comparative cohort study was conducted in multiple US academic medical centers participating in the Cancer of the Pancreas Screening program, which screens high-risk individuals with a familial or genetic predisposition for PDAC. The comparison cohort comprised patients with PDAC matched for age, sex, and year of diagnosis from the Surveillance, Epidemiology, and End Results (SEER) program. The Cancer of the Pancreas Screening program originated in 1998, and data collection was done through 2021. The data analysis was performed from April 29, 2022, through April 10, 2023.

Endoscopic ultrasonography or magnetic resonance imaging performed annually and standard-of-care surgical and/or oncologic treatment.

Stage of PDAC at diagnosis, overall survival (OS), and PDAC mortality were compared using descriptive statistics and conditional logistic regression, Cox proportional hazards regression, and competing risk regression models. Sensitivity analyses and adjustment for lead-time bias were also conducted.

A total of 26 high-risk individuals (mean [SD] age at diagnosis, 65.8 [9.5] years; 15 female [57.7%]) with PDAC were compared with 1504 SEER control patients with PDAC (mean [SD] age at diagnosis, 66.8 [7.9] years; 771 female [51.3%]). The median primary tumor diameter of the 26 high-risk individuals was smaller than in the control patients (2.5 [range, 0.6-5.0] vs 3.6 [range, 0.2-8.0] cm, respectively; P < .001). The high-risk individuals were more likely to be diagnosed with a lower stage (stage I, 10 [38.5%]; stage II, 8 [30.8%]) than matched control patients (stage I, 155 [10.3%]; stage II, 377 [25.1%]; P < .001). The PDAC mortality rate at 5 years was lower for high-risk individuals than control patients (43% vs 86%; hazard ratio, 3.58; 95% CI, 2.01-6.39; P < .001), and high-risk individuals lived longer than matched control patients (median OS, 61.7 [range, 1.9-147.3] vs 8.0 [range, 1.0-131.0] months; 5-year OS rate, 50% [95% CI, 32%-80%] vs 9% [95% CI, 7%-11%]).

These findings suggest that surveillance of high-risk individuals may lead to detection of smaller, lower-stage PDACs and improved survival.

The goal of surveillance programs for individuals at risk (IAR) from familial pancreatic cancer (FPC) families or families with other inherited tumor syndromes predisposing to the development of pancreatic adenocarcinoma (PDAC), such as hereditary pancreatitis or Peutz-Jeghers syndrome, is the dectection and consecutive curative resection of early PDAC or even better its high-grade precursor lesions. Although the indication for surgery is quite established, the extent of surgery is not well defined due to the lack of evidence-based data. In addition, multiple factors have to be taken into account to determine an optimal personalized surgical strategy. This holds especially true since pancreatic surgery is associated with a relatively high morbidity and might impair the quality of life significantly. In this article the surgical aspects in the setting of hereditary PDAC are discussed.

Pancreatic cancer has a dismal prognosis in the general population. However, early detection and treatment of disease in high-risk individuals can improve survival, as patients with localized disease and especially patients with lesions smaller than 10 mm show greatly improved 5-year survival rates. To achieve early detection through MRI surveillance programs, optimization of imaging is required. Advances in MRI technologies in both hardware and software over the years have enabled reliable detection of pancreatic cancer at a small size and early stage. Standardization of dedicated imaging protocols for the pancreas are still lacking. In this review we discuss state of the art scan techniques, sequences, reduction of artifacts and imaging strategies that enable early detection of lesions. Furthermore, we present the imaging features of small pancreatic cancers from a large cohort of high-risk individuals. Refinement of MRI techniques, increased scan quality and the use of artificial intelligence may further improve early detection and the prognosis of pancreatic cancer in a screening setting.

Individuals at high risk of developing pancreatic ductal adenocarcinoma are eligible for surveillance within research programs. These programs employ periodic imaging in the form of magnetic resonance imaging/magnetic resonance cholangiopancreatography or endoscopic ultrasound for the detection of early cancer or high-grade precursor lesions. This narrative review discusses the role of endoscopic ultrasound within these surveillance programs. It details its overall strengths and limitations, yield, burden on patients, and how it compares to magnetic resonance imaging. Finally, recommendations are given when and how to incorporate endoscopic ultrasound in the surveillance of high-risk individuals.

The Spanish Familial Pancreatic Cancer Registry (PANGENFAM) was established in 2009 and aims to characterize the genotype and phenotype of familial pancreatic cancer (FPC). Furthermore, an early detection screening program for pancreatic ductal adenocarcinoma (PDAC) is provided to healthy high-risk individuals from FPC and hereditary pancreatic cancer families (first-degree relatives). This article describes our experience over the last 10 years in high-risk screening. Hereditary and familial pancreatic cancer families were identified through the oncology and gastroenterology units. High-risk individuals underwent annual screening with endoscopic ultrasound (EUS) and magnetic resonance (MRI) from age 40 or 10 years younger than the youngest affected family member. Results: PANGENFAM has enrolled 290 individuals from 143 families, including 52 PDAC cases and 238 high-risk individuals. All high-risk individuals eligible for screening were offered to enter the surveillance program, with 143 currently participating. Pancreatic abnormalities were detected in 94 individuals (median age 53 years (29-83), with common findings including cystic lesions and inhomogeneous parenchyma. Imaging test concordance was 66%. Surgical intervention was performed in 4 high-risk individuals following highly suspicious lesions detected by imaging. PANGENFAM is a valuable resource for science innovation, such as biobanking, with clinical and imaging data available for analysis. For high-risk families, it may offer a potential for early diagnosis. Collaboration with other national and international registries is needed to increase our understanding of the disease biology and to standardize criteria for inclusion and follow-up, optimizing cost-effectiveness and efficacy.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths and is associated with a poor prognosis. The majority of these cancers are detected at a late stage, contributing to the bad prognosis. This underscores the need for novel, enhanced early detection strategies to improve the outcomes. While population-based screening is not recommended due to the relatively low incidence of PDAC, surveillance is recommended for individuals at high risk for PDAC due to their increased incidence of the disease. However, the outcomes of pancreatic cancer surveillance in high-risk individuals are not sorted out yet. In this review, we will address the identification of individuals at high risk for PDAC, discuss the objectives and targets of surveillance, outline how surveillance programs are organized, summarize the outcomes of high-risk individuals undergoing pancreatic cancer surveillance, and conclude with a future perspective on pancreatic cancer surveillance and novel developments.

In the early years of my GI fellowship, a healthy 40-year-old man came to my clinic and announced that he was going to die of pancreatic cancer. His brothers, father and uncles had all died of the disease; he felt his fate was inescapable. I asked whether his family members had seen doctors or had any tests. His answer was yes to both. Even so, doctors could not diagnose the pancreatic cancer at early stages. CT scans were always negative. I thought to myself, in order to help this patient-CT scans may not be reliable for early detection. Perhaps other methods of imaging the pancreas might be of more benefit. This patient opened a door that led to a 30-year journey of trying to detect pancreatic cancer at earlier stages when it is curable.

Individuals with a germline CDKN2A pathogenic variant (PV) have a highly increased life time risk of melanoma and pancreatic cancer. This cross-sectional study assessed the attitudes among toward genetic testing, family planning, and preimplantation genetic testing (PGT) in confirmed CDKN2A PV carriers and individuals with a 50% risk of the PV (at-risk carriers) using of a one-time questionnaire.A total of 537 individuals were screened for eligibility, of whom 208 of 366 (57%) confirmed carriers (56% female, median age 54 years [IQR 46-63]) and 39 of 171 (23%) at-risk carriers (59% female, median age of 26 years [IQR 22-32]) participated in the study. Primary motivations for genetic testing were to gain control over their personal and children's cancer risk, as well as increasing cancer surveillance practices. In contrast, concerns about obtaining a mortgage and life insurance were frequently cited as reasons for postponing genetic testing. Family planning decisions remained largely unaffected in both confirmed and at-risk carriers; however, the majority of confirmed carriers were still unaware of their familial or personal cancer risk when starting a family. More than 60% of the participants were unfamiliar with PGT and only a minority (19% of confirmed carriers and 10% of at-risk carriers) would be open to considering PGT as a reproductive option. This study found different attitudes toward genetic testing, family planning, and PGT among individuals affected by the CDKN2A PV. Understanding these different attitudes can help clinicians to address the complexities surrounding these issues, especially for younger individuals facing difficult decisions about the timing of genetic testing, family planning, and the potential use of assisted reproductive options.

Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive cancers. It has a poor 5-year survival rate of 12%, partly because most cases are diagnosed at advanced stages, precluding curative surgical resection. Early-stage PDA has significantly better prognoses due to increased potential for curative interventions, making early detection of PDA critically important to improved patient outcomes. We examine current and evolving early detection concepts, screening strategies, diagnostic yields among high-risk individuals, controversies, and limitations of standard-of-care imaging.

Substantial differences exist in pancreatic cancer outcomes across ethnoracial stratifications. We sought to assess racial, ethnic, sex, and age reporting and inclusion of participants in pancreatic cancer screening studies.

A systematic search of Cochrane Library, Ovid Embase, Google Scholar, Ovid MEDLINE, PubMed, Scopus, and Web of Science Core Collection from inception to 2022 was conducted. Original studies on pancreatic cancer screening were identified and assessed for reporting and inclusion on race, ethnicity, sex, and age. The pooled proportions of study participants for these characteristics were calculated and compared with population-based benchmarks.

Among 27 eligible pancreatic cancer screening studies, 26 reported data on either sex, race, or ethnicity, with a total of 5273 participants. Information on participant sex was reported by 26, race by 12, and ethnicity by 8 studies. Participants in these studies were almost all white (pooled proportion, 93.1%; 95% confidence interval [CI], 89.7-96.4) and non-Latino (pooled proportion, 97.4%; 95% CI, 94.0-100), and these groups were over-represented when compared with the general population. Female participants were well represented, with a pooled proportion of 63.2% (95% CI, 59.9-66.6). When reported, mean or median participant age was <60 years. Meta-regression revealed higher proportions of female participants in studies from the United States (P = .002). No association between increasing participation of racial or ethnic under-represented populations and study quality, ascending year of publication, or source of study funding was noted.

Substantial disparities in race, ethnicity, sex, and age reporting and inclusion in pancreatic cancer studies were noted, even among high-quality and publicly funded studies.

Pancreatic ductal adenocarcinoma (PDAC) is a solid organ malignancy with a high mortality rate. Statistics indicate that its incidence has been increasing as well as the associated deaths. Most patients with PDAC show poor response to therapies making the clinical management of this cancer difficult. Stromal cells in the tumor microenvironment (TME) contribute to the development of resistance to therapy in PDAC cancer cells. Cancer-associated fibroblasts (CAFs), the most prevalent stromal cells in the TME, promote a desmoplastic response, produce extracellular matrix proteins and cytokines, and directly influence the biological behavior of cancer cells. These multifaceted effects make it difficult to eradicate tumor cells from the body. As a result, CAF-targeting synergistic therapeutic strategies have gained increasing attention in recent years. However, due to the substantial heterogeneity in CAF origin, definition, and function, as well as high plasticity, majority of the available CAF-targeting therapeutic approaches are not effective, and in some cases, they exacerbate disease progression. This review primarily elucidates on the effect of CAFs on therapeutic efficiency of various treatment modalities, including chemotherapy, radiotherapy, immunotherapy, and targeted therapy. Strategies for CAF targeting therapies are also discussed.

A blood test that enables surveillance for early-stage pancreatic ductal adenocarcinoma (PDAC) is an urgent need. Independent laboratories have reported PDAC biomarkers that could improve biomarker performance over CA19-9 alone, but the performance of the previously reported biomarkers in combination is not known. Therefore, we conducted a coordinated case/control study across multiple laboratories using common sets of blinded training and validation samples (132 and 295 plasma samples, respectively) from PDAC patients and non-PDAC control subjects representing conditions under which surveillance occurs. We analyzed the training set to identify candidate biomarker combination panels using biomarkers across laboratories, and we applied the fixed panels to the validation set. The panels identified in the training set, CA19-9 with CA199.STRA, LRG1, TIMP-1, TGM2, THSP2, ANG, and MUC16.STRA, achieved consistent performance in the validation set. The panel of CA19-9 with the glycan biomarker CA199.STRA improved sensitivity from 0.44 with 0.98 specificity for CA19-9 alone to 0.71 with 0.98 specificity (p < 0.001, 1000-fold bootstrap). Similarly, CA19-9 combined with the protein biomarker LRG1 and CA199.STRA improved specificity from 0.16 with 0.94 sensitivity for CA19-9 to 0.65 with 0.89 sensitivity (p < 0.001, 1000-fold bootstrap). We further validated significantly improved performance using biomarker panels that did not include CA19-9. This study establishes the effectiveness of a coordinated study of previously discovered biomarkers and identified panels of those biomarkers that significantly increased the sensitivity and specificity of early-stage PDAC detection in a rigorous validation trial.