Endoscopic Ultrasound Through-The-Needle Biopsy of Pancreatic Cysts: Toward Procedure Standardization.

BACKGROUND AND AIMS: EUS-guided through-the-needle microforceps biopsy (EUS-TTNB) was introduced as a new diagnostic tool to establish pancreatic cyst histotype and help to better risk stratify the patients. The aim of this study was to describe the technical success, diagnostic yield, and adverse events of through-the-needle biopsy and discuss the technique variations, focusing on future procedure standardization. METHODS: We performed a prospective single-center study including patients with presumed mucinous cysts harboring worrisome features or indeterminate cyst type on imaging, submitted to EUS-TTNB using Moray® microforceps between March 2018 and September 2021. Specimens were processed as a cell-block. RESULTS: We included 40 patients. Technical success was 97.5%. The diagnostic yield was 72.5% for TTNB whereas for cyst fluid cytology/analysis it was 27.5%. Moreover, without TTNB 5 mucinous lesions would not have been diagnosed. TTNB had a sensitivity of 76% and a specificity of 91%, while FNA cytology had a sensitivity and specificity of 35% and 91%, respectively. Moreover for IPMN lesions, subtyping was possible in 63% of cases. TTNB resulted in change in clinical management in 20% of patients. We registered three adverse events: 2 self-limited intracystic bleeding and 1 patient with abdominal pain not associated with pancreatitis. CONCLUSION: TTNB proved superior to cyst fluid analysis and cytology for the definition of cyst histotype and mucinous cyst diagnosis with acceptable risk profile. Further studies should explore the best steps for procedure standardization.

Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to fuel tumour progression.

OBJECTIVE: Intratumor heterogeneity drives cancer progression and therapy resistance. However, it has yet to be determined whether and how subpopulations of cancer cells interact and how this interaction affects the tumour. DESIGN: We have studied the spontaneous flow of extracellular vesicles (EVs) between subpopulations of cancer cells: cancer stem cells (CSC) and non-stem cancer cells (NSCC). To determine the biological significance of the most frequent communication route, we used pancreatic ductal adenocarcinoma (PDAC) orthotopic models, patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMMs). RESULTS: We demonstrate that PDAC tumours establish an organised communication network between subpopulations of cancer cells using EVs called the EVNet). The EVNet is plastic and reshapes in response to its environment. Communication within the EVNet occurs preferentially from CSC to NSCC. Inhibition of this communication route by impairing Rab27a function in orthotopic xenographs, GEMMs and PDXs is sufficient to hamper tumour growth and phenocopies the inhibition of communication in the whole tumour. Mechanistically, we provide evidence that CSC EVs use agrin protein to promote Yes1 associated transcriptional regulator (YAP) activation via LDL receptor related protein 4 (LRP-4). Ex vivo treatment of PDXs with antiagrin significantly impairs proliferation and decreases the levels of activated YAP.Patients with high levels of agrin and low inactive YAP show worse disease-free survival. In addition, patients with a higher number of circulating agrin+ EVs show a significant increased risk of disease progression. CONCLUSION: PDAC tumours establish a cooperation network mediated by EVs that is led by CSC and agrin, which allows tumours to adapt and thrive. Targeting agrin could make targeted therapy possible for patients with PDAC and has a significant impact on CSC that feeds the tumour and is at the centre of therapy resistance.

Bronchial-biliary fistula secondary to cholangiocarcinoma: long-term efficacy of biliary self-expandable metal stent.

A 77-year-old female with previous medical history of non-cirrhotic chronic hepatitis B and hepatocellular carcinoma treated with sequential partial hepatectomy followed by transarterial chemoembolization complained of pruritus and jaundice. Magnetic resonance cholangiopancreatography revealed a peri-hilar ill-defined stenosing lesion suggestive of malignancy. Endoscopic retrograde cholangiopancreatography with cholangioscopy confirmed a circumferential peri-hilar stenosis with fragile mucosa and tortuous dilated vessels and biopsies of this area were consistent cholangiocarcinoma. After 3 months, she presented with new-onset dyspnea and bilioptysis and abdominal computed tomography revealed a bronchial-biliary fistula. ERCP was performed to place a self-expandable metal stent in the biliary tract, which resulted in rapid clinical improvement. The patient has been followed for 2 years and remains globally stable with two episodes of worsening of bilioptysis secondary to stent obstruction by lithiasis that were easily resolved with Fogarty balloon-assisted extraction, with rapid improvement. This case demonstrates the long-term efficacy of endoscopic biliary drainage with self-expandable metallic stent for bronchial-biliary fistula in the setting of cholangiocarcinoma. .

The role of endoscopic submucosal dissection in the management of gastric inflammatory fibroid polyps: a single-center experience.

BACKGROUND AND AIM: gastric inflammatory fibroid polyps constitute only 0.1 % of all gastric polyps. They are usually amenable to resection by snare polypectomy. However, on rare occasions, these lesions may require resection by endoscopic submucosal dissection. This study aimed to evaluate the effectiveness and safety of endoscopic submucosal dissection in the management of gastric inflammatory fibroid polyps not amenable to resection with snare polypectomy. METHODS: a retrospective observational study of all consecutive patients who underwent endoscopic submucosal dissection for gastric inflammatory fibroid polyps between January 2011 and December 2020 was performed. RESULTS: there were nine cases of gastric inflammatory fibroid polyps resected by endoscopic submucosal dissection. Most patients were female (7/9) with a mean age of 62.2 years. All gastric inflammatory fibroid polyps were described as solitary antral subepithelial lesions with a mean diameter of 16.7 mm, which appeared well-circumscribed and homogeneous lesions located at muscularis mucosa and submucosa without deeper invasion on endoscopic ultrasound. All lesions were successfully resected by en bloc and complete resection with free margins obtained in 8/9 specimens. Adverse events were reported in 2/9 cases including one intra-procedural bleeding successfully controlled with hemostatic clips and one aspiration pneumonia that evolved favorably. Mean follow-up duration was 33.7 months and no delayed complications or cases of recurrence were reported. CONCLUSIONS: endoscopic submucosal dissection appears safe and effective for the resection of gastric inflammatory fibroid polyps that present as large subepithelial lesions, if performed by experienced endoscopists after adequate characterization by endoscopic ultrasound, with high rates of technical success and low recurrence rates.

Development of an Online App to Predict Post-Endoscopic Retrograde Cholangiopancreatography Adverse Events Using a Single-Center Retrospective Cohort.

INTRODUCTION: Endoscopic retrograde cholangiopancreatography (ERCP) is a technically demanding procedure with a high risk for adverse events (AEs). AIM: evaluate patient- and procedure-related risk factors for ERCP-related AEs and develop an online app to estimate risk of AEs. METHODS: retrospective study of 1,491 consecutive patients who underwent 1,991 ERCPs between 2012 and 2017 was conducted. AEs definition and severity were classified according to most recent ESGE guidelines. Each variable was tested for association with occurrence of overall AEs, post-ERCP pancreatitis (PEP) and cholangitis. For each outcome, 2 regression models were built, from which an online Shiny-based app was created. RESULTS: Overall AE rate was 15.3%; in 19 procedures, >1 AE occurred. Main post-ERCP AE was PEP (7.5%), followed by cholangitis (4.9%), bleeding (1.3%), perforation (1%), cardiopulmonary events (0.9%), and cholecystitis (0.3%). Seventy-eight percent of AEs were mild/moderate; of severe (n = 55) and fatal (n = 20) AEs, more than half were related to infection, cardiac/pulmonary AEs, and perforation. AE-related mortality rate was 1%. When testing precannulation, procedural covariates, and ERCP findings, AE occurrence was associated with age (odds ratio [OR] 0.991), previous PEP (OR 2.198), ERCP complexity grade III/IV (OR 1.924), standard bile duct cannulation (OR 0.501), sphincterotomy (OR 1.441), metal biliary stent placement (OR 2.014), periprocedural bleeding (OR 3.024), and biliary duct lithiasis (OR 0.673). CONCLUSION: Our app may allow an optimization of the patients' care, by helping in the process of decision-making, not only regarding patient or endoscopist's selection but also definition of an adequate and tailored surveillance plan after the procedure.

Exosomal glypican-1 for risk stratification of pancreatic cystic lesions: A case of pathological progression in the absence of any suspicious imaging finding.

The clinical management of patients with pancreatic cystic lesions is of utmost importance to identify those at high risk for pathological progression. Current recommendations are guided by clinical presentation and radiologic criteria, but the results fall short for a disease that the only curative option is surgical resection. There is an urgent need for the introduction of biomarkers that can help in risk assessment of such lesions. We report a case of a pancreatic cystic lesion without imagiological findings suggestive of advanced disease, and high levels of a circulating biomarker, glypican-1 (GPC-1), which parallel those of patients with pancreatic cancer. One year after, the patient revealed malignant progression at follow-up. Our report is unprecedented in the literature. It describes a clinical case in which a biomarker was positive for a patient that only showed progression one year after its detection. This clinical information goes beyond the current knowledge in the field because it shows that the introduction of liquid biopsy and biomarkers is a highly promising clinical tool for the non-invasive assessment of pancreatic cancer precursor lesions, ultimately increasing the rate of patients eligible for surgical resection.

Pancreatic cancer screening: Still a delusion?

Pancreatic adenocarcinoma represents the fourth most common cause of cancer mortality and death due to pancreatic cancer (PC) have increased since 2003. Its incidence has also raised about 30% in the past decade and it is expected to become the second cause of cancer mortality by 2020 in the USA. Most PC present with metastatic disease and improvements in treatment outcomes for this group have been disappointing. These observations support the idea that screening to identify patients at an earlier stage might be an important strategy in improving overall PC outcomes. Many protocols have been tested, nevertheless, by now there is no effective screening program. Given the overall low incidence of disease and the current lack of accurate, inexpensive and noninvasive screening tests, the consensus is that widespread population-based screening for PC in the general population or in patients with only one affected first-degree relative is neither practicable nor indicated in most countries. However, a different scenario is screening patients with higher risk for PC, most of them with hereditary conditions predisposing the development of this neoplasia. In fact, some guidelines are now available helping to select these individuals at risk and to screen them, in order to achieve early detection of PC.

Endoscopic management of late complication of blunt traumatic total pancreatic transection.

An 11-year-old girl was admitted elsewhere due to severe abdominal pain after a fall with abdominal blunt trauma. CT-scan showed total pancreatic transection of the distal body with suspected injury of main pancreatic duct.

Self-expanding metal stents in postoperative esophageal leaks.

BACKGROUND: Postoperative esophageal leaks have a high morbidity and mortality. Self-expanding metal stents (SEMS) have been used as an alternative to re-operation. AIM: Evaluating predictors of success of SEMS in postoperative esophageal leaks. METHODS: Retrospective study of patients with postoperative esophageal leaks referred for SEMS placement in a reference center during a period of 3 years. Technical success was defined as closure of the leak in barium swallow at 15 days. Clinical success was considered as endoscopic and/or radiographic confirmation of closure after stent removal. RESULTS: Thirteen patients placed SEMS. Median follow-up was 58 days. Leaks had a median size of 20 mm. Time between surgery and SEMS placement was 20 days. One patient died 2 days after SEMS placement and one had worsening of the fistula after SEMS expansion. Time till stent migration was 9 days. Technical success was achieved in 9 of 11 patients, with clinical success without recurrence in 5 patients. All leaks with less than 20 mm were solved endoscopically. Technical and clinical success was higher when time between surgery and SEMS placement was lower, even though without statistical significance (respectively, p = 0.228 and 0.374). In the 8 patients who died during follow-up, median survival was 59 days. CONCLUSIONS: Technical success of SEMS was higher than 80%; however, due to high morbidity and mortality, only 45% of patients had their stent removed. Lower time from diagnosis to SEMS placement and leak size less than 20 mm may be associated with better results.

Outcome of endoscopic self-expandable metal stents in acute malignant colorectal obstruction at a tertiary center.

BACKGROUND: Malignant colorectal obstruction (MCRO) by advanced colonic cancer occurs in 8-13% of colonic cancer patients. Emergent surgery carries a high mortality and morbidity risk. Endoscopic self-expanding metal stents (SEMS) may be used in acute MCRO. AIM: Evaluate clinical outcome of SEMS in acute MCRO and efficacy of SEMS placement considering fluoroscopy guidance. METHODS: Retrospective study of patients with acute MCRO that placed SEMS in a 3 years period. RESULTS: SEMS were placed in 47 patients, followed-up for a median time of 150 days. The intent of stenting was bridge to definitive surgery in 40% of the patients (n = 19) and palliation in the remaining 60% (n = 28). The location of the tumor did not influence the presence of lymph node involvement (p = 0.764) nor metastasis (p = 0.885). Mortality rate at year 1 was 61%. Survival was significantly higher in patients submitted later to combination therapy compared to chemotherapy, surgery or symptomatic treatment (p < 0.001). Fluoroscopy was used in 57% of the procedures. Clinical success was 79%. A second SEMS was needed during the procedure in 6% of the patients. Rate of early and late complications was 11% and 5%, respectively. Fluoroscopy guidance did not influence the occurrence of immediate (p = 0.385), early (p = 0.950) or late complications (p = 0.057). Thirty-three percent of patients underwent surgery at a later stage, with neo-adjuvant therapy in 18%. CONCLUSIONS: SEMS provide a relative safe and successful treatment in a palliative or bridge-to-surgery indication. No significant differences were found in SEMS placement success, early complications or late complications considering fluoroscopy guidance.

Performance of Intracystic Glucose Measurement for the Characterization of Pancreatic Cystic Lesions.

BACKGROUND AND AIMS: Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is essential for the classification of pancreatic cystic lesions (PCLs). Recently, intracystic glucose has been suggested as an alternative to carcinoembryonic antigen (CEA) level as a predictor of mucinous cystic lesions (M-PCLs). This study aims to evaluate the diagnostic performance of intra-cystic glucose in distinguishing between M-PCLs and non M-PCLs (NM-PCLs) and to analyze the possibility of on-site glucose measurement with a standard glucometer. METHODS: Patients with PCLs submitted to EUS-FNA with simultaneous intracystic glucose measurement between 2017 and 2022 were included. The diagnostic performance of glucose versus CEA for the differentiation between M-PCLs and NM-PCLs was compared to a final diagnosis based on the analysis of surgical specimen, intracystic biopsy or, if this data was unavailable, multidisciplinary evaluation. A cut-off of <50 mg/dL was used for the diagnosis of MCLs. Additionally, the agreement between on-site glucose determination with a standard glucometer and laboratory glucose measurement was assessed. RESULTS: Mucinous lesions accounted for 56% of all PCLs. The median values of glucose and CEA for M-PCLs were 18 mg/dL and 286 ng/mL, respectively. Intracystic glucose had a sensitivity and specificity of 93.2% and 76.5%, respectively, for the diagnosis of MCLs (versus 55.6% and 87.5%, respectively, for CEA). The area under the curve was 0.870 for on-site glucose (versus 0.806 for CEA). An excellent correlation was observed between on-site and laboratory glucose measurement (ρ=0.919). CONCLUSIONS: The measurement of intracystic glucose showed superior performance compared with CEA in distinguishing between M-PCLs and NM-PCLs, with excellent correlation between on-site and conventional lab glucose measurement. Thus, on-site intracystic glucose appears to be an excellent biomarker for the characterization of PCLs due to its low cost, high availability, and the need for a minimal cyst fluid volume for its determination.

Deep Learning and Automatic Differentiation of Pancreatic Lesions in Endoscopic Ultrasound: A Transatlantic Study.

INTRODUCTION: Endoscopic ultrasound (EUS) allows for characterization and biopsy of pancreatic lesions. Pancreatic cystic neoplasms (PCN) include mucinous (M-PCN) and nonmucinous lesions (NM-PCN). Pancreatic ductal adenocarcinoma (P-DAC) is the commonest pancreatic solid lesion (PSL), followed by pancreatic neuroendocrine tumor (P-NET). Although EUS is preferred for pancreatic lesion evaluation, its diagnostic accuracy is suboptimal. This multicentric study aims to develop a convolutional neural network (CNN) for detecting and distinguishing PCN (namely M-PCN and NM-PCN) and PSL (particularly P-DAC and P-NET). METHODS: A CNN was developed with 378 EUS examinations from 4 international reference centers (Centro Hospitalar Universitário São João, Hospital Universitario Puerta de Hierro Majadahonda, New York University Hospitals, Hospital das Clínicas Faculdade de Medicina da Universidade de São Paulo). About 126.000 images were obtained-19.528 M-PCN, 8.175 NM-PCN, 64.286 P-DAC, 29.153 P-NET, and 4.858 normal pancreas images. A trinary CNN differentiated normal pancreas tissue from M-PCN and NM-PCN. A binary CNN distinguished P-DAC from P-NET. The total data set was divided into a training and testing data set (used for model's evaluation) in a 90/10% ratio. The model was evaluated through its sensitivity, specificity, positive and negative predictive values, and accuracy. RESULTS: The CNN had 99.1% accuracy for identifying normal pancreatic tissue, 99.0% and 99.8% for M-PCN and NM-PCN, respectively. P-DAC and P-NET were distinguished with 94.0% accuracy. DISCUSSION: Our group developed the first worldwide CNN capable of detecting and differentiating the commonest PCN and PSL in EUS images, using examinations from 4 centers in 2 continents, minimizing the impact of the demographic bias. Larger multicentric studies are needed for technology implementation.

Solid Pseudopapillary Neoplasm of the Pancreas: Unfolding an Intriguing Condition.

Pancreatic cancer is one of the most lethal malignant neoplasms, with a 1-year survival rate after diagnosis of 24%, and a 5-year survival rate of only 9%. While this illustrates the behavior of its main histologic type - ductal adenocarcinoma, there are other histologic subtypes of pancreatic cancer that can harbor excellent prognosis. Solid pseudopapillary neoplasm, described as a rare low-grade malignant neoplasm by the World Health Organization, is the best example of that, having an overall 5-year survival rate of about 97%. Not only the prognosis, but everything about this entity is unique: its histogenesis, epidemiology, presentation, imaging characteristics, cytology features, immunohistochemical profile, and treatment. This explains the urge to improve our understanding about this entity and thus our ability to accurately recognize and manage it. Having this in mind, this article aims to summarize the most relevant topics regarding this entity.

O cancro do pâncreas é uma das neoplasias malignas mais letais, com uma taxa de sobrevida 1 ano após o diagnóstico de 24% e 5 anos após o diagnóstico de apenas 9%. Estes dados espelham, contudo, o comportamento do subtipo histológico mais prevalente − o adenocarcinoma ductal. Porém, nem todas as neoplasias malignas do pâncreas são adenocarcinomas e nem todas estão a associadas a um prognóstico tão reservado. A Neoplasia Pseudopapilar Sólida do Pâncreas é o exemplo disso: descrita pela Organização Mundial da Saúde como uma neoplasia maligna de baixo grau, é um tumor raro associado a um excelente prognóstico, com uma taxa de sobrevida aos 5 anos de 97%. Mais que uma neoplasia com um prognostico peculiarmente favorável, é uma neoplasia única em todas as suas componentes: histogénese, epidemiologia, apresentação clínica, características imagiológicas, citológicas e imunohistoquímicas e no tratamento. Estas particularidades devem estar presentes e consolidadas no raciocínio clínico de qualquer médico, para que estas neoplasias sejam devidamente reconhecidas e tratadas. Neste sentido, foi realizado este artigo de revisão que visa sumariar os mais relevantes tópicos relacionados com esta entidade clínica.

Retrospective analysis of the outcomes of endoscopic submucosal dissection for the diagnosis and treatment of subepithelial lesions in a center with high expertise.

BACKGROUND: Use of endoscopic submucosal dissection (ESD) for the diagnosis and treatment of subepithelial lesions (SELs) is limited in the West, and the best approach for these lesions is still debated. In this study we describe our experience regarding the usefulness, safety and outcomes of ESD for SELs. METHOD: We performed a retrospective analysis of ESD in the diagnosis and treatment of SELs between November 2010 and February 2021. RESULTS: A total of 634 ESDs were reviewed. Fifty-five (9%) were performed in SELs, 6 in the esophagus, 34 in the stomach, and 15 in the rectum. ESD was technically successful in 53 lesions (96%). Most of them (82%) had previous endoscopic ultrasound evaluation, but only 20% had a histological diagnosis previous to the ESD. Neuroendocrine tumors, gastrointestinal stromal tumors, and granular cell tumors accounted for 38% of the procedures, with a 100% rate of en bloc resection and 65% of R0 resection; the main criterion for non-curative resection was a deep positive margin, and none of the patients treated with complementary surgery had lesions on the gastrointestinal wall. Most of the procedures (62%) were performed in lesions with very low malignant potential, providing the definitive diagnosis of SELs where the previous diagnostic workup was inconclusive. We had a total of 2 delayed bleedings and 1 perforation, all treated endoscopically. CONCLUSION: Our real-life experience showed that ESD can be an effective and safe diagnostic tool for undetermined SELs, as well as an effective treatment for neoplastic SELs with malignant potential.

Deep Learning for Automatic Differentiation of Mucinous versus Non-Mucinous Pancreatic Cystic Lesions: A Pilot Study.

Endoscopic ultrasound (EUS) morphology can aid in the discrimination between mucinous and non-mucinous pancreatic cystic lesions (PCLs) but has several limitations that can be overcome by artificial intelligence. We developed a convolutional neural network (CNN) algorithm for the automatic diagnosis of mucinous PCLs. Images retrieved from videos of EUS examinations for PCL characterization were used for the development, training, and validation of a CNN for mucinous cyst diagnosis. The performance of the CNN was measured calculating the area under the receiving operator characteristic curve (AUC), sensitivity, specificity, and positive and negative predictive values. A total of 5505 images from 28 pancreatic cysts were used (3725 from mucinous lesions and 1780 from non-mucinous cysts). The model had an overall accuracy of 98.5%, sensitivity of 98.3%, specificity of 98.9% and AUC of 1. The image processing speed of the CNN was 7.2 ms per frame. We developed a deep learning algorithm that differentiated mucinous and non-mucinous cysts with high accuracy. The present CNN may constitute an important tool to help risk stratify PCLs.

Exosomal glypican-1 is elevated in pancreatic cancer precursors and can signal genetic predisposition in the absence of endoscopic ultrasound abnormalities.

BACKGROUND: Individuals within specific risk groups for pancreatic ductal adenocarcinoma (PDAC) [mucinous cystic lesions (MCLs), hereditary risk (HR), and new-late onset diabetes mellitus (NLOD)] represent an opportunity for early cancer detection. Endoscopic ultrasound (EUS) is a premium image modality for PDAC screening and precursor lesion characterization. While no specific biomarker is currently clinically available for this purpose, glypican-1 (GPC1) is overexpressed in the circulating exosomes (crExos) of patients with PDAC compared with healthy subjects or those harboring benign pancreatic diseases. AIM: To evaluate the capacity of GPC1+ crExos to identify individuals at higher risk within these specific groups, all characterized by EUS. METHODS: This cross-sectional study with a prospective unicentric cohort included 88 subjects: 40 patients with MCL, 20 individuals with HR, and 20 patients with NLOD. A control group (CG) was submitted to EUS for other reasons than pancreatic pathology, with normal pancreas and absence of hereditary risk factors (n = 8). The inclusion period was between October 2016 and January 2019, and the study was approved by the Ethics Committee of Centro Hospitalar Universitário de São João, Porto, Portugal. All patients provided written informed consent. EUS and blood tests for quantification of GPC1+ crExos by flow cytometry and carbohydrate antigen 19-9 (CA 19-9) levels by ELISA were performed in all subjects. EUS-guided tissue acquisition was done whenever necessary. For statistical analysis, SPSS® 27.0 (IBM Corp., Armonk, NY, United States) version was used. All graphs were created using GraphPad Prism 7.00 (GraphPad Software, San Diego, CA, United States). RESULTS: Half of MCLs harbored worrisome features (WF) or high-risk stigmata (HRS). Pancreatic abnormalities were detected by EUS in 10.0% and 35.0% in HR and NLOD individuals, respectively, all considered non-malignant and "harmless." Median levels of GPC1+ crExos were statistically different: MCL [99.4%, interquartile range (IQR): 94.9%-99.8%], HR (82.0%, IQR: 28.9%-98.2%), NLOD (12.6%, IQR: 5.2%-63.4%), and CG (16.2%, IQR: 6.6%-20.1%) (P < 0.0001). Median levels of CA 19-9 were within the normal range in all groups (standard clinical cut-off of 37 U/mL). Within HR, individuals with a positive history of cancer had higher median levels of GPC1+ crExos (97.9%; IQR: 61.7%-99.5%), compared to those without (59.7%; IQR: 26.3%-96.4%), despite no statistical significance (P = 0.21). Pancreatic cysts with WF/HRS were statistically associated with higher median levels of GPC1+ crExos (99.6%; IQR: 97.6%-99.8%) compared to those without (96.5%; IQR: 81.3%-99.5%) (P = 0.011), presenting an area under the receiver operating characteristic curve value of 0.723 (sensitivity 75.0% and specificity 67.7%, using a cut-off of 98.5%; P = 0.012). CONCLUSION: GPC1+ crExos may act as biomarker to support the diagnosis and stratification of PDAC precursor lesions, and in signaling individuals with genetic predisposition in the absence of EUS abnormalities.