Recent Advances in Intrahepatic Biliary Epithelial Heterogeneity.

Biliary epithelium (i.e., cholangiocytes) is a heterogeneous population of epithelial cells in the liver, which line small and large bile ducts and have individual responses and functions dependent on size and location in the biliary tract. We discuss the recent findings showing that the intrahepatic biliary tree is heterogeneous regarding (1) morphology and function, (2) hormone expression and signaling (3), response to injury, and (4) roles in liver regeneration. This review overviews the significant characteristics and differences of the small and large cholangiocytes. Briefly, it outlines the in vitro and in vivo models used in the heterogeneity evaluation. In conclusion, future studies addressing biliary heterogeneity's role in the pathogenesis of liver diseases characterized by ductular reaction may reveal novel therapeutic approaches.

Gastric Cancer Risk in Patients with Long-Term Use of Proton Pump Inhibitors: A Systematic Review and Meta-Analysis of Observational and Interventional Studies.

BACKGROUND: A growing number of studies that differ in design, quality, and results report an association between the use of proton pump inhibitors (PPIs) and the risk of gastric cancer (GC). We conducted a systematic review and meta-analysis, when possible, of observational and interventional studies examining PPI use and risk of GC. METHODS: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We identified studies fully published in English through January 2023 using MeSH and non-MeSH keywords. We used random effects models to calculate pooled risk estimates with 95% confidence interval (CI) between PPI use and overall GC, cardia GC, and non-cardia GC. We estimated heterogeneity (I2) among studies. We examined the effect of study design and quality, GC site, H. pylori infection, and PPI duration. We assessed quality using the Newcastle-Ottawa Quality Assessment Scale and Risk Of Bias In Non-randomized Studies of Interventions. RESULTS: We identified 15 observational studies, of which 13 were included in the meta-analysis (six cohort and seven case-control). There was a modest 1.67-fold increase in overall GC risk (95% CI 1.39, 2.00) and no increase in cardia GC risk [odds ratio (OR) 1.12; 95% CI 0.80, 1.56] with PPI use. However, there was high heterogeneity (I2 = 61.3%, p = 0.004) among studies. All but one study had at least moderate risk of bias. In the six studies accounting for H. pylori, GC risk associated with PPI use increased slightly (OR 1.78; 95% CI 1.25, 2.52). Duration response was not reported consistently to allow pooled estimates. We identified only one interventional randomized controlled study that included GC as an outcome of interest, and it did not show increased GC risk. CONCLUSIONS: The overall available evidence is not supportive of a meaningful change in GC risk, either cardia or non-cardia, with PPI use.

The relationship between postoperative opioid consumption and the incidence of hypoxemic events following total hip arthroplasty: a post hoc analysis.

Background: Postoperative opioid analgesia may cause respiratory depression. We assessed whether following total hip arthroplasty, placebo-adjusted reductions in morphine consumption at 48 hours with parecoxib (47.0%), propacetamol (35.1%) or parecoxib plus propacetamol (67.9%) translated into a reduction in hypoxemic events. Methods: This was a post hoc analysis of a randomized, placebo-controlled, noninferiority study. Patients were randomly assigned to receive intravenous parecoxib (40 mg twice daily), propacetamol (2 g 4 times daily), parecoxib plus propacetamol (40 mg twice daily + 2 g 4 times daily) or placebo. Dose, date and time of morphine administration via patient-controlled analgesia were monitored throughout the study. In patients not receiving supplemental oxygen, peripheral blood oxygenation was assessed continuously for 48 hours after surgery. Hypoxemia was defined as peripheral oxygen saturation less than 90%. The times and oximeter readings of hypoxemic events were recorded. Pearson correlation coefficient was used to assess for correlations between cumulative morphine consumption at 48 hours and mean number of hypoxemic events. Results: A significantly smaller proportion of patients who received the combined treatment with parecoxib and propacetamol had hypoxemia versus placebo (2.8% v. 13.2%, p < 0.05), and the mean number of hypoxemic events was significantly smaller for parecoxib (0.12), propacetamol (0.06) and parecoxib plus propacetamol (0.03) versus placebo (0.36; all p < 0.05). There was no correlation between the reduction in cumulative morphine consumption at 48 hours and the mean number of hypoxemic events in any treatment group (all p > 0.1). Conclusion: Following total hip arthroplasty, a greater than 70% reduction in morphine consumption may be necessary to translate into a corresponding reduction in hypoxemic events.

Contexte: L'utilisation d'analgésiques opioïdes en période postopératoire peut provoquer une dépression respiratoire. Nous avons voulu déterminer si, après une arthroplastie totale de la hanche, une réduction de la consommation de morphine à 48 heures par l'administration de parécoxib (47,0 %), de propacétamol (35,1 %) ou d'une combinaison des deux (67,9 %) ­ avec ajustement selon un groupe placebo ­ se traduirait par une réduction du nombre d'épisodes d'hypoxémie. Méthodes: Nous avons effectué une analyse post hoc d'une étude randomisée de non-infériorité avec témoins sous placebo. Après une répartition aléatoire, chaque patient a reçu par intraveineuse du parécoxib (40 mg 2 fois par jour), du propacétamol (2 g 4 fois par jour), une combinaison de parécoxib et de propacétamol (40 mg 2 fois par jour + 2 g 4 fois par jour) ou un placebo. Tout au long de l'étude, la dose, la date et le moment de l'administration de morphine contrôlée par le patient ont été notés. Chez les patients qui ne recevaient pas d'oxygène d'appoint, la saturation périphérique en oxygène a été surveillée de manière continue pendant les 48 heures suivant l'opération. L'hypoxémie a été définie comme une saturation inférieure à 90 %. Le moment et les données d'oxymétrie ont été notés pour chaque épisode d'hypoxémie. Le coefficient de corrélation de Pearson a été utilisé pour évaluer la présence de corrélations entre la consommation cumulative de morphine durant les premières 48 heures et le nombre moyen d'épisodes d'hypoxémie. Résultats: Une proportion significativement plus faible de patients ayant reçu le traitement combiné de parécoxib et de propacétamol ont connu des épisodes d'hypoxémie, comparativement aux patients qui avaient reçu le placebo (2,8 % c. 13,2 %, p < 0,05), et le nombre moyen d'épisodes d'hypoxémie était significativement plus faible dans le groupe ayant reçu du parécoxib (0,12), du propacétamol (0,06) ou une combinaison de parécoxib et de propacétamol (0,03), par rapport au groupe placebo (0,36, p < 0,05 pour tous). Aucune corrélation n'a été observée entre la réduction de la quantité totale de morphine consommée à 48 heures et le nombre moyen d'épisodes d'hypoxémie pour tous les groupes (p > 0,1 pour tous). Conclusion: Après une arthroplastie totale de la hanche, une réduction de la consommation de morphine de plus de 70 % pourrait être nécessaire pour obtenir une réduction correspondante du nombre d'épisodes d'hypoxémie.

Ectopic fibroblast growth factor receptor 1 promotes inflammation by promoting nuclear factor-κB signaling in prostate cancer cells.

Initiation of expression of fibroblast growth factor receptor 1 (FGFR1) concurrent with loss of FGFR2 expression is a well-documented event in the progression of prostate cancer (PCa). Although it is known that some FGFR isoforms confer advantages in cell proliferation and survival, the mechanism by which the subversion of different FGFR isoforms contributes to PCa progression is incompletely understood. Here, we report that fibroblast growth factor (FGF) promotes NF-κB signaling in PCa cells and that this increase is associated with FGFR1 expression. Disruption of FGFR1 kinase activity abrogated both FGF activity and NF-κB signaling in PCa cells. Of note, the three common signaling pathways downstream of FGFR1 kinase, extracellular signal-regulated kinase 1/2 (ERK1/2), phosphoinositide 3-kinase (PI3K/AKT), and phosphoinositide phospholipase Cγ (PLCγ), were not required for FGF-mediated NF-κB signaling. Instead, transforming growth factor ß-activating kinase 1 (TAK1), a central regulator of the NF-κB pathway, was required for FGFR1 to stimulate NF-κB signaling. Moreover, we found that FGFR1 promotes NF-κB signaling in PCa cells by reducing TAK1 degradation and thereby supporting sustained NF-κB activation. Consistently, Fgfr1 ablation in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model reduced inflammation in the tumor microenvironment. In contrast, activation of the FGFR1 kinase in the juxtaposition of chemical-induced dimerization (CID) and kinase 1 (JOCK1) mouse model increased inflammation. As inflammation plays an important role in PCa initiation and progression, these findings suggest that ectopically expressed FGFR1 promotes PCa progression, at least in part, by increasing inflammation in the tumor microenvironment.

Safety and efficacy of ertugliflozin in Asian patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy: VERTIS Asia.

AIM: Phase III, randomized, double-blind study evaluating the efficacy and safety of ertugliflozin in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin, including evaluation in the China subpopulation. MATERIALS AND METHODS: A 26-week, double-blind study of 506 Asian patients (80.2% from mainland China), randomized 1:1:1 to placebo, ertugliflozin 5- or 15 mg, was performed. Primary endpoint was change from baseline in HbA1c at week 26. Secondary endpoints were change from baseline at week 26 in fasting plasma glucose (FPG), body weight (BW), systolic/diastolic blood pressure (SBP/DBP), and proportion of patients with HbA1c <7.0%. Hypotheses for the primary endpoint and FPG and BW secondary endpoints were tested in the China subpopulation. RESULTS: At week 26, least squares mean (95% CI) change from baseline HbA1c was significantly greater with ertugliflozin 5- and 15 mg versus placebo: -1.0% (-1.1, -0.9), -0.9% (-1.0, -0.8), -0.2% (-0.3, -0.1), respectively. Ertugliflozin significantly reduced FPG, BW and SBP. Reductions in DBP with ertugliflozin were not significant. At week 26, 16.2%, 38.2% and 40.8% of patients had HbA1c <7.0% with placebo, ertugliflozin 5- and 15 mg, respectively. 59.3%, 56.5% and 53.3% of patients experienced adverse events with placebo, ertugliflozin 5- and 15 mg, respectively. Incidence of symptomatic hypoglycaemia was higher for ertugliflozin 15 mg vs placebo. Results in the China subpopulation were consistent. CONCLUSIONS: Ertugliflozin significantly improved glycaemic control and reduced BW and SBP in Asian patients with T2DM. Ertugliflozin was generally well-tolerated. Results in the China subpopulation were consistent with the overall population. ClinicalTrials.gov: NCT02630706.

Intranasal hydromorphone for treatment of acute pain in children: A pilot study.

OBJECTIVES: We aimed to describe the analgesic efficacy, duration of analgesia, and adverse event profile associated with intranasal hydromorphone in children with acute pain presenting to an emergency department. METHODS: Prospective dose titration pilot study of otherwise healthy children 4 to 17-years-old with moderate to severe pain who required a parenteral opioid. All patients received an initial intranasal hydromorophone dose of 0.03 mg/kg. The need for additional analgesia was assessed at 15 and 30 min; an additional 0.015 mg/kg was given at each assessment, if required. Need for rescue analgesic, pain intensity and adverse events were assessed until 6 h after hydromorphone administration or until patients were discharged, underwent a procedure to treat their painful condition, or received a rescue analgesic. RESULTS: We enrolled 35 children. Fifteen, 11, and 9 children required a total dose of 0.03, 0.045, and 0.06 mg/kg, respectively. Patients in each dose group experienced an absolute decrease in pain score of ≥3/10 and percent reduction >40% within 5-15 min of completing dose-titration administration of hydromorphone. Duration of analgesia (i.e. time until rescue analgesic administered) >1 h was observed in 85.7% of patients. Patients not requiring rescue analgesics had mild or no pain until discharged or their painful conditions were treated. Three (8.6%) patients required a rescue analgesic <1 h after hydromorphone administration. There were no major adverse events. CONCLUSIONS: Intranasal hydromorphone led to rapid, clinically significant and frequently sustained decreases in pain intensity in children. No major adverse events were observed in this preliminary sample. Clinical Trials Registration Number: NCT02437669.

Efficacy and safety of first-line sunitinib in Chinese patients with metastatic renal cell carcinoma.

AIM: We report the first prospective study of sunitinib for metastatic renal cell carcinoma (mRCC) in China. METHODS: Chinese mRCC patients received first-line sunitinib 50 mg daily (4/2 regimen). Overall survival (OS), progression-free survival (PFS), objective response rate and safety were assessed. Potential efficacy biomarkers were explored in post hoc analyses. RESULTS: Median PFS was 61.7 weeks; median OS was 133.4 weeks; objective response rate was 31.1%. Most frequent adverse events (AEs) were: hand-foot syndrome (63.8%), decreased white blood cell count (52.4%), fatigue (51.4%) and decreased platelet count (51.4%). AEs were identified that predicted longer PFS and OS. CONCLUSION: Sunitinib showed efficacy and manageable AE profile in treatment-naive Chinese mRCC patients. Larger prospective studies are required to confirm identified AEs as predictors of efficacy.

Preoperative Low-Dose Aspirin Exposure and Outcomes After Emergency Neurosurgery for Traumatic Intracranial Hemorrhage in Elderly Patients.

BACKGROUND: Antiplatelet medications are usually discontinued before elective neurosurgery, but this is not an option for emergent neurosurgery. We performed a retrospective cohort study to examine whether preoperative aspirin use was associated with worse outcomes after emergency neurosurgery in elderly patients. METHODS: We analyzed all cases of emergency neurosurgical procedures for traumatic intracranial hemorrhage from 2008 to 2012 at a level 1 trauma center. Demographics, comorbidities, and outcomes were compared for patients ≥65 years by preoperative aspirin exposure. Exclusion criteria were: (1) polytrauma, (2) concomitant use of other preoperative anticoagulants or antiplatelet agents, (3) surgical indication other than subdural, extradural, or intraparenchymal hemorrhage, and (4) repeat neurosurgical procedures within a single admission. Estimated intraoperative blood loss, postprocedural intracranial bleeding requiring reoperation, death in hospital, intensive care unit, and hospital lengths of stay and perioperative blood product transfusion from 48 hours before 48 hours after surgery were the study outcomes. We also examined whether platelet transfusion had an impact on outcomes for patients on aspirin. RESULTS: The cohort included 171 patients. Patients receiving preoperative aspirin (n = 87, 95% taking 81 mg/day) were the same age as patients not receiving aspirin (n = 84; 78.3 ± 7.8 vs 75.9 ± 7.9 years, P > .05), had slightly higher admission Glasgow Coma Scale scores (12.8 ± 3.4 vs 11.4 ± 4, P = .02) and tended to have more coronary artery disease (P< .05). Adjusted for Glasgow Coma Scale and coronary artery disease, patients receiving preoperative aspirin had a higher odds of perioperative platelet transfusion (adjusted odds ratio 9.89, 95% confidence interval, 4.24-26.25). There were no other differences in outcomes between the 2 groups. Preoperative or intraoperative platelet transfusion was not associated with better outcomes among aspirin patients. CONCLUSIONS: In patients age ≥65 years undergoing emergency neurosurgery for traumatic intracranial hemorrhage, preoperative low-dose aspirin treatment was not associated with increased perioperative bleeding, hospital lengths of stay, or in-hospital mortality.

Efficacy and safety of celecoxib in chinese patients with ankylosing spondylitis: a 6-week randomized, double-blinded study with 6-week open-label extension treatment.

BACKGROUND: Nonsteroidal anti-inflammatory drugs are the first-line option for treating ankylosing spondylitis (AS) in China. However, no large-scale controlled trials have been conducted in this ethnic population. OBJECTIVE: To evaluate the efficacy and safety of 6 weeks' treatment with celecoxib in patients with AS in China. METHODS: This Phase 3, double-blind, parallel-group study randomized patients with AS aged ≥18 to 65 years 1:1 to receive celecoxib 200 mg once daily or diclofenac sustained release 75 mg once daily. After 6 weeks, patients could use celecoxib 400 mg once daily or maintain blinded therapy. The primary efficacy end point was mean change from baseline at Week 6 for Patient's Global Assessment of Pain Intensity score (100-mm visual analog scale). Noninferiority was established if the upper bound of the CI was <10 mm. Secondary objectives included patients' and physicians' assessments of disease activity, change from baseline in C-reactive protein level, and safety. RESULTS: In the per-protocol analysis set the least squares mean change from baseline in the Patient's Global Assessment of Pain Intensity score at Week 6 was -23.8 mm and -27.1 mm in patients receiving celecoxib (n = 111) and diclofenac (n = 108), respectively. The 2-sided 95% CI for the treatment difference (celecoxib - diclofenac) was -2.2 to 8.8. Overall, 4.2% and 6.7% of patients in the celecoxib and diclofenac groups, respectively, reported treatment-related adverse events. All were mild to moderate in severity. CONCLUSIONS: Celecoxib 200 mg once daily is noninferior to diclofenac sustained release 75 mg once daily for pain treatment in Chinese patients with AS. ClinicalTrials.gov identifier: NCT00762463.

An eruption of basal cell carcinoma after ibrutinib.

Ibrutinib is a therapy targeting tyrosine kinase that has been used for various hematologic malignancies. It is associated with a variety of adverse effects, several of which are dermatologic. While there are few discussions of basal cell carcinoma as an adverse event, there have not yet been reports of a significantly increased incidence. Here, we present a patient with no dermatologic history who subsequently developed nearly 30 incidents of basal cell carcinoma after starting ibrutinib, leading to discontinuation of the therapy.

Idiopathic toxic epidermal necrolysis in a pediatric patient.

Stevens-Johnson syndrome and toxic epidermal necrolysis are potentially life-threatening cutaneous diseases that are rarely seen in the pediatric population. We describe a case of a 7-year-old female who presented with fever, cough, mucosal erosions, and a widespread maculopapular eruption with flaccid bullae for 4 days. She had no sick contacts and no new medications, supplements, or vitamins. She then rapidly developed ulcerations in her oral mucosa and genital area, numerous scattered tense bullae throughout her body, and patchy areas of desquamation. Infectious disease workup revealed positivity only for Bordetella parapertussis, and she was subsequently diagnosed with idiopathic toxic epidermal necrolysis.

Intramuscular ziprasidone versus haloperidol for managing agitation in Chinese patients with schizophrenia.

Intramuscular (IM) antipsychotics are preferred for efficient control of agitation symptoms. Previous studies have demonstrated that IM ziprasidone is efficacious and safe for treatment of agitation in schizophrenia. However, clinicians now recognize that racial differences may contribute to altered therapeutic response and tolerability. This study compared the efficacy and tolerability of IM ziprasidone versus IM haloperidol for the management of agitation in Chinese subjects with schizophrenia. Subjects with acute schizophrenia were randomized to either ziprasidone (n = 189, 10 to 20 mg as required up to a maximum of 40 mg/d) or haloperidol (n = 187, 5 mg every 4 to 8 hours to a maximum of 20 mg/d) for 3 days. Psychiatric assessments and adverse events were assessed at baseline, 2, 4, 24, 48, and 72 hours. In the ziprasidone group, 2.1% of subjects discontinued versus 3.7% in the haloperidol group. The least squares mean change (SE) from baseline to 72 hours in Brief Psychiatry Rating Scale total score was -17.32 (0.7) for ziprasidone (n = 167) and -18.44 (0.7) for haloperidol (n = 152), with a 95% confidence interval treatment difference of -0.7 to 2.9. Fewer subjects experienced adverse events after ziprasidone (n = 54, 28.6%) than haloperidol (n = 116, 62.0%), with a notably higher incidence of extrapyramidal symptoms in the haloperidol group (n = 69, 36.9%) compared to the ziprasidone group (n = 4, 2.1%). For controlling agitation in schizophrenia in this Chinese study, ziprasidone had a favorable tolerability profile and comparable efficacy and safety compared to haloperidol.

A Case of Eosinophilic Dermatosis of Hematologic Malignancy Treated With Narrow-Band Ultraviolet B (NBUVB).

Chronic lymphocytic leukemia (CLL) is one of the most common leukemias in adults. It has been associated with a number of dermatologic manifestations, such as leukemia cutis and erythema multiforme. Among the rarer of these findings is eosinophilic dermatosis of hematologic malignancy (EDHM). EDHM was originally characterized as a hypersensitive insect bite-like reaction, despite most patients having no distinct recollection of being bit or having any risk of exposure. Typically, EDHM presents as a pruritic, erythematous eruption, often with papulovesicular lesions, throughout the body. Due to its relapsing course, a number of treatment methods have been proposed, but no standard of care has been established. In this report, we present a recalcitrant case of EDHM in a patient with CLL that responded well to treatment with narrow-band ultraviolet B (NBUVB) light therapy.

Extranodal Natural Killer/T-cell Lymphoma Isolated to the Leg: A Case Report.

Extranodal natural killer/T-cell lymphoma (ENKTL) is a subtype of non-Hodgkin's lymphoma, and it is exceedingly rare in North America. The "extranasal" subtype of ENKTL frequently involves the skin and typically has an aggressive course with no current standard of treatment available. In this report, we present a case of cutaneous ENKTL in an otherwise healthy middle-aged male.

Clinical presentation of idiopathic CD4 lymphocytopenia.

An otherwise healthy man (60s) presented to our emergency department 5 years ago with stroke-like symptoms. Underlying cryptococcal meningitis infection was ultimately discovered leading to extensive workup to rule out underlying malignancy and HIV infection. Results returned negative with the exception of a CD4 count less than 25 /mm3 Several years later, he again presented to the emergency department with fatigue. He was then found to have severe anaemia with underlying Mycobacterium avium complex (MAC) infection involving the bone marrow and a left psoas abscess. After multiple courses of antibiotic therapy targeted towards MAC, the infection persisted due to bone marrow involvement. By diagnosis of exclusion, he was eventually found to have idiopathic CD4 lymphocytopenia. Here we describe this condition, which has the potential to cause significant morbidity, and obligates the need for high clinical suspicion for timely diagnosis to enhance life quality and outcomes for patients.

Pancreatic Cancer Presenting to the Dermatology Clinic.

In patients with skin of color, jaundice may present more discretely, which can lead to a delay in diagnosing underlying disease and widening racial disparity gaps. It is important for clinicians to recognize the subtleties of jaundice to achieve the most optimal outcomes for patients. Careful examination of the sclera and palms, sites where yellowing is most obvious, as well as asking patients if they have noticed any skin color changes can be beneficial. We present a case of a patient who presented to the dermatology clinic with jaundice and pruritus refractory to standard treatment, ultimately leading to a diagnosis of pancreatic cancer.

Pediatric health care use during the COVID-19 pandemic: Lessons learned from the initial 2020 wave.

Objective: During the height of the coronavirus disease-2019 (COVID-19) pandemic, there was a decline and shift in pediatric medical care use. We aimed to assess changes to pediatric medical use and perceptions/barriers that influenced caregivers' decision-making during the New York State mandated lockdown from March 22 to June 8, 2020, in a population that opted to use the pediatric emergency department (PED) during this period. This study was conducted in New York City (NYC), one of the epicenters at the height of the COVID-19 pandemic. Methods: From June 14 to December 28, 2020, a convenience sample of caregivers who brought children 0-17 years to a NYC PED completed a survey. Results: Participants in the survey included 290 caregivers: 76% were Hispanic; 91% reported having accessed medical care when their children were ill during the lockdown. In-person primary care visits decreased from 64% before to 9% during lockdown; 28% missed well-child checkups or vaccinations, and 26% missed specialist appointments. Telemedicine usage increased from 10% to 54%; none reported lack of internet or electronic devices as barriers to using telemedicine. Regarding access to care: 36% perceived increased difficulty during the lockdown, whereas 56% felt no difference. Barriers included fear of contracting COVID-19 and government advice to avoid health care visits for minor problems. Conclusion: During the initial wave of the COVID-19 pandemic, medical care shifted from an in-person to a virtual platform. Identification of factors and barriers surrounding caregivers' decision-making may positively inform strategies toward future public health emergencies.

Proteomes of Extracellular Vesicles From Pancreatic Cancer Cells and Cancer-Associated Fibroblasts.

OBJECTIVES: Extracellular vesicles (EVs) are lipid bound vesicles secreted by cells into the extracellular environment. Studies have implicated EVs in cell proliferation, epithelial-mesenchymal transition, metastasis, angiogenesis, and mediating the interaction of tumor cells and microenvironment. A systematic characterization of EVs from pancreatic cancer cells and cancer-associated fibroblasts (CAFs) would be valuable for studying the roles of EV proteins in pancreatic tumorigenesis. METHODS: Proteomic and functional analyses were applied to characterize the proteomes of EVs released from 5 pancreatic cancer lines, 2 CAF cell lines, and a normal pancreatic epithelial cell line (HPDE). RESULTS: More than 1400 nonredundant proteins were identified in each EV derived from the cell lines. The majority of the proteins identified in the EVs from the cancer cells, CAFs, and HPDE were detected in all 3 groups, highly enriched in the biological processes of vesicle-mediated transport and exocytosis. Protein networks relevant to pancreatic tumorigenesis, including epithelial-mesenchymal transition, complement, and coagulation components, were significantly enriched in the EVs from cancer cells or CAFs. CONCLUSIONS: These findings support the roles of EVs as a potential mediator in transmitting epithelial-mesenchymal transition signals and complement response in the tumor microenvironment and possibly contributing to coagulation defects related to cancer development.