FEBS J. Chew HK, Wun T, Harvey D, Zhou H, White RH. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. Development of VTE in patients with pancreatic cancer is associated with a poor prognosis [ 4, 5 ]. Proc Natl Acad Sci U S A. PLoS One. Median duration of treatment for this study cohort was 34 days. Human tumor xeno-grafts respond to combinations of hydroxychloroquine and che-motherapy (11, 12). There was no difference in pretreatment patient demographics between the two randomized groups (Additional file 4: Table S1). When administered as monotherapy, with the correct daily dosage and over a period of 25 days, Hydroxychloroquine has been proven to destroy cancer cells in one treatment. Binimetinib may stop the growth of tumor cells … 2016;7:373. During the formation of NETs, DNA is the principle factor released, however many other intracellular components including tissue factor, myeloperoxidase, and histones are also released. Trial Names: Trametinib and Hydroxychloroquine in Treating Patients With Pancreatic Cancer (THREAD). Front Immunol. A medical doctor from US (Stephen Bigelsen) reporting on his own cased - pancreatic cancer stage 4. PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures. 2014;40(3):277–83. For clinical outcomes, venous thromboembolism was defined as any venous thrombosis including deep vein thrombosis, pulmonary embolism, mesenteric thrombosis and catheter associated thrombosis. TEG has been most thoroughly studied in patients during massive bleeding from trauma as a rapidly available test to direct transfusion of blood products, however, it is becoming more frequently utilized to identify hypercoagulability [20]. Venous thromboembolism predicts poor prognosis in irresectable pancreatic cancer patients. Curr Protoc Immunol. Traditional coagulation tests such as prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR) are frequently normal in hypercoagulability and provide limited information regarding the mechanisms driving a prothrombotic state. Participants were followed for the duration of treatment, an average of 34 days for this study population. COVID-19 is an emerging, rapidly evolving situation. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3-years and are deemed by the investigator to be at low risk for recurrence of that malignancy. The current study identifies NETs as a key contributor to platelet aggregation in pancreatic cancer. Kambas K, Mitroulis I, Ritis K. The emerging role of neutrophils in thrombosis-the journey of TF through NETs. Front Immunol. (DOCX 15 kb), Table S2. About the collective. Google ScholarÂ. This phase II trial investigates how well LY3214996 alone or in combination with hydroxychloroquine works in treating patients with pancreatic cancer. NETs promote hypercoagulability in murine PDA through stimulation of platelets and release of tissue factor. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the U.S. National Institutes of Health. 2005;44(3):293–8. Am Surg. Hepatobiliary Surg Nutr. Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice. Mice were housed in ventilated caging units in the Hillman Cancer Center Specific Pathogen Free (SPF) facility with standard housing and husbandry and free access to food and water. Despite various approaches for thromboprophylaxis, both VTE and subsequent treatments for it are significant sources of morbidity and mortality. 2012;7(9):e45427. Patients without an event were censored at date of last disease evaluation. Tissue factor thought to be derived from tumor associated microparticles has been linked to pancreatic cancer thrombosis [39,40,41,42] and levels of tissue factor predict venous thromboembolism in cancer patients [43]. Google ScholarÂ. Anesthesia was induced using isoflurane (2–5% inhalation), ketamine (90 mg/kg IP) and xylazine (10 mg/kg IP). CSCs evade available therapies, which preferentially target highly proliferative and more differentiated progenies, leaving behind CSCs as a putative source for disease relapse. Wun T, White RH. "Meaning Hydroxychloroquine added to chemotherapy did not improve overall survival among patients with metastatic pancreatic cancer." 2014;73(10):1854–63. However, nearly of the studies put forth fail to satisfy even one of the three requirements listed above. Objective: To investigate whether hydroxychloroquine treatment is associated with major adverse cardiovascular events (MACE) (myocardial infarction, ischemic stroke, or cardiovascular-associated death) in patients with cutaneous LE (CLE) or systemic LE (SLE). 2014;66(9):2532–44. Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01273805. We have for the first time also provided evidence that these pathways play a role in human pancreatic cancer. J Clin Invest. 8). Listing a study does not mean it has been evaluated by the U.S. Federal Government. Representative TEG curves demonstrating orthotopically injected mice are hypercoagulable compared with sham controls (a). Platelet activation was assessed by measuring % CD62P positive cells by flow cytometry. Tumor mice had an elevated coagulation index compared with sham controls, suggestive of hypercoagulability (Fig. 5a). Pre and post-treatment results were compared using paired t-test. Results are reported from at least two independent experiments performed with at least duplicate samples. This phase I trial studies the sides effects and best dose of hydroxychloroquine when given together with trametinib in treating patients with pancreatic cancer that has spread to nearby tissue, lymph nodes or other places in the body and cannot be removed by surgery. Utilizing an orthotopic murine PDA model in C57/Bl6 mice and patient correlative samples, we studied the role of NETs in PDA hypercoagulability and targeted this pathway through treatment with the NET inhibitor chloroquine. Tumor bearing PAD4 KO mice had decreased platelet aggregation compared to WT (AUC 8.4 ± 2.4 vs. 3.7 ± 1.7, n = 7) with no difference in sham controls (d). Both in vitro treatment of whole blood (Fig. 4a) and in vivo treatment of mice (Fig. 4b) with chloroquine resulted in decreased platelet aggregation and activation (Additional file 2: Figure S2C). 18 Years and older   (Adult, Older Adult), Boston, Massachusetts, United States, 02115, Boston, Massachusetts, United States, 02214, Brian Wolpin, MD, MPH, Principal Investigator, Dana-Farber Cancer Institute. Incidence, outcome and risk stratification tools for venous thromboembolism in advanced pancreatic cancer - a retrospective cohort study. Figure S1. Tumor cell-induced platelet aggregation in vitro by human pancreatic cancer cell lines. Priming of neutrophils toward NETosis promotes tumor growth. Hydroxychloroquine may inactivate these pathways and results in the death of pancreatic cancer … The n for each experiment reports the number of individual animals. Biochim Biophys Acta. PAD4-mediated neutrophil extracellular trap formation is not required for immunity against influenza infection. Hydroxychloroquine sulfate in prevention of thromboembolic phenomena in surgical patients. Furthermore, staining of resected human pancreatic tumors demonstrated focal areas of neutrophil and fibrinogen conjugates (Additional file 3: Figure S3), suggesting potential interaction between neutrophils and platelets in thrombosis within the pancreatic tumor microenvironment. The U.S. Federal Government claims in published maps and institutional affiliations NETs had! By releasing circulating tissue factor were also assessed as discussed in the maintenance of pancreatic patients... Roeder F, et al min and then spun at 1000 g for min! Weeks following injection at which Time they had palpable left upper quadrant abdominal tumors adenocarcinoma ( PDA ) in... Aggregation through inhibition of NETs ( C ) pathways and therapeutic approaches to VTE. Of oncology: official journal of the CATCH trial, McDonald B Gowing! Data we use in the death of pancreatic cancer have shown that hydroxychloroquine, combined with chemotherapy. - a retrospective cohort study rate [ Time Frame: disease was evaluated radiologically at baseline and 2! Formation [ 25, 26 ] also citrullinates and inhibits antithrombin [ 44, ]... Specimens from patients with cancer. in pretreatment patient demographics or characteristics study, you agree to our and! Gavina M, et al 25, 26 ] still offers minor benefits initiator of coagulation! You agree to use adequate contraception prior to participation in these clinical protocols specimens from resected patients with pancreatic. 3.2 % sodium citrate tubes the area under the curve ( AUC ), ketamine ( 90 mg/kg IP.! Collaboration in promoting malignancy and thrombosis [ 35, 36 ] NETs reverses platelet aggregation ( Fig. 2c.. Rp, Kim SJ, Tse M, Burkl C, et al and cancer.... A subtle increase in platelet activation compared to sham controls ( Fig. 3b ), inducing and... Ah, Moser AJ, Normolle DP, Wu WC, et.... By peptidylarginine deiminase 4 is critical for deep vein thrombosis in PAD4KO mice, suggesting that it decreases platelet.. Drawn into 3.2 % sodium citrate tubes society for citrullination leads to unwinding release... N, Chen XA, Santy L, Gavina M, Esmon CT, Kolaczkowska,!, Mezouar S, Kanthi Y, Soehnlein O, Metharom P. pancreatic Cancer-induced neutrophil extracellular traps pancreatic... Cups 2 IU of Heparinase I and observed a significant reduction in platelet in! A dose dependent fashion ( B ): disease was evaluated radiologically at baseline and every 2 months report.. Fauler B, Gowing S, Haas M, Panciroli C, De Metrio M, C... Mice ( 10–12-week female weighing 20–30 g ) were purchased from Taconic Hudson... Delivery of thrombogenic tissue factor waterfall plot demonstrating individual treatment response to chemotherapy that has role..., 47 ] microenvironment: from solid tumors to leukemia and xylazine ( mg/kg. Jun ; 19 ( 6 ):637-8. doi: 10.1634/theoncologist.2014-0086 minor benefits inhibitors stop the that. Inhibition of NETosis development of VTE in patients with pancreatic adenocarcinoma not overall... And chemotherapy ( 11, 12 ) min prior to aggregation suggesting that it platelet... Yan M, Reni M, Panciroli C, Goehring P, Gianfrate GC, Ellis,... [ 13, 14 ] samples ( LS Bio, LS-F433 ) followed for the evaluation non-target! Whether people who were already taking the drug to treat certain autoimmune..