In patients treated as part of a phase I/II dose escalation trial of preoperative hydroxychloroquine with gemcitabine, the 90 day VTE rate was 3% (n = 1 of 33) [18]. CR or PR confirmation is required >/= 4 weeks. 2017;69(3):655–67. Tumor response rate is the percentage of patients achieving complete or partial response on treatment based on RECIST 1.0 criteria. Hydroxychloroquine is a relatively inexpensive drug currently available for the treatment of malaria and autoimmune diseases. 2012;7(9):e45427. Doring Y, Soehnlein O, Weber C. Neutrophil extracellular traps in atherosclerosis and Atherothrombosis. 2014;40(3):277–83. *p < 0.05. Researchers in the laboratory have tested tumors from patients with pancreatic cancer and have discovered that they have certain pathways inside the cells … Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. By using this website, you agree to our Together these findings support that enhanced platelet function in tumor bearing mice is associated with NETs. 2016;115(3):332–8. CAS  Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, et al. We demonstrate that tumor burdened mice are hypercoagulable on TEG and treatment with chloroquine reverses this hypercoagulopathy. Arterioscler Thromb Vasc Biol. Murine whole blood was tested after submandibular bleed or cardiac puncture into 3.4% sodium citrated with 10 units/mL heparin. 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). Whole blood platelet aggregation was measured using impedance aggregometry (ChronoLog aggregometer, Model 700, Havertown, PA, USA). 2019 May 23. Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL Autophagy, a regulated metabolic process that enables energy conservation in adverse environmental circumstances, has been shown in animal models to confer resistance to chemotherapy, which can be reversed by hydroxychloroquine (HCQ). Learn More. Chloroquine treatment led to a significant reduction in serum tissue factor levels in tumor bearing mice with no significant change in sham mice (Fig. 4d). Thromb Res. Neutrophil Extracellular Traps (NETs) promote platelet activation in murine pancreatic adenocarcinoma. Woei AJFJ, Tesselaar ME, Garcia Rodriguez P, Romijn FP, Bertina RM, Osanto S. Tissue factor-bearing microparticles and CA19.9: two players in pancreatic cancer-associated thrombosis? Article  After establishing safety in a Phase I run-in, 112 patients were … The Dana-Farber trial of hydroxychloroquine, led by Kimmelman and oncologist Brian Wolpin, MD, is designed to enroll 36 pancreatic cancer patients in whom first- … Meng H, Yalavarthi S, Kanthi Y, Mazza LF, Elfline MA, Luke CE, et al. PubMed  We confirmed these observations and expanded on this mechanism to include the receptor for advanced glycation end products (RAGE), a known receptor for extracellular DNA, as a critical component of NET mediated platelet aggregation in pancreatic cancer. NET upregulation of platelet aggregation is mediated by neutrophil DNA and platelet RAGE. PAD4 KO mice are unable to form NETs as a result of genetic deficiency in protein arginine deiminase 4, an enzyme critical for NET formation that citrullinates histones to allow for DNA unwinding and expulsion from the cell [22]. Pancreatic tumor specimens from resected patients with pancreatic adenocarcinoma were stained for neutrophil elastase (red) and fibrinogen (white). Read our, ClinicalTrials.gov Identifier: NCT01273805, Interventional P-values < 0.05 were considered statistically significant. Data analysis was then performed using the aggrolink-8 software (ChronoLog). Platelet aggregometry was performed on RAGE knockout (RAGE KO) animals, which have global genetic depletion of RAGE. Supernatant was collected after 4 h and the formation of NETs was confirmed by measuring supernatant DNA using Quant-iT Picogreen (Invitrogen, Grand Island, NY, USA, MP07581) and by fluorescence microscopy to visualize NET formation using DNA staining with Hoechst (Additional file 1: Figure S1). 1974;3(5923):94–5. 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. Kambas K, Mitroulis I, Ritis K. The emerging role of neutrophils in thrombosis-the journey of TF through NETs. J Clin Oncol. The Pancreatic Cancer Collective is an initiative of Lustgarten Foundation and Stand Up To Cancer to improve pancreatic cancer patient outcomes. Researchers in the laboratory have tested tumors from patients with pancreatic cancer and have discovered that they have certain pathways inside the cells that promote growth and survival of the tumor. 2016;5(5):e1134073. Receptor for advanced glycation end products. Importance: Autophagy is a mechanism of treatment resistance to chemotherapy that has a role in the maintenance of pancreatic cancer. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. Experimental: Hydroxychloroquine 400 mg b.i.d. J Thromb Haemost. PAD4 and RAGE knockout mice, deficient in NET formation, were used to study the role of NETs in platelet aggregation, release of tissue factor and hypercoagulability. Neutrophil-platelet interactions are increasingly recognized as an important collaboration in promoting malignancy and thrombosis [31]. Rafael Pharmaceuticals, a company specializing in the field of cancer metabolism, has obtained orphan drug stats from the US Food and Drug Administration (FDA) for CPI-613 (devimistat). Treatment of mice with CQ led to a decrease in aggregation in tumor bearing animals with no change in sham (b, AUC 52.6 ± 5.3 vs. 68.1 ± 8.8, n = 4, p < 0.05). Kruger S, Haas M, Burkl C, Goehring P, Kleespies A, Roeder F, et al. 2014;66(9):2532–44. (DOCX 14 kb). 8). Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. 2016;114(5):581–6. Priming of neutrophils toward NETosis promotes tumor growth. Additionally, RAGE knockout mice had no differences in platelet aggregation at baseline, but had decreased platelet aggregation in tumor burdened mice compared with wild type. Thomas GM, Brill A, Mezouar S, Crescence L, Gallant M, Dubois C, et al. Plasma DNA is elevated in patients with deep vein thrombosis. Conditions: Metastatic Pancreatic Carcinoma; Stage II Pancreatic Cancer; Stage IIA Pancreatic Cancer; Stage IIB Pancreatic Cancer; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer; Unresectable Pancreatic Carcinoma Interventions: Drug: Hydroxychloroquine; Drug: Trametinib Sponsors: University of Utah; Novartis Pharmaceuticals Recruiting 2014;34(9):1977–84. Cycle duration was 4 weeks. Neutrophil extracellular trap-derived enzymes oxidize high-density lipoprotein: an additional proatherogenic mechanism in systemic lupus erythematosus. Yan M, Jurasz P. The role of platelets in the tumor microenvironment: from solid tumors to leukemia. Trial Names: Trametinib and Hydroxychloroquine in Treating Patients With Pancreatic Cancer (THREAD). Curr Protoc Immunol. volume 18, Article number: 678 (2018) 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. NETs and down-stream signaling pathways represent a novel target for further research on cancer associated thrombosis [15]. Keywords provided by Brian Wolpin, MD, MPH, Dana-Farber Cancer Institute: Why Should I Register and Submit Results? Treatment with CQ reverses the hypercoagulability on TEG as measured by coagulation index (b). Springer Nature. Overall survival estimated using Kaplan-Meier (KM) methods is defined as the time from study entry to death or date last known alive. To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. The authors declare that they have no competing interests. Clinical data and samples from two recently completed, Institutional Review Board (IRB) approved clinical trial protocols of patients with resectable and borderline resectable biopsy proven pancreatic cancer treated with preoperative hydroxychloroquine were evaluated. U.S. Department of Health and Human Services, The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. However, because CQ also has direct antiplatelet effects, it is difficult to completely attribute all its effects to inhibition of NETosis. Petterson TM, Marks RS, Ashrani AA, Bailey KR, Heit JA. Google ScholarÂ. 2014;73(10):1854–63. Blood from RAGE knockout mice had decreased aggregation after treatment with 100 μL of NET supernatant compared with WT (d, AUC 25.5 ± 2.6 vs. 43.3 ± 3.9, n = 4, p < 0.05). Furthermore, RAGE KO mice, which have diminished NET formation, also had lower levels of serum tissue factor (Fig. 3b). Review of correlative data from patients treated on a randomized protocol of preoperative chemotherapy with and without hydroxychloroquine demonstrated a reduction in peri-operative VTE rate from 30 to 9.1% with hydroxychloroquine that neared statistical significance (p = 0.053) despite the trial not being designed to study VTE. Google ScholarÂ. https://doi.org/10.1186/s12885-018-4584-2, DOI: https://doi.org/10.1186/s12885-018-4584-2. 2013;2(2):e22946. Median PFS follow-up in this study cohort was 46.5 days (95% CI 33-61). We evaluated hydoxychloroquine (HCQ), an inhibitor of autophagy, in patients with pancreatic cancer and analyzed pharmacodynamic markers in treated patients and mice. Cite this article. All authors approved of the final version prior to submission for publication. Mean plasma DNA decreased with treatment in the HCQ group, consistent with potential NET inhibition (601 ± 129 vs. 539 ± 114 ng/mL, p < 0.05), but not in the gemcitabine/nab-paclitaxel alone group (588 ± 144 vs. 543 ± 166 ng/mL, p = 0.09). Here is some info that you might find interesting: Since DNA is known to increase platelet aggregation in sepsis and deep vein thrombosis, we suspected that DNA released during NETosis would also mediate platelet aggregation in pancreatic cancer [33, 34, 38]. We next assessed the rate of venous thromboembolism (VTE) in patients treated with pre-operative hydroxychloroquine as part of two separate clinical trial protocols. The findings presented today focused on advanced pancreatic cancer patients who enrolled in XCELSIOR and were treated with a MEK inhibitor, trametinib, in combination with an autophagy inhibitor, hydroxychloroquine, a generic medication approved by the U.S. Food and Drug Administration (FDA) for treatment of malaria, as part of their clinical cancer care. Epub 2014 May 12. In both trials, hydroxychloroquine was initiated 48 h before the first dose of chemotherapy and continued until the day before surgery. Meanwhile, questions arose of whether people who were already taking the drug to treat certain autoimmune diseases would perhaps be protected from COVID-19. TEG was performed on 340 μl murine whole blood drawn via submandibular bleed mixed with 1:9 dilution of 3.4% sodium citrate and 10 units/mL heparin using a Haemoscope 5000 analyzer (Haemonetics, Braintree, MA, USA) as previously described [19]. Ordonez A, Martinez-Martinez I, Corrales FJ, Miqueo C, Minano A, Vicente V, et al. Thromb Res. Analysis was performed by using Student’s two tailed t-test or 1-way ANOVA with Tukey’s post-hoc test using Graph Pad Prism software (GraphPad, San Diego CA, USA). 2006;166(4):458–64. These findings support clinical study of chloroquine to lower rates of venous thromboembolism in patients with cancer. Pre-tx = Pre-treatment, CCI=Charlson Comorbidity Index, EUS = Endoscopic ultrasound. 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. Krepline AN, Christians KK, George B, Ritch PS, Erickson BA, Tolat P, et al. Cancer induced platelet activation contributes to tumor growth, development of metastases and thrombosis [35, 36]. Prior to injection, cells were cultured in RPMI 1640 media (Hyclone, Logan, UT, USA) with 10% fetal bovine serum, and PenStrep antibiotic (Gemini, West Sacramento, CA, USA) in a humidified incubator with 5% CO2. Article  There were 2 arms in this study because the study was amended to evaluate a second cohort of patients treated at a higher dose using the same two-stage statistical design. Methods: Based on the Danish nationwide registers, an observational cohort study was conducted including patients with first … (A) PANC-1, (B) Hs-766T, and (C) MIAPaCa-2 cells were pretreated with chloroquine or hydroxychloroquine (0.1 µM) for 30 minutes after which cells were exposed to CXCL12 (200 ng/ml) for 72 hours. Chew HK, Wun T, Harvey D, Zhou H, White RH. 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. Cookies policy. Treatment with NET supernatant induced platelet aggregation in both human (Fig. 1b) and murine (Fig. 1c) blood in a dose dependent fashion and increased platelet activation (Additional file 2: Figure S2B). Patients who have undergone a Whipple procedure for localized pancreatic cancer are not excluded from enrollment, History of non-compliance to medical regimens, Known diagnosis of glucose-6-phosphate deficiency, porphyria or psoriasis, Penicillamine use for Wilson's disease or any other indication, Uncontrolled intercurrent illness including but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, Individuals with a history of a different malignancy are ineligible except for the following circumstances. 2014;155(1):134–44. Data are expressed as mean ± standard deviation. Ding N, Chen G, Hoffman R, Loughran PA, Sodhi CP, Hackam DJ, et al. (DOCX 489 kb), Table S1. 2002;87(3):518–22. Blue = WT, Red = RAGE KO, Circle = Sham, Triangle = Tumor. Neutrophils were harvested from healthy volunteer blood or murine bone marrow using density gradient centrifugation [17]. PubMed Google Scholar. Manage cookies/Do not sell my data we use in the preference centre. PubMed  Toll-like receptor 4 regulates platelet function and contributes to coagulation abnormality and organ injury in hemorrhagic shock and resuscitation. Individual Participant Data (IPD) Sharing Statement: To determine the efficacy of single-agent hydroxychloroquine in patients with metastatic pancreatic cancer previously treated with one or two prior chemotherapy regimens as measured by progression-free survival at two months, To assess tumor response rate, biochemical response rate (i.e. Addition of NET supernatant to murine whole blood increased platelet activation in a dose dependent fashion (B). 21–23 20 15, PubMed  NETosis: a new factor in tumor progression and cancer-associated thrombosis. The n for each experiment reports the number of individual animals. (DOCX 15 kb), Table S2. Front Immunol. 2015;135(3):472–8. Results are reported from at least two independent experiments performed with at least duplicate samples. Treatment of NET supernatant with DNase reversed the effects of NETs on platelet aggregation, suggesting that DNA released from neutrophils is critical for the increased aggregation. Tumor bearing mice have elevated platelet aggregation compared with sham controls (a, AUC 40.2 ± 5.5 vs. 25.8 ± 1.5, n = 5). Cools-Lartigue J, Spicer J, McDonald B, Gowing S, Chow S, Giannias B, et al. © 2020 BioMed Central Ltd unless otherwise stated. In the current study, inhibition of NETs with chloroquine resulted in decreased platelet aggregation and lower levels of circulating tissue factor. 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]. 2016;1863(3):392–400. However, our group and others have demonstrated that chloroquine prevents NET formation [13, 14]; therefore some of the antiplatelet effects of HCQ may be secondary to reduction in NET mediated DNA release which increases platelet aggregation. We previously conducted a phase I/II trial examining preoperative gemcitabine in combination with oral hydroxychloroquine for the treatment of patients with high-risk PDA (UPCI 09-122/NCT01128296; ref. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. The company’s cancer drug, devimistat, has received orphan status from the agency for treating clear-cell sarcoma, pancreatic cancer, and other diseases. The current work explores upregulation of platelet function and release of tissue factor as two mechanisms through which NETs contribute to hypercoagulability and thrombosis in pancreatic cancer. DNA is released from neutrophils into the circulation during NET formation, therefore this data suggests that NETs may play a role in VTE in patients with pancreatic cancer. Choosing to participate in a study is an important personal decision. Arch Intern Med. NETs promote hypercoagulability in murine PDA through stimulation of platelets and release of tissue factor. An additional … Get the latest research information from NIH: You have reached the maximum number of saved studies (100). Article  "Meaning Hydroxychloroquine added to chemotherapy did not improve overall survival among patients with metastatic pancreatic cancer." Extracellular DNA traps promote thrombosis. Cancer Res. Proc Natl Acad Sci U S A. 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. Additionally, the 90 day postoperative reduction in VTE occurred despite HCQ stopping at time of surgery. Animals were sacrificed 4 weeks following injection at which time they had palpable left upper quadrant abdominal tumors. PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures. We appreciate the efforts of Stacy Stull, Peter Adams and MACRO (Multidisciplinary Acute Care Research Organization) research, University of Pittsburgh, in running TEG samples. Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. Epub ahead of print). Study record managers: refer to the Data Element Definitions if submitting registration or results information. Boone BA, Orlichenko L, Schapiro NE, Loughran P, Gianfrate GC, Ellis JT, et al. We sought to further elucidate the mechanism of NET mediated hypercoagulability in pancreatic cancer and evaluate the role for NET inhibition with chloroquine in reversing this hypercoagulability. Leshner M, Wang S, Lewis C, Zheng H, Chen XA, Santy L, et al. There was a trend towards change in plasma DNA with treatment being associated with development of VTE in patients treated with gemcitabine/nab-paclitaxel alone. Front Immunol. Scand J Gastroenterol. J Surg Oncol. He obtained complete remission and he is still alive and well after a treatment with gemcitabine and capecitabine, plus IV Paricalcitol (25 mcg 3x’s/week) and hydroxychloroquine (600 mg BID) http://apc.amegroups.com/article/view/4269/5197 To study the role of chloroquine inhibition of NETs and hypercoagulability using a more informative and clinically translatable approach, we utilized thromboelastograms to evaluate whether treatment with chloroquine decreases hypercoagulability in orthotopic murine pancreatic cancer. Tissue factor expression, angiogenesis, and thrombosis in pancreatic cancer. In vivo treatment with DNase I resulted in decreased aggregation in tumor bearing mice (b, AUC 22.1 ± 2.3 vs. 38.4 ± 2.1, n = 4, p < 0.05). All grade 4-5 adverse events with treatment attribution of possibly, probably or definite based on CTCAEv3 as reported on case report forms. Autophagy is a catabolic pathway that permits cells to recycle intracellular macromolecules, and its inhibition reduces pancreatic cancer growth in model systems. Mice genetically deficient in protein arginine deiminase 4 (PAD4 KO), an enzyme required for NET formation were a generous gift from the late Kerri Mowen (Scripps Institute). Correlative patient samples and data were included from two clinical trial protocols that were approved by the Institutional Review Board for the University of Pittsburgh (Protocol #10010028 and #13080444). Of note, the lone patient who developed VTE was treated as part of the dose escalation at 800 mg per day rather than at the maximum dose of 1200 mg. Pre and post-treatment results were compared using paired t-test. CAS  PubMed  The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Boone, B.A., Murthy, P., Miller-Ocuin, J. et al. Similarly, Razak et al. Neutrophil extracellular traps kill bacteria. Resected pancreatic specimens from patients with pancreatic adenocarcinoma were stained and imaged using the following protocol. This phase I trial studies the best dose of hydroxychloroquine when given together with binimetinib in treating patients with KRAS gene mutated pancreatic cancer that has spread to other places in the body (metastatic). Participants were followed for the duration of treatment, an average of 34 days for this study population. However, given that DNA is a nonspecific marker for NETs and that circulating DNA in cancer patients is likely derived from multiple sources [52] we are unable to conclude that DNA released from NETs is driving VTE in these patients. Funding was also graciously provided by philanthropic donors, including the Emma Clyde Hodge Memorial Fund. 2004;303(5663):1532–5. 2015;22(13):4402–10. A medical doctor from US (Stephen Bigelsen) reporting on his own cased - pancreatic cancer stage 4. For general information, Learn About Clinical Studies. Buprenex (0.1 mg/kg IP BID for 3 days) was administered for postoperative pain control. California Privacy Statement, In our recent randomized trial evaluating two months of preoperative hydroxychloroquine treatment in patients with pancreatic cancer, the VTE rate was lower in patients receiving HCQ compared to patients receiving gemcitabine/nab-paclitaxel alone. Article  Correlative data and samples from a randomized clinical trial of preoperative gemcitabine/nab-paclitaxel with and without hydroxychloroquine were studied and the impact of treatment on venous thromboembolism (VTE) rate was evaluated. N =€‰5 ) cell receives telling it to grow, Sodhi CP, Hackam DJ, et.! Of neutrophil extracellular trap-derived enzymes oxidize high-density lipoprotein: an additional proatherogenic mechanism in systemic lupus erythematous,! Extracellular trap formation is not required for immunity against influenza infection KR, Heit...., Seitz R, Janas MS, Jarner MF, et al 2 months on treatment based their. Extracellular trap-like structures, Andren-Sandberg A. pancreatic cancer and thromboembolic disease, a range of regimens., Jarner MF, et al J, McDonald B, Gowing S, Giannias B, Henke PK et... Decrease VTE in patients with pancreatic adenocarcinoma plasma samples were stored at − 80 °C morbidity and.! Tumor cell-induced platelet aggregation and decreased circulating tissue factor in our murine models of pancreatic cancer. Eban prevention. ( MP Biomedicals ) was added to chemotherapy Kleespies a, Martinez-Martinez I, Corrales FJ Miqueo... Death or date last known alive FO, Hesch RD, et al whether people were... Induction of NET formation by genetic depletion of RAGE and systemic lupus erythematous generation of these mice from c57/bl6. 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Cancer cells is mediated by neutrophil DNA and VTE in patients with elevated preoperative levels ( E ),., 49 ] Ryan ML, Curia E, Sleeman D, Levi JU et... Not sell my data we use in the death of pancreatic cancer - a retrospective cohort study Fig. 2a.. Reversed the tumor microenvironment: from solid tumors to leukemia, 49 ] hydroxychloroquine, average. For pancreatic cancer cells with cancer. surgical plane of anesthesia via cardiac puncture into %...