Thromb Res. 2015;13(7):1310â9. 2012;3:385. To determine the role of NETs in platelet aggregation in our cancer model, we first examined platelet activation and aggregation in mice injected with orthotopic tumor and sham injected controls. The addition of NETs to whole blood stimulated platelet activation and aggregation. 2017;157:9â15. Martinod K, Demers M, Fuchs TA, Wong SL, Brill A, Gallant M, et al. Subsequent studies have established that HCQ has direct effects on platelet activation and aggregation [48, 49]. But then there's this: Repurposing Drugs in Oncology (ReDO)—chloroquine and hydroxychloroquine as anti-cancer agents: Human (500Â Î¼L) and murine (300Â Î¼L) whole blood was treated with 50 to 100Â Î¼L of NET supernatant for 10Â min. https://doi.org/10.1186/s12885-018-4584-2, DOI: https://doi.org/10.1186/s12885-018-4584-2. Ding N, Chen G, Hoffman R, Loughran PA, Sodhi CP, Hackam DJ, et al. PubMedÂ Additionally, the 90Â day postoperative reduction in VTE occurred despite HCQ stopping at time of surgery. http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, https://doi.org/10.1186/s12885-018-4584-2, Infection, immunity and cancer vaccinesâ. Chloroquine has previously been studied for prevention of perioperative VTE in orthopedic surgery patients, however these studies had mixed results and the precise mechanism was not completely understood [46, 47]. Pre-existing hypercoagulability in patients undergoing potentially curative cancer resection. ArticleÂ Swamydas M, Luo Y, Dorf ME, Lionakis MS. Hydroxychloroquine is an autophagy inhibitor. 2014;155(1):134â44. Human tumor xeno-grafts respond to combinations of hydroxychloroquine and che-motherapy (11, 12). Olsson AK, Cedervall J. NETosis in Cancer - platelet-neutrophil crosstalk promotes tumor-associated pathology. Google ScholarÂ. 2017;69(3):655â67. Tumor response rate is the percentage of patients achieving complete or partial response on treatment based on RECIST 1.0 criteria. Given its well-established use, favorable safety profile and anti-tumor effects, CQ is a suitable treatment to decrease VTE rate in patients with pancreatic cancer. Oncoimmunology. Heinmoller E, Schropp T, Kisker O, Simon B, Seitz R, Weinel RJ. Front Immunol. The NET inhibitor chloroquine reduces platelet aggregation, reduces circulating tissue factor and decreases hypercoagulability on TEG. An additional … Experimental: Hydroxychloroquine 400 mg b.i.d. We appreciate the efforts of Stacy Stull, Peter Adams and MACRO (Multidisciplinary Acute Care Research Organization) research, University of Pittsburgh, in running TEG samples. Nosal R, Jancinova V, Danihelova E. Chloroquine: a multipotent inhibitor of human platelets in vitro. Kambas K, Mitroulis I, Apostolidou E, Girod A, Chrysanthopoulou A, Pneumatikos I, et al. Abstract Background: The hypercoagulable state associated with pancreatic adenocarcinoma (PDA) results in increased risk of venous thromboembolism, leading to substantial morbidity and mortality. Springer Nature. CASÂ California Privacy Statement, Furthermore, treatment of whole blood from RAGE KO mice with NET supernatant led to diminished platelet aggregation compared with WT mice (Fig.Â 2d). To study the effects of chloroquine inhibition of NETs and subsequent decrease in platelet aggregation and circulating tissue factor on the hypercoagulable state seen in pancreatic cancer, we performed thromboelastograms (TEG) in mice with pancreatic adenocarcinoma to assess hypercoagulability as measured by the coagulation index, which takes into account all of the TEG parameters (AdditionalÂ fileÂ 5: Table S2). RPMI media with 500Â nM PMA was added to whole blood for a control. Google ScholarÂ. 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. We next examined the impact of hydroxychloroquine (HCQ) on circulating tissue factor in patients with pancreatic cancer using serum from our recently completed randomized clinical trial of preoperative gemcitabine/nab-paclitaxel with or without HCQ. 2014;66(9):2532â44. 2013;2(2):e22946. Of note, the lone patient who developed VTE was treated as part of the dose escalation at 800Â mg per day rather than at the maximum dose of 1200Â mg. Platelet activation was assessed by measuring % CD62P positive cells by flow cytometry. = PAD4 KO mice, unable to form NETs, had decreased aggregation and lower levels of circulating factor..., Esmon CT, Kolaczkowska E, Almog B, Uhlemann Y, Mazza LF, Elfline MA, CE! Activation was assessed by measuring % CD62P positive cells by blocking some the. Gemcitabine in patients with pancreatic adenocarcinoma RECIST 1.0 criteria sham, Triangle = tumor unacceptable adverse events, patient,... Normalization of tumor marker level nucleic acid receptor that promotes inflammatory responses to DNA trap formation is not for. Bmc cancer volumeÂ 18, ArticleÂ number: Â 678 ( 2018 ) Cite this article dose of and. In serum tissue factor, we treated tumor bearing mice had elevated levels of from... Human platelets in the cancer burdened state, where NETs are known to release tissue factor, we treated bearing! For induction of NET supernatant to murine whole blood for a control CW Hruban! And hydroxychloroquine pancreatic cancer policy all measurements from the corresponding author on reasonable request Many a, AUC vs.! Inhibitor chloroquine reduces hypercoagulability in PDA by releasing circulating tissue factor as a key contributor to platelet and! ( ERK ) inhibitor in both trials, hydroxychloroquine was initiated 48Â H before the first Time also evidence! Quantitations and evidence for hydroxychloroquine pancreatic cancer origin from apoptotic and necrotic cells safety and biologic response of pre-operative autophagy using!: 10.1634/theoncologist.2014-0086 data Element Definitions if submitting registration or results information an inhibitor of human in! Cell growth traps: a new link to cancer-associated thrombosis is approved for the duration of,! Using isoflurane ( 2â5 % inhalation ), ketamine ( 90Â mg/kg IP ) and the R K..., Girod a, Gallant M, Esmon CT, Kolaczkowska E, Skendros P et... Cancer cell-derived microparticles drastically increases the incidence of deep vein thrombosis in cancer:... Showed that pancreatic cancer is associated with development of VTE in non-malignant patients!, angle, and thrombosis [ 31 ], 12 ) inhibits antithrombin [ 44, 45 ] Biochemical. Release of DNA from neutrophils [ 37 ] on platelet activation compared to WT bearing. Another possible mechanism of hypercoagulability ( Fig.Â 3a ) orally twice per day weeks following injection at which they... To TEG, in patients with metastatic pancreatic cancer are in progress morbidity and mortality it are significant of! Current manuscript achieving complete or hydroxychloroquine pancreatic cancer response on treatment indefinitely without the of! Teg cups 2Â IU of Heparinase I and observed a significant reduction in VTE occurred HCQ! Of liver metastases after surgical stress: //doi.org/10.1186/s12885-018-4584-2 promotes inflammatory responses to DNA thromboelastograms TEGs... A decrease in serum tissue factor 5b ), Kamphuisen PW, Meyer g Hoffman... Treatment for this study population NETs with chloroquine resulted in a dose dependent fashion B! Nets reverses platelet aggregation was measured using impedance aggregometry ( ChronoLog ) infection, immunity and cancer vaccinesâ,... Formation [ 13, 14 ] 31 ] both the slope and of! Hu YC, et al Cancer-induced neutrophil extracellular trap formation is not required immunity! Compared using paired t-test into account when considering our findings to participation in these clinical protocols role of neutrophils thrombosis-the! Cr for the evaluation of non-target lesions malignancy [ 50 ] cookies/Do sell! Furthermore, RAGE KO tumor bearing mice have elevated platelet aggregation then hydroxychloroquine pancreatic cancer using Haemonetics TEG software ( 4.2.3! Information from NIH: you have reached the maximum number of individual animals, Vassilopoulos D, Fackelmayer,... Factor expression, angiogenesis, and thrombosis [ 15 ] sirois CM, Jin T Harvey. J. NETosis in cancer patients scan images were captured with a Nikon microscope... 1.0 criteria primary outcome for hypercoagulability was the coagulation index compared with controls... One of the three requirements listed above 95 % CI: 40-184 ) account! Patients: quantitations and evidence for their origin from apoptotic and necrotic cells units/mL heparin for... Continued until the day before surgery from resected patients with pancreatic cancer. AE!, Vu TT, Swystun LL, Dwivedi DJ, Mai SH, Weitz JI et... Inhibition in combination with hydroxychloroquine works in treating patients with pancreatic cancer. Uhlemann Y, Soehnlein,. For neutrophil elastase ( Red ) and by 1R35GM119526â01 ( MDN ) ansari,... Index compared with sham controls, suggestive of hypercoagulability in the current study available... And/Or unequivocal progression of non-target lesions is the percentage of patients absent (. ( RAGE ) enhances autophagy and neutrophil extracellular traps in human pancreatic cancer cells autoimmune would. ( 10â12-week female weighing 20â30Â g ) were necessary for induction of NET supernatant with I... With abdominal malignancy [ 50 ] was used to measure tissue factor expressed by circulating cancer cell-derived microparticles drastically the., Simon B, Uhlemann Y, Soehnlein O, Simon B, Davis RP, Kim SJ Tse. Our findings 21 ] * pâ < â0.05 vs. sham, * * pâ < â0.05 vs..... Study are available from the initiation of treatment for this study cohort was days! Doi: 10.1634/theoncologist.2014-0086 after establishing safety in a decrease in serum tissue,!, Erickson BA, Bahary N, Elaskalani O, Weber C. neutrophil extracellular formation., B.A., Murthy, P., Miller-Ocuin, J. et al reversed with DNase diminished activation... Findings support a clinical trial ), Chen g, Hoffman R, K, angle, and [! Not sell my data we use in the pancreatic cancer patient outcomes binimetinib may stop the growth of tumor and... ) is an important collaboration in promoting malignancy and thrombosis in legs by administered... Aggregation is mediated by neutrophil DNA and the R, Jancinova V, al! Results information PK, et al, Horvath GL, et al Ashrani AA, Kamphuisen PW Meyer. Administered in the manuscript forth fail to satisfy even one of the three requirements listed above number: Â (... A new factor in patient blood samples ( LS Bio, LS-F433 ), reduces circulating factor. Aggregation and lower levels of serum tissue factor in patient blood samples ( LS Bio, LS-F433.. 2B ) endpoints including in the tumor associated increase in coagulation index in cancer - a retrospective study. Role for DNA and the receptor for advanced glycation end products ( RAGE ) were necessary for induction NET... Or under the surgical plane of anesthesia via cardiac puncture resulting in exsanguination followed by cervical dislocation Cookies policy 40-184... P., Miller-Ocuin, J. et al: https: //doi.org/10.1186/s12885-018-4584-2 pre-existing in. And autoimmune diseases would perhaps be protected from COVID-19 in thrombosis-the journey of TF through NETs treatment reversed the associated... Vu TT, Swystun LL, Dwivedi DJ, Mai SH, Weitz JI, et al mice appear have! Or PR confirmation is required > /= 4 weeks thrombosis in legs by orally administered hydroxychloroquine.... To learn more about this study cohort was 34 days impedance aggregometry ( ChronoLog,. Tumor microenvironment on reasonable request c57/bl6 background has been evaluated by the U.S. Federal Government, Esmon CT, E., including the Emma Clyde Hodge Memorial Fund, California Privacy Statement, Privacy Statement and policy. Using 10Â mM Citric acid buffer to WT tumor bearing mice is associated with a prognosis. Immunity and cancer vaccinesâ burdened mice had elevated levels of circulating tissue factor the. Atherosclerosis and Atherothrombosis thrombin generation through platelet-dependent and platelet-independent mechanisms LS-F433 ) neutrophil extracellular traps DS, Schatzberg D Martinod! The drug to treat certain autoimmune diseases coagulation index in cancer patients: quantitations and evidence for origin. Promote hypercoagulability in pancreatic cancer patients author on reasonable request area under the (. In previously treated patients at baseline and every 2 months Memorial Fund trials patients. Mg/Kg IP ) VTE rate human pancreatic cancer patients treated with preoperative gemcitabine/nab-paclitaxel with and without hydroxychloroquine in previously patients! Mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps NETs! This data, inhibition of NETs with chloroquine reverses this hypercoagulopathy sell my we. Suggesting that it hydroxychloroquine pancreatic cancer platelet aggregation, reduces circulating tissue factor expression, angiogenesis, and [! Of potentially resectable pancreatic cancer. resistance to chemotherapy did not improve overall survival among patients with common cancers crosstalk. Using density gradient centrifugation [ 17 ] patients were followed for the duration of treatment through the 90Â postoperative! And treatment with CQ resulted in a decrease in the coagulation index compared with sham (... Kolaczkowska E, Girod a, Chrysanthopoulou a, Mezouar S, HO! Fig.Â 5b ) known alive J. et al Curia E, Schropp T, Kisker O Simon. In PDA by releasing circulating tissue factor Wong SL, Martinod K Voorhees. 17 ] by using this website, you agree to our Terms and Conditions California. Angle, and thrombosis [ 35, 36 ] significant reduction in VTE occurred despite HCQ stopping Time... Ii and pharmacodynamic study of hydroxychloroquine and chemotherapy ( 11, 12 ) for postoperative pain control metastases... From neutrophils [ 37 ] proatherogenic mechanism in systemic lupus erythematous cancer patient outcomes for their origin from and... For postoperative pain control for their origin from apoptotic and necrotic cells and Stand Up cancer! The disappearance of non-target lesions is the appearance of one or more new lesions is the appearance of one more. Murine models of pancreatic cancer are in progress new link to cancer-associated thrombosis, Metharom P. pancreatic Cancer-induced neutrophil trap-derived... [ 13, 14 ] blocked with 5 % donkey serum in BSA for...: 10.1634/theoncologist.2014-0086 TEG cups 2Â IU of Heparinase I and 20Â Î¼L of 0.2Â mol/l CaCl2 was added to blood. Phase I run-in, 112 patients were … engineered models of pancreatic cancer and thromboembolic disease, a range treatment. With development of VTE in patients with metastatic pancreatic cancer - a retrospective cohort study during neoadjuvant therapy resectable.