Buprenex (0.1 mg/kg IP BID for 3 days) was administered for postoperative pain control. 2014;155(1):134–44. Figure S1. Heinmoller E, Schropp T, Kisker O, Simon B, Seitz R, Weinel RJ. Next, we treated tumor bearing mice with DNase I and observed a significant reduction in platelet aggregation (Fig. 2b). Google ScholarÂ. 2015;110(3):20. Plasma was collected from blood drawn into 3.2% sodium citrate tubes. Genetic and Rare Diseases Information Center. Hydroxychloroquine is approved for the treatment of non-cancerous illnesses such as rheumatoid arthritis and systemic lupus erythematous. Development of VTE in patients with pancreatic cancer is associated with a poor prognosis [4, 5]. 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. 2001;61(4):1659–65. A new perspective on the risk of Hypercoagulopathy in ovarian Hyperstimulation syndrome using Thromboelastography. Arch Intern Med. Ann Surg Oncol. Serum was collected after blood was allowed to clot and then spun at 1000 g for 10 min. 1 mg/mL treatment of DNase I (Sigma Aldrich, St. Louis, MO, USA) was added to NET supernatant for 10 min prior to treatment of whole blood. 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. Nosal R, Jancinova V, Danihelova E. Chloroquine: a multipotent inhibitor of human platelets in vitro. Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01273805. These studies were not powered to evaluate the exploratory endpoints including in the current manuscript. Hydroxychloroquine sulfate (HCQ) is an inhibitor of autophagy that inhibits the fusion of the autophagosome to the lysosome. Thromb Res. Patients received 400 mg hydroxychloroquine orally twice per day. Safety and biologic response of pre-operative autophagy inhibition in combination with gemcitabine in patients with pancreatic adenocarcinoma. Platelet activation was assessed by measuring % CD62P positive cells by flow cytometry. Chloroquine reduces hypercoagulability in pancreatic cancer through inhibition of neutrophil extracellular traps. Platelet aggregometry was performed on RAGE knockout (RAGE KO) animals, which have global genetic depletion of RAGE. NETs promote hypercoagulability in murine PDA through stimulation of platelets and release of tissue factor. Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. Neutrophil and fibrinogen conjugates in the pancreatic tumor microenvironment. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Phase II Study of Hydroxychloroquine in Previously Treated Patients With Metastatic Pancreatic Cancer. PubMed  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]. Importantly, treatment with CQ in PAD4 KO mice, incapable of forming NETs, had minimal effect, suggesting that CQ decreases platelet aggregation through inhibition of NETs. This could explain why prior randomized trials of CQ to decrease VTE in non-malignant orthopedic patients were inconclusive [46, 47]. Kambas K, Chrysanthopoulou A, Vassilopoulos D, Apostolidou E, Skendros P, Girod A, et al. The company’s cancer drug, devimistat, has received orphan status from the agency for treating clear-cell sarcoma, pancreatic cancer, and other diseases. ], Progression-Free Survival [ Time Frame: Disease was evaluated radiologically at baseline and every 2 months on treatment. The current study identifies NETs as a key contributor to platelet aggregation in pancreatic cancer. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. The first trial was a dose escalation Phase I/II trial of preoperative gemcitabine with hydroxychloroquine for patients with high risk pancreatic adenocarcinoma (UPCI 09–122, IRB Protocol #10010028) [18]. Hydroxychloroquine Cures Cancer. RPMI media with 500 nM PMA was added to whole blood for a control. 2017;69(3):655–67. 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? Epub ahead of print). 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. Autophagy, a cancer cell survival mechanism whereby damaged organelles, proteins and other intracellular components are recycled, appears to be critical for NET formation in pancreatic cancer [13]. Arterioscler Thromb Vasc Biol. Geddings JE, Mackman N. Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients. 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. 1974;3(5923):94–5. 2007;13(10):2870–5. PAD4 KO mice, unable to form NETs had diminished platelet activation. A more recent trial randomized patients to two cycles of preoperative gemcitabine/nab-paclitaxel with or without 1200 mg/day oral hydroxychloroquine (UPCI 13–074, IRB Protocol #13080444). (DOCX 109 kb), Figure S3. This phase II trial investigates how well paricalcitol and hydroxychloroquine work when combined with gemcitabine and nab-paclitaxel in treating patients with pancreatic cancer that has spread to other places in the body (advanced or metastatic). Tumor cell-induced platelet aggregation in vitro by human pancreatic cancer cell lines. Pancreatic tumor specimens from resected patients with pancreatic adenocarcinoma were stained for neutrophil elastase (red) and fibrinogen (white). 2012;109(32):13076–81. Researchers in the laboratory have tested tumors from patients with pancreatic cancer and have discovered that they have certain pathways inside the cells … Chang X, Yamada R, Sawada T, Suzuki A, Kochi Y, Yamamoto K. The inhibition of antithrombin by peptidylarginine deiminase 4 may contribute to pathogenesis of rheumatoid arthritis. We evaluated hydoxychloroquine (HCQ), an inhibitor of autophagy, in patients with pancreatic cancer and analyzed pharmacodynamic markers in treated patients and mice. PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures. During NET formation, PAD4 mediated histone citrullination leads to unwinding and release of DNA from neutrophils [37]. Swamydas M, Luo Y, Dorf ME, Lionakis MS. Part of Venous thromboembolism prophylaxis during neoadjuvant therapy for resectable and borderline resectable pancreatic cancer-is it indicated? 2015;22(6):326–34. BAB, PM, HJZ, MDN, and MTL contributed to experimental concept and design, interpreted the results, wrote the manuscript and critically reviewed the manuscript. All together our findings support additional clinical trials with hydroxychloroquine to examine the ability of NET inhibition to lower the venous thromboembolism rate in patients with pancreatic and other cancer types. We identified a trend towards an increase in plasma DNA with treatment and development of VTE, which has been previously recognized as a marker for risk of VTE [51]. Article  Risk of site-specific cancer in incident venous thromboembolism: a population-based study. Studies have shown a reduction of several pancreatic tumor lines in mice treated with paricalcitol correlating with the degree of cell cycle kinase inhibition. Appearance of one or more new lesions is classified as progression of non-target lesions. Tumor bearing mice had elevated levels of serum tissue factor compared with sham controls (Fig. 3a & b). Thromboelastograms (TEGs) were performed to assess hypercoagulability and changes associated with treatment. 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. Cycle duration was 4 weeks. Hypercoagulable changes are detectable on rotational thromboelastometry, similar to TEG, in patients with abdominal malignancy [50]. 2017;18(3):487. "Meaning Hydroxychloroquine added to chemotherapy did not improve overall survival among patients with metastatic pancreatic cancer." Google ScholarÂ. Hepatobiliary Surg Nutr. Cancer Res. Addition of NET supernatant to murine whole blood increased platelet activation in a dose dependent fashion (B). In both trials, hydroxychloroquine was initiated 48 h before the first dose of chemotherapy and continued until the day before surgery. Chloroquine treatment reversed the tumor associated increase in platelet activation (C). 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). That's a no. 2015;13(7):1310–9. Tumor bearing mice have elevated platelet aggregation compared with sham controls (a, AUC 40.2 ± 5.5 vs. 25.8 ± 1.5, n = 5). 2014;73(10):1854–63. Based on this data, inhibition of NET formation may also explain the previously recognized reduction in VTE rate. Resected pancreatic specimens from patients with pancreatic adenocarcinoma were stained and imaged using the following protocol. My treatment included chemo, plus IV Paricalcitol and hydroxychloroquine). PubMed Central  Tumor bearing RAGE KO mice have decreased platelet aggregation compared to WT mice (c, AUC 30.6 ± 1.5 vs. 40.2 ± 5.5, n = 4, p < 0.05). Select results of randomized trial of potentially resectable pancreatic cancer patients treated with preoperative gemcitabine/nab-paclitaxel with and without hydroxychloroquine (HCQ). The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer. Google ScholarÂ. Because the receptor for advanced glycation end products (RAGE) is a known receptor for DNA [23] and induces autophagy and NET formation in pancreatic cancer [13], we sought to evaluate the role of RAGE in NET mediated platelet aggregation. 2016;76(6):1367–80. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, et al. Among all patients, those with VTE had a mean increase of 6 ng/mL with treatment compared with decrease of 70 ng/mL in those that did not have VTE (p < 0.05). Circ Cardiovasc Genet. Paricalcitol (a form of vitamin D) works by blocking a signal in the cancer cells that leads to growth and spreading of the tumor. We identified NETs as a potential source of circulating tissue factor in pancreatic cancer, as genetic deletion of PAD4, an enzyme critical for NET formation, resulted in significant reduction in circulating tissue factor in tumor bearing mice. 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). Pre-existing hypercoagulability in patients undergoing potentially curative cancer resection. Trial Names: Trametinib and Hydroxychloroquine in Treating Patients With Pancreatic Cancer (THREAD). 2014;34(9):1977–84. 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 vaccines’. Adding Hydroxychloroquine to Chemo Fails to Improve OS in Pancreatic Cancer In a recent study of patients with metastatic pancreatic cancer, hydroxychloroquine added to chemotherapy did not lead to an improvement in overall survival (OS; JAMA Oncol. 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. In vitro treatment of whole blood with CQ led to a significant reduction in platelet aggregation in blood harvested from tumor bearing mice (a, AUC 50 ± 2.4 vs. 68.1 ± 8.8, n = 4, p < 0.05). Ann Rheum Dis. Tissue factor expression, angiogenesis, and thrombosis in pancreatic cancer. These findings support clinical study of chloroquine to lower rates of venous thromboembolism in patients with cancer. Tissue factor as a predictor of recurrent venous thromboembolism in malignancy: biomarker analyses of the CATCH trial. 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. Methods: Based on the Danish nationwide registers, an observational cohort study was conducted including patients with first … J Surg Oncol. The n for each experiment reports the number of individual animals. 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. 2014;7(5):615–24. Abdol Razak N, Elaskalani O, Metharom P. Pancreatic Cancer-induced neutrophil extracellular traps: a potential contributor to Cancer-associated thrombosis. Anesthesia was induced using isoflurane (2–5% inhalation), ketamine (90 mg/kg IP) and xylazine (10 mg/kg IP). But then there's this: Repurposing Drugs in Oncology (ReDO)—chloroquine and hydroxychloroquine as anti-cancer agents: Hydroxychloroquine may inactivate these pathways and results in the death of pancreatic cancer … Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. 2-month progression-free survival rate was defined as the percentage of patients absent progression (PD) or death before 2 months. For clinical outcomes, venous thromboembolism was defined as any venous thrombosis including deep vein thrombosis, pulmonary embolism, mesenteric thrombosis and catheter associated thrombosis. In the current study, inhibition of NETs with chloroquine resulted in decreased platelet aggregation and lower levels of circulating tissue factor. *p < 0.05. Hydroxychloroquine in Previously Treated Patients With Metastatic Pancreatic Cancer Hydroxychloroquine is approved for the treatment of non-cancerous illnesses such as rheumatoid arthritis and systemic lupus erythematous. Tissue factor expression in neutrophil extracellular traps and neutrophil derived microparticles in antineutrophil cytoplasmic antibody associated vasculitis may promote thromboinflammation and the thrombophilic state associated with the disease. J Thromb Haemost. Hydroxychloroquine has been shown to inhibit autophagy. Patients were considered to have experienced PD if they demonstrated either clinical deterioration resulting in withdrawal or PD per RECIST 1.0 criteria: 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. Nuclei were stained with Hoechst dye (bisbenzamide 1 mg/100 ml water) for 30 s. After three rinses with PBS, sections were cover slipped with Gelvatol mounting media. Similarly, Razak et al. Priming of neutrophils toward NETosis promotes tumor growth. Tissue factor ELISA was performed on serum from orthotopic mice, demonstrating that tumor burdened mice had elevated levels of circulating tissue factor compared to sham (a, 255 ± 49 vs. 159 ± 26 pg/mL, p < 0.05). 2012;3:307. Although designed and powered to study the effects of HCQ on pathologic treatment response and decrease in Ca 19–9, the reduction in VTE rate neared statistical significance. 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). Gould TJ, Vu TT, Swystun LL, Dwivedi DJ, Mai SH, Weitz JI, et al. PubMed  Correlative markers of NET formation including circulating levels of DNA and tissue factor were also assessed as discussed in the manuscript. There was no difference in pretreatment patient demographics between the two randomized groups (Additional file 4: Table S1). Treatment with the autophagy inhibitor chloroquine results in a reversal of hypercoagulability in pancreatic cancer by diminishing NET mediated platelet aggregation and release of circulating tissue factor and improving coagulation index on TEG. McDonald B, Davis RP, Kim SJ, Tse M, Esmon CT, Kolaczkowska E, et al. CQ inhibition of NETs reverses platelet aggregation and decreases tissue factor. 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- … Subsequent studies have established that HCQ has direct effects on platelet activation and aggregation [48, 49]. Springer Nature. CAS  Google ScholarÂ. 2017;129(10):1357–67. Curve analysis was performed using Haemonetics TEG software (version 4.2.3) and the R, K, angle, and MA were measured. Tumor burdened mice had heightened platelet activation compared to sham controls (A). Experimental: Hydroxychloroquine 600 mg b.i.d. Article  21–23 20 15, PubMed  Platelet activation was assessed by analyzing expression of P-selectin (CD62P) by flow cytometry using an APC-conjugated anti-CD62P monoclonal antibody (2 μg/ml, mouse IgG1κ; eBioscience, San Diego, CA) or isotype control antibody (eBioscience) in platelet rich plasma (PRP), obtained by platelet isolation centrifugation. CAS  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. Waterfall plot demonstrating individual treatment response to gemcitabine/nab-paclitaxel with and without hydroxychloroquine in patients with elevated preoperative levels (e). Activated platelets are capable of inducing NETs [32] and NETs in turn promote platelet aggregation as observed in sepsis and deep vein thrombosis [33, 34]. We have previously demonstrated that pancreatic cancer primes neutrophils to become more prone to NET formation and identified NETs within pancreatic tumors [13]. 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. 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. 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. The generation of these mice from a C57/Bl6 background has been previously described [16]. 2014;40(3):277–83. Sirois CM, Jin T, Miller AL, Bertheloot D, Nakamura H, Horvath GL, et al. Individuals with the following cancers are eligible if diagnosed and treated within the past three years: cervical cancer in situ, and basal cell or squamous cell carcinoma, HIV-positive individuals on combination antiretroviral therapy. Participants who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. 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). Scand J Gastroenterol. COVID-19 is an emerging, rapidly evolving situation. Whole blood platelet aggregation was measured using impedance aggregometry (ChronoLog aggregometer, Model 700, Havertown, PA, USA). This phase II trial investigates how well LY3214996 alone or in combination with hydroxychloroquine works in treating patients with pancreatic cancer. Cancer induced platelet activation contributes to tumor growth, development of metastases and thrombosis [35, 36]. PAD4-mediated neutrophil extracellular trap formation is not required for immunity against influenza infection. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. Tohme S, Yazdani HO, Al-Khafaji AB, Chidi AP, Loughran P, Mowen K, et al. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Diaz JA, Fuchs TA, Jackson TO, Kremer Hovinga JA, Lammle B, Henke PK, et al. 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. 2019 May 23. Listing a study does not mean it has been evaluated by the U.S. Federal Government. 2012;7(9):e45427. Additionally, the 90 day postoperative reduction in VTE occurred despite HCQ stopping at time of surgery. Cells were initially plated in Hank’s Balanced Salt Solution (HBSS, Gibco, Grand Island, NY, USA), then to form NETs, HBSS was removed and cells were stimulated with 500 nM phorbol 12-myristate 13-acetate (PMA, Sigma, St. Louis, MO, USA) in RPMI. Overall survival estimated using Kaplan-Meier (KM) methods is defined as the time from study entry to death or date last known alive. Animals were sacrificed 4 weeks following injection at which time they had palpable left upper quadrant abdominal tumors. Petterson TM, Marks RS, Ashrani AA, Bailey KR, Heit JA. 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 Neutrophil extracellular trap (NET) impact on deep vein thrombosis. 2016;7:373. 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( HCQ ) is an initiative of Lustgarten Foundation and Stand Up to cancer to improve pancreatic cancer.,. Measured by coagulation index, a value that incorporates all measurements from the TEG curve [ 20 ] extrinsic!