Publications by authors named "Frederick R Rickles"

35 Publications

Preface.

Thromb Res 2018 04;164 Suppl 1:S1-S2

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http://dx.doi.org/10.1016/j.thromres.2018.01.051DOI Listing
April 2018

The International Conference on Thrombosis and Hemostasis Issues in Cancer (ICTHIC) at the Peak of Adolescence - 15 Years and Counting.

Thromb Res 2016 Apr;140 Suppl 1:S99-102

Division of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy.

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http://dx.doi.org/10.1016/S0049-3848(16)30107-4DOI Listing
April 2016

Preface.

Thromb Res 2016 Apr;140 Suppl 1:ix-x

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http://dx.doi.org/10.1016/S0049-3848(16)30089-5DOI Listing
April 2016

Deep vein thrombosis (DVT) and pulmonary embolism (PE): awareness and prophylaxis practices reported by patients with cancer.

Cancer Invest 2015 16;33(9):405-10. Epub 2015 Jul 16.

a 1 George Washington University and Veterans Affairs Medical Center , Washington, DC.

Patients with cancer are at increased risk for venous thromboembolism (VTE). An online survey to measure PE/DVT terminology awareness and understanding of VTE risks revealed 24% and 15% of the 500 cancer patients surveyed had heard of term DVT/PE; 19% and 17% could name signs/ symptoms of DVT/PE; 3% recognized cancer treatments as risk factors for DVT/PE. Only 25% of the patients received prevention education from providers; <50% received VTE prophylaxis. Cancer patient awareness of VTE terminology and cancer and/or its treatment as risk for VTE is low. More effective patient/physician dialogue about VTE risk and thromboprophylaxis is needed.
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http://dx.doi.org/10.3109/07357907.2015.1048871DOI Listing
February 2016

Pattern of frequent but nontargeted pharmacologic thromboprophylaxis for hospitalized patients with cancer at academic medical centers: a prospective, cross-sectional, multicenter study.

J Clin Oncol 2014 Jun 5;32(17):1792-6. Epub 2014 May 5.

Jeffrey I. Zwicker, Adam Rojan, and Renee Funches, Beth Israel Deaconess Medical Center and Harvard Medical School; Federico Campigotto and Donna Neuberg, Dana-Farber Cancer Institute, Boston, MA; Nadia Rehman and Ted Wun, University of California at Davis School of Medicine; Nadia Rehman and Ted Wun, VA Northern California Health Care System, Sacramento, CA; Gregory Connolly, University of Rochester Medical Center, Rochester, NY; Jonathan Webster and Michael B. Streiff, Johns Hopkins University School of Medicine, Baltimore, MD; Anita Aggarwal, Dalia Mobarek, Charles Faselis, and Frederick R. Rickles, Veterans Administration Medical Center and The George Washington University, Washington, DC; and Alok A. Khorana, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH.

Purpose: Hospitalized patients with cancer are considered to be at high risk for venous thromboembolism (VTE). Despite strong recommendations in numerous clinical practice guidelines, retrospective studies have shown that pharmacologic thromboprophylaxis is underutilized in hospitalized patients with cancer.

Patients And Methods: We conducted a prospective, cross-sectional study of hospitalized patients with cancer at five academic hospitals to determine prescription rates of thromboprophylaxis and factors influencing its use during hospitalization.

Results: A total of 775 patients with cancer were enrolled across five academic medical centers. Two hundred forty-seven patients (31.9%) had relative contraindications to pharmacologic prophylaxis. Accounting for contraindications to anticoagulation, the overall rate of pharmacologic thromboprophylaxis was 74.2% (95% CI, 70.4% to 78.0%; 392 of 528 patients). Among the patients with cancer without contraindications for anticoagulation, individuals hospitalized with nonhematologic malignancies were significantly more likely to receive pharmacologic thromboprophylaxis than those with hematologic malignancies (odds ratio [OR], 2.34; 95% CI, 1.43 to 3.82; P=.007). Patients with cancer admitted for cancer therapy were significantly less likely to receive pharmacologic thromboprophylaxis than those admitted for other reasons (OR, 0.37; 95% CI, 0.22 to 0.61; P<.001). Sixty-three percent of patients with cancer classified as low risk, as determined by the Padua Scoring System, received anticoagulant thromboprophylaxis. Among the 136 patients who did not receive anticoagulation, 58.8% were considered to be high risk by the Padua Scoring System.

Conclusion: We conclude that pharmacologic thromboprophylaxis is frequently administered to hospitalized patients with cancer but that nearly one third of patients are considered to have relative contraindications for prophylactic anticoagulation. Pharmacologic thromboprophylaxis in hospitalized patients with cancer is commonly prescribed without regard to the presence or absence of concomitant risk factors for VTE.
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http://dx.doi.org/10.1200/JCO.2013.53.5336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039867PMC
June 2014

Safety and feasibility of a diagnostic algorithm combining clinical probability, d-dimer testing, and ultrasonography for suspected upper extremity deep venous thrombosis: a prospective management study.

Ann Intern Med 2014 Apr;160(7):451-7

Background: Although well-established for suspected lower limb deep venous thrombosis, an algorithm combining a clinical decision score, d-dimer testing, and ultrasonography has not been evaluated for suspected upper extremity deep venous thrombosis (UEDVT).

Objective: To assess the safety and feasibility of a new diagnostic algorithm in patients with clinically suspected UEDVT.

Design: Diagnostic management study. (ClinicalTrials.gov: NCT01324037) SETTING: 16 hospitals in Europe and the United States.

Patients: 406 inpatients and outpatients with suspected UEDVT.

Measurements: The algorithm consisted of the sequential application of a clinical decision score, d-dimer testing, and ultrasonography. Patients were first categorized as likely or unlikely to have UEDVT; in those with an unlikely score and normal d-dimer levels, UEDVT was excluded. All other patients had (repeated) compression ultrasonography. The primary outcome was the 3-month incidence of symptomatic UEDVT and pulmonary embolism in patients with a normal diagnostic work-up.

Results: The algorithm was feasible and completed in 390 of the 406 patients (96%). In 87 patients (21%), an unlikely score combined with normal d-dimer levels excluded UEDVT. Superficial venous thrombosis and UEDVT were diagnosed in 54 (13%) and 103 (25%) patients, respectively. All 249 patients with a normal diagnostic work-up, including those with protocol violations (n = 16), were followed for 3 months. One patient developed UEDVT during follow-up, for an overall failure rate of 0.4% (95% CI, 0.0% to 2.2%).

Limitations: This study was not powered to show the safety of the substrategies. d-Dimer testing was done locally.

Conclusion: The combination of a clinical decision score, d-dimer testing, and ultrasonography can safely and effectively exclude UEDVT. If confirmed by other studies, this algorithm has potential as a standard approach to suspected UEDVT.

Primary Funding Source: None.
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http://dx.doi.org/10.7326/M13-2056DOI Listing
April 2014

Capture of lipopolysaccharide (endotoxin) by the blood clot: a comparative study.

PLoS One 2013 25;8(11):e80192. Epub 2013 Nov 25.

Marine Biological Laboratory, Woods Hole, Massachusetts, United States of America ; Department of Molecular and Cellular Biology, University of California Davis, Davis, California, United States of America.

In vertebrates and arthropods, blood clotting involves the establishment of a plug of aggregated thrombocytes (the cellular clot) and an extracellular fibrillar clot formed by the polymerization of the structural protein of the clot, which is fibrin in mammals, plasma lipoprotein in crustaceans, and coagulin in the horseshoe crab, Limulus polyphemus. Both elements of the clot function to staunch bleeding. Additionally, the extracellular clot functions as an agent of the innate immune system by providing a passive anti-microbial barrier and microbial entrapment device, which functions directly at the site of wounds to the integument. Here we show that, in addition to these passive functions in immunity, the plasma lipoprotein clot of lobster, the coagulin clot of Limulus, and both the platelet thrombus and the fibrin clot of mammals (human, mouse) operate to capture lipopolysaccharide (LPS, endotoxin). The lipid A core of LPS is the principal agent of gram-negative septicemia, which is responsible for more than 100,000 human deaths annually in the United States and is similarly toxic to arthropods. Quantification using the Limulus Amebocyte Lysate (LAL) test shows that clots capture significant quantities of LPS and fluorescent-labeled LPS can be seen by microscopy to decorate the clot fibrils. Thrombi generated in the living mouse accumulate LPS in vivo. It is suggested that capture of LPS released from gram-negative bacteria entrapped by the blood clot operates to protect against the disease that might be caused by its systemic dispersal.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080192PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839915PMC
January 2015

Evidence for enhanced tissue factor expression in age-related macular degeneration.

Lab Invest 2011 Apr 1;91(4):519-26. Epub 2010 Nov 1.

Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA.

Tissue factor (TF) is the primary initiator of blood coagulation. In addition to hemostasis, TF can initiate intracellular signaling and promote inflammation and angiogenesis, the key processes underlying the pathogenesis of age-related macular degeneration (AMD). AMD, the leading cause of irreversible blindness among the elderly, involves many genetic and environmental risk factors, including oxidative stress and inflammation. In this study, TF expression was examined in human AMD tissue and in the eyes of a model of AMD, the Ccl2(-/-)/Cx3cr1(-/-) (DKO) mouse, as well as in the ARPE-19 cell line after lipopolysaccharide (LPS) and H(2)O(2) stimulation. Total RNA was extracted from tissue samples and further analyzed by real-time RT-PCR. Immunohistochemistry was performed to evaluate TF protein expression. In the human retina, a 32-fold increase of TF mRNA expression was detected in AMD macular lesions compared with normal maculae. TF protein expression was also enhanced in human AMD maculae. Similarly, TF transcript and protein expression were moderately increased in retinal lesions, neuroretinal tissue, and cultured RPE cells of DKO mice compared with age-matched wild-type mice. TF expression level correlated with age in both wild-type and DKO mice. In order to better understand how AMD might lead to enhanced TF expression, 1, 5, and 10 μg/ml LPS as well as 100 and 200 μM H(2)O(2) were used to stimulate ARPE-19 cells for 24 and 2 h, respectively. LPS treatment consistently increased TF transcript and protein expression. H(2)O(2) alone or in combination with LPS also moderately enhanced TF expression. These results indicate that upregulated TF expression may be associated with AMD, and inflammatory and oxidative stress may contribute to TF expression in AMD eyes.
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http://dx.doi.org/10.1038/labinvest.2010.184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068211PMC
April 2011

Asymptomatic factor VII deficiency: gene analysis and structure-function relationships.

Blood Coagul Fibrinolysis 2010 Jan;21(1):91-4

Department of Medicine, Division of Hematology-Oncology, The George Washington University School of Medicine and Health Sciences and the Children's National Medical Center, Washington, District of Columbia 20037, USA.

Factor VII Padua is a variant form of factor VII deficiency characterized by a prolongation of the prothrombin time (PT), when the assay is performed using rabbit brain thromboplastin. The PT is normal when performed using either human or ox brain thromboplastin reagents, or a recombinant human tissue factor-based thromboplastin. We report a case of an African-American woman with asymptomatic factor VII deficiency, who had a prolonged PT and factor VII activity levels of 5-8% using rabbit brain thromboplastin, but a normal PT and factor VII activity levels when measured using recombinant human brain thromboplastin or tissue factor. The amino acid substitution (R304Q), which gives rise to factor VII Padua, was found in our patient, making this only the fourth African-American case described to date with this mutation. Our report emphasizes the importance of identifying this benign form of factor VII deficiency in order to avoid unnecessary exposure of patients to treatment with either plasma-derived products or recombinant activated factor VII.
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http://dx.doi.org/10.1097/MBC.0b013e328331e708DOI Listing
January 2010

Activation of clotting factors in cancer.

Cancer Treat Res 2009 ;148:31-41

Division of Hematology-Oncology, Department of Medicine, The George Washington University, 2150 Pennsylvania Ave NW Suite 3-428, Washington, DC 20037, USA.

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http://dx.doi.org/10.1007/978-0-387-79962-9_3DOI Listing
October 2010

Thrombosis associated with angiogenesis inhibitors.

Best Pract Res Clin Haematol 2009 Mar;22(1):115-28

Department of Cell Therapy and Haematology, San Bortolo Hospital, Via Rodolfi 37, 36100 Vicenza, Italy.

Recent advances in the understanding of the pathogenesis of cancer have led to the introduction of a variety of biological agents with novel mechanisms of action into clinical trials and even into clinical practice. In particular, tumour-associated neoangiogenesis has become a major target for this new class of antineoplastic agents. Five anti-angiogenic agents (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib) have already obtained US Food and Drug Administration approval for clinical use, and many others have entered clinical trials. Many new biological agents with anti-angiogenic properties appear to be associated with an increased risk for thrombosis and, paradoxically, bleeding. Although the mechanisms underlying the increased thromboembolic risk remain ill defined, the main hypothesis is that perturbation of tumour-associated endothelial cells can switch the endothelium from a naturally anticoagulant surface to a prothrombotic surface, thus mediating the activation of systemic coagulation in cancer patients, who are already more susceptible to thromboembolism due to their underlying disease. The toxicity profile differs between the anti-angiogenic agents. Thalidomide, lenalidomide, semaxibin (SU5416) and prinomastat have produced more venous thromboembolic complications, whereas bevacizumab, sunitinib, sorafenib and ZD6126 have been associated with a higher risk of arterial thromboembolism and, in particular, myocardial ischaemia. The observation of these vascular toxicities suggests the need to establish, in randomized clinical trials, the usefulness of thrombosis prophylaxis when anti-angiogenic agents are used in cancer patients, especially when associated with chemotherapy. In addition, careful reporting of haemostatic complications during treatment with new anti-angiogenic drugs is warranted.
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http://dx.doi.org/10.1016/j.beha.2009.01.001DOI Listing
March 2009

Cancer and thrombosis in women - molecular mechanisms.

Thromb Res 2009 ;123 Suppl 2:S16-20

Departments of Medicine, Pediatrics and Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.

Both women and men with cancer are at increased risk for developing venous thromboembolism (VTE), a propensity that has been known for many years. Until recently it was assumed, however, that the association between cancer and thrombosis is an epiphenomenon - not causally related to the transforming malignant events. The pathophysiology of thrombosis in patients with cancer is complex involving multiple tumor-related and host-related factors. Several recent studies have provided strong evidence that activation of blood coagulation, perhaps most often mediated by tissue factor (TF)-rich microparticles (MPs), is linked directly to oncogene-induced malignant transformation. In addition, the development of VTE, either before or concurrent with the diagnosis of cancer, appears to predict an aggressive behavior of a tumor, and correlates with increased tumor angiogenesis and early onset of distant metastasis. The regulation of expression of TF in tumor cells is controlled at the molecular level by several oncogenes, as appears to be true for cyclooxygenase-2 (COX-2), an important regulator of platelet function and plasminogen activator inhibitor type 1 (PAI-1), an inhibitor of fibrinolysis. In addition, engagement of protease-activated receptors (PARs) by the TF-factor VIIa complex, factor Xa and/or thrombin, have now been shown to be important for tumor growth, angiogenesis and metastasis. Targeting blood clotting reactions in cancer, therefore, may provide a unique approach to cancer treatment.
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http://dx.doi.org/10.1016/S0049-3848(09)70004-0DOI Listing
May 2009

Hemostatic complications of angiogenesis inhibitors in cancer patients.

Am J Hematol 2008 Nov;83(11):862-70

Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy.

Tumor vasculature and tumor-associated neo-angiogenesis have recently become major targets for rational drug design of antineoplastic agents. Five such agents with angiogenesis inhibiting activity (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib) have already obtained US Food and Drug Administration approval for clinical use and many others have entered clinical trials. Vascular complications, including venous or arterial thromboembolism and hemorrhage, have emerged as relevant toxicities in several clinical trials with angiogenesis inhibitors. Given the well-known interplay between the blood clotting system, angiogenesis, and tumor growth, a better understanding of the impact of these new drugs on overall hemostatic balance is required. In this brief overview, we discuss the incidence of hemostatic complications, the likely pathogenetic mechanisms involved, and the critical need to establish in randomized clinical trials the usefulness of thrombosis prophylaxis to prevent these complications. Careful documentation of hemostatic complications during treatment with each of the new antiangiogenic drugs is warranted. Further studies are urgently required to better define the causal association of these new agents with hemostatic complications and to establish the best prophylactic strategy.
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http://dx.doi.org/10.1002/ajh.21277DOI Listing
November 2008

Cancer and thrombosis is a sticky business.

Blood 2008 Oct;112(7):2594-5

The George Washington University, USA.

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http://dx.doi.org/10.1182/blood-2008-07-165647DOI Listing
October 2008

Hypercoagulability and tissue factor gene upregulation in hematologic malignancies.

Semin Thromb Hemost 2008 Mar;34(2):204-10

Department Hematology/Oncology, Ospedali Riuniti di Bergamo, Bergamo, Italy.

Thrombotic complications in patients with hematologic malignancies are as frequent as in those with solid tumors and significantly affect morbidity and mortality. In acute leukemia, thrombosis and bleeding manifestations may occur concomitantly as a part of the same thrombo-hemorrhagic syndrome. In patients with Philadelphia chromosome-negative chronic myeloproliferative disorders (i.e., essential thrombocythemia [ET] and polycythemia vera [PV]), a thrombosis rate as high as 40% has been recorded. A hypercoagulable state is present in virtually all of these patients, even without clinical manifestations. In this review, we focus on the pathogenic mechanisms underlying the hypercoagulable state of these two hematologic malignancies. Although the pathogenesis of hypercoagulability is complex, a central role is played by the fundamental molecular changes of both the leukemic cells and of the progeny arising from the hematopoietic progenitor cells that have undergone clonal rearrangement. These cells overexpress procoagulant factors, as well as adhesion molecules and cytokines capable of inducing procoagulant changes in the vascular wall and stimulating increased cellular interactions. Recent molecular studies in experimental models of human tumors have demonstrated for the first time that oncogene- and repressor gene-mediated neoplastic transformation induces activation of blood coagulation. Similarly, in cells from patients with acute promyelocytic leukemia, the T15-17 translocation induces hyperexpression of tissue factor (TF) and renders the patient hypercoagulable. Furthermore, in blood cells from patients with PV or ET, the presence of the JAK2V617F mutation translates into activation of hemostasis, with increased expression of platelet-associated TF microparticles and the formation of increased platelet/neutrophil aggregates. Understanding the pathophysiology of hypercoagulability is critical to the design of appropriate measures for intervention in these hematologic disorders to prevent thromboembolic complications.
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http://dx.doi.org/10.1055/s-2008-1079262DOI Listing
March 2008

Tissue factor and cancer.

Semin Thromb Hemost 2008 Mar;34(2):143-5

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http://dx.doi.org/10.1055/s-2008-1079253DOI Listing
March 2008

Management of Thrombohemorrhagic Syndromes (THS) in hematologic malignancies.

Hematology Am Soc Hematol Educ Program 2007 :165-71

The George Washington University, 3910 Highwood Ct, NW, Washington DC 20007, USA.

The rate of venous thromboembolism (VTE) in patients with acute leukemia or lymphomas is comparable with that of other "high-risk" cancer types. Chemotherapy and anti-angiogenic drugs increase the thrombotic risk in patients with lymphomas, acute leukemias and multiple myeloma (MM). Patients with hematologic malignancies often present with a hypercoagulable state or chronic disseminated intravascular coagulation (DIC) in the absence of active thrombosis and/or bleeding. Malignant cell procoagulant properties, cytotoxic therapies, and concomitant infections are major determinants for clotting activation in hematologic malignancies. In acute leukemia, clinical manifestations range from localized venous or arterial thrombosis to a diffuse, life-threatening thrombohemorrhagic syndrome (THS). All-trans retinoic acid (ATRA) has greatly improved the management of acute promyelocytic leukemia (APL), but has not significantly changed the rate of early hemorrhagic deaths and may actually promote thrombosis. Randomized, controlled trials (RCTs) of different prophylactic regimens to prevent VTE or THS in hematologic malignancies are urgently needed, particularly in patients with lymphoma or MM during chemotherapy and in patients with APL. Anticoagulant therapy is a particular challenge in patients with hematologic malignancies, since these patients are at very high risk for hemorrhage. No guidelines are available for the prophylaxis or treatment of VTE; extrapolations can be made from existing guidelines for management of patients with other malignancies; prolonged periods of treatment-induced thrombocytopenia in patients with hematologic malignancies, however, require a more judicious application of standard anticoagulant approaches. Use of the newer anticoagulants will require careful assessment of hemorrhagic risk in this group of high-risk patients but may be justified under special circumstances.
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http://dx.doi.org/10.1182/asheducation-2007.1.165DOI Listing
July 2009

Bleeding and thrombosis in acute leukemia: what does the future of therapy look like?

Thromb Res 2007 ;120 Suppl 2:S99-106

George Washington University, Washington, DC, USA, Nobis, Fall Church, VA, USA.

Bleeding and thrombosis are major risk factors for early death in patients with acute leukemia; chemotherapy increases the likelihood of both of these complications. Patients with acute leukemia often present with a hypercoagulable state or with evidence for chronic disseminated intravascular coagulation, even in the absence of active thrombosis and/or bleeding. Leukemic cell procoagulant properties, cytotoxic therapies, and concomitant infections are major determinants of clotting activation in acute leukemia. Clinical manifestations range from localized venous or arterial thrombosis to diffuse life-threatening bleeding. All-trans retinoic acid has greatly improved the management of acute promyelocytic leukemia, but has not significantly changed the rate of early hemorrhagic deaths and may actually promote thrombosis. Randomized, controlled trials of different prophylactic regimens to prevent thrombosis and/or bleeding in acute leukemia are urgently needed, particularly in patients with acute promyelocytic leukemia. Anticoagulant therapy is a unique challenge in patients with acute leukemia, who are at high risk for hemorrhage. Although no guidelines are available for prophylaxis or treatment of thrombosis, extrapolation can be made from existing guidelines for management of patients with other malignancies prolonged periods of treatment-induced thrombocytopenia in patients with acute leukemia, however, require a more judicious application of standard anticoagulant approaches. Use of the newer anticoagulants will require careful assessment of hemorrhagic risk in this group of high risk patients but may be justified under special circumstances.
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http://dx.doi.org/10.1016/S0049-3848(07)70137-8DOI Listing
March 2008

Enhancing participation in clinical research: keys to obtaining informed consent.

J Support Oncol 2007 Jan;5(1):48-50

Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

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January 2007

Mechanisms of cancer-induced thrombosis in cancer.

Pathophysiol Haemost Thromb 2006 ;35(1-2):103-10

The George Washington University School of Medicine and Health Sciences Washington, DC 20037, USA.

Substantial epidemiologic, laboratory, pathologic and clinical evidence supports the historic association between activation of blood coagulation and progression of cancer. The increased risk for venous thromboembolism(VTE) in cancer has been considered an epiphenomenon. However, recent studies from several laboratories have linked more closely malignanttransformation (oncogenesis), tumor angiogenesis and metastasis to the generation of clotting intermediates(e.g. tissue factor [TF], factor Xa and thrombin),clotting or platelet function inhibitors (e.g. COX-2) or fibrinolysis inhibitors (e.g. plasminogen activator inhibitor, type 1 [PAI-1]). Furthermore, TF, Xa and thrombin may induce important tumor cell signaling cascades in a clotting-dependent and/or clotting independent manner (e.g. thru engagement of protease-activated receptors [PARs]). Targeting blood clotting reactions in cancer may provide a unique approach to cancer treatment.
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http://dx.doi.org/10.1159/000093551DOI Listing
September 2006

Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism.

J Clin Oncol 2005 Apr 7;23(10):2123-9. Epub 2005 Feb 7.

Hamilton Health Science, Henderson Hospital, Room 9, 90 Wing, 711 Concession St, Hamilton, ON L8V 1C3, Canada.

Purpose: Experimental studies and indirect clinical evidence suggest that low molecular weight heparins may have antineoplastic effects. We investigated the influence of a low molecular weight heparin dalteparin on the survival of patients with active cancer and acute venous thromboembolism.

Patients And Methods: Survival data were examined in a posthoc analysis in patients with solid tumors and venous thromboembolism who were randomly assigned to dalteparin or a coumarin derivative for 6 months in a multicenter, open-label, randomized, controlled trial. All-cause mortality at 12 months was compared between treatment groups in patients with and without metastatic malignancy. The effect of dalteparin on survival was compared between the two patient subgroups.

Results: During the 12-month follow-up period, 356 of 602 patients with solid tumors and acute venous thromboembolism died. Among patients without metastatic disease, the probability of death at 12 months was 20% in the dalteparin group, as compared with 36% in the oral anticoagulant group (hazard ratio, 0.50; 95% CI, 0.27 to 0.95; P = .03). In patients with metastatic cancer, no difference in mortality between the treatment groups was observed (72% and 69%, respectively; hazard ratio, 1.1; 95% CI, 0.87 to 1.4; P = .46). The observed effects of dalteparin on survival were statistically significantly different between patients with and without metastatic disease (P = .02).

Conclusion: The use of dalteparin relative to coumarin derivatives was associated with improved survival in patients with solid tumors who did not have metastatic disease at the time of an acute venous thromboembolic event. Additional studies are warranted to investigate these findings.
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http://dx.doi.org/10.1200/JCO.2005.03.133DOI Listing
April 2005

Meeting report. Acute promyelocytic leukemia-associated coagulopathy, 21 January 2004, London, United Kingdom.

Leuk Res 2005 Mar;29(3):347-51

Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Robert H Lurie Comprehensive Cancer Centre, 676 N. St. Clair Street, Suite 850, Chicago, IL 60611, USA.

Despite successful treatment with all-trans retinoic acid and chemotherapy, life-threatening bleeding remains a challenging complication of acute promyelocytic leukemia (APL). Indeed, bleeding and thrombosis are major complications of APL that lead to early death in approximately 10% of patients despite the success of current treatment. This condition may be attributed, in part, to the diffuse activation of coagulation, hyperfibrinolysis, and non-specific proteolytic activity that is observed in patients with APL. Therapeutic agents that induce the differentiation of leukemia cells improve outcomes compared with those observed using chemotherapy alone. They also correct the hyperactivity of the coagulation and fibrinolytic systems, thereby reducing early death from bleeding. Prophylactic therapy with newer anticoagulants may prove beneficial in patients with APL, but this must be confirmed in well-designed, randomized, controlled trials. A workshop was convened 21 January 2004 in London, England, to discuss the clinical and biological aspects of the APL-associated coagulopathy and the application of recent findings to the management of patients with APL. Eight speakers participated in the workshop. This meeting report provides synopses of their presentations and a summary of highlights from the meeting.
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http://dx.doi.org/10.1016/j.leukres.2004.04.021DOI Listing
March 2005

Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents.

Bioorg Med Chem 2004 Jul;12(14):3871-83

Winship Cancer Institute and Department of Chemistry, Emory University, Atlanta, GA 30322, USA.

A series of novel curcumin analogs were synthesized and screened for anti-cancer and anti-angiogenesis activities at Emory University and at the National Cancer Institute (NCI). These compounds are symmetrical alpha,beta-unsaturated and saturated ketones. The majority of the analogs demonstrated a moderate degree of anti-cancer activity. Compounds 10, 11, and 14 exhibited a high degree of cytotoxicity in the NCI in vitro anti-cancer cell line screen. In addition, this screen revealed that these compounds inhibit tumor cell growth with a higher potency than the commonly used chemotherapeutic drug, cisplatin. In independent in vitro screens conducted at Emory, the same compounds plus 4, 5, 8, 9, and 13 exhibited a high degree of cytotoxicity to tumor cells. Analogs that were effective in the anti-cancer screens were also effective in in vitro anti-angiogenesis assays. Compounds 4, 9, 11, and 14 were most effective in the anti-angiogenesis assays run at Emory. In the assays conducted by the NCI, compound 14 was almost as potent as the anti-angiogenic drug TNP-470, which has undergone clinical trials. Based on the favorable in vitro anti-cancer and anti-angiogenesis results with 14, further in vivo tests were conducted. This compound effectively reduced the size of human breast tumors grown in female athymic nude mice and showed little toxicity. This data, coupled with the remarkable in vitro data, suggests that compound 14 may potentially be an effective chemotherapeutic agent. As a follow-up, a 3D quantitative structure relationship based on 14 has been developed. It shows a cross-validated r2(q2) and a predictive r2(p2) = 0.71. COMPARE analysis suggests the compound to be a possible RNA/DNA antimetabolite, but also implies that the compound's cytotoxicity may arise from a presently unknown mechanism.
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http://dx.doi.org/10.1016/j.bmc.2004.05.006DOI Listing
July 2004

Tissue factor and fibrin in tumor angiogenesis.

Semin Thromb Hemost 2004 Feb;30(1):31-44

Department of Pharmacology, George Washington University Medical Center, Washington, DC, USA.

The hypercoagulability exhibited by most cancer patients leads to serious complications such as venous thromboembolism and contributes to the pathogenesis of tumor growth and metastasis by promoting angiogenesis. The key player in this vicious cycle is tissue factor (TF), the initiator of blood coagulation. Although TF normally safeguards vascular integrity by inducing hemostasis upon injury, abnormal expression of TF in different tumors and related vascular endothelial cells contributes to unnecessary clot formation in cancer patients. Clotting-dependent induction of tumor angiogenesis is primarily mediated by TF-induced generation of thrombin and subsequent deposition of cross-linked fibrin. A cross-linked fibrin network provides a provisional proangiogenic matrix that facilitates blood vessel infiltration. Clotting-independent mechanisms of TF-induced tumor angiogenesis have also been described, mediated primarily by the cytoplasmic tail of the TF receptor. TF activation could contribute to the venous thromboembolism that has been reported as a complication of the use of novel antiangiogenic agents in combination with chemotherapy. Anticoagulants, such as low-molecular-weight heparin, may act to prevent these complications both by interfering with TF-mediated activation of clotting and by directly down-regulating angiogenesis. Thus, TF may prove to be a novel target for cancer therapy.
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http://dx.doi.org/10.1055/s-2004-822969DOI Listing
February 2004

Tissue factor, thrombin, and cancer.

Chest 2003 Sep;124(3 Suppl):58S-68S

Department of Medicine, George Washington University, Washington, DC, USA.

In addition to its primary role in hemostasis and blood coagulation, thrombin is a potent mitogen capable of inducing cellular functions. Therefore, it should come as no surprise that thrombin has proved to be of importance in the behavior of cancer. In this review, we focus on the ability of tissue factor (TF) and thrombin to influence tumor angiogenesis. Both exert their influence on angiogenesis through clotting-dependent and clotting-independent mechanisms: (1). directly affecting signaling pathways that mediate cell functions, and (2). mediating clot formation, thereby providing a growth media for tumor cells. Therefore, anticoagulant drugs may prove efficacious in cancer treatment due to their ability to reduce the characteristic hypercoagulability of cancer and alter the fundamental biology of cancer.
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http://dx.doi.org/10.1378/chest.124.3_suppl.58sDOI Listing
September 2003