warfarin and Lung-Neoplasms

Diagnostic bronchoscopy and tissue sampling techniques using forceps (endobronchial biopsy [EBB] and transbronchial biopsies [TBB]) or needle aspiration (transbronchial needle aspiration-TBNA), all performed with a flexible bronchoscope, are the basic elements of any interventional procedure. The flexible fibrobronchoscopy allows the visualization of the airways and is used both for diagnostic and therapeutic purposes. The working channel of both fibrobronchoscopes with optical fibers and videobronchoscopes, even if of relatively small diameter, allows the insertion of various diagnostic and therapeutic accessories. Fiber optic systems have been widely replaced by video cameras using a miniaturized charge-coupled device camera positioned at the end of the scope that provides electronic transmission of images to a monitor. The indications for both diagnostic and therapeutic fibrobronchoscopy derive from a correct evaluation of symptoms and objective signs of the patient and from the correct interpretation of imaging methods. Although bronchoscopy techniques keep evolving at a rapid pace, basic procedures such as bronchoalveolar lavage, transbronchial lung biopsy, and transbronchial needle aspiration still play a key role in pulmonary disease diagnostics, and therefore, these methods must still be part of the training of interventional pulmonologists. Trainees will acquire a thorough knowledge of thoracic anatomy and become skilled in the interpretation of thoracic imaging, after which they will be given a theoretical and practical training course on virtual reality simulators, on animal or cadaver models, the effectiveness of which has been fully demonstrated by scientific studies. Specific DOPS tests have been developed for a qualitative evaluation of procedures on simulators, on animal models and on the patient.

Topics: Anticoagulants; Biopsy, Needle; Bronchoscopy; Clinical Competence; Computer Simulation; Endoscopy; Equipment Design; Humans; Lung; Lung Diseases; Lung Diseases, Interstitial; Lung Neoplasms; Optical Fibers; Platelet Aggregation Inhibitors; Pulmonary Medicine; Purinergic P2Y Receptor Antagonists; Video Recording; Warfarin

Venous thromboembolism (VTE) is a common problem in cancer patients and the incidence is increasing, especially for patients with lung cancer. Common features of these patients, like advanced stage, male gender, old age and chemotherapy, are risk factors of VTE. Here we reported a case in which the patient with lung cancer developed deep vein thrombosis (DVT) when receiving chemotherapy.. A 53-year-old male who was diagnosed with lung cancer with multiple metastasis developed severe DVT during chemotherapy. Despite the use of aspirin, warfarin and low molecular weight heparin (LMWH) for anticoagulant and thrombolytic therapy, the condition was still deteriorating, resulting in amputation finally.. It's rare that the conditions of cancer patients who develop venous thromboembolism (VTE) keep deteriorating despite the administration of aspirin, warfarin and low weight molecular heparin. Both early diagnosis and prophylactic use of anticoagulants are suggested for cancer patients to improve the prognosis.

Topics: Amputation, Surgical; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Humans; Lung Neoplasms; Male; Middle Aged; Paclitaxel; Treatment Failure; Venous Thrombosis; Warfarin

Venous thromboembolism (Wickham et al., 2012 [1]) is a leading cause of morbidity and mortality among patients with cancer; however, primary thromboprophylaxis is not routinely recommended. We performed a systematic review and meta-analysis of randomized control trials (RCTs) to measure the impact of primary VTE prevention and its effect on mortality among patients with lung cancer.. With assistance from a master librarian, we searched Ovid, Scopus, DARE, CINAHL, MEDLINE, EMBASE, EBM reviews-Cochrane database of systematic reviews, EBM reviews-ACP journal, and EBM Reviews-Databases for relevant studies following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We included articles addressing the role of anticoagulation in patients with lung cancer for primary VTE prevention for outpatients. The clinical outcomes were VTE occurrence, all-cause mortality, major and clinically relevant non-major bleeding. The results are presented as odds ratio (OR) and data were analyzed using R and R META package (Version 0.8-2, Author: Guido Schwarzer).. Eleven studies with 5107 patients were included for the final analysis. We found 50% lower VTE occurrence in the prophylaxis group with low molecular weight heparin (LMWH) (OR: 0.50; 95% Confidence Interval (CI): 0.38-0.66; I2: 0%) without an increased bleeding risk (OR: 2.03; 95% CI: 0.78-5.25; I2: 71.1%). We found a mortality benefit when we grouped all VTE prevention modalities [LMWH, Warfarin, unfractionated heparin (UFH)] (OR: 0.75; 95% CI: 0.58-0.96; I2: 18.4%), but no significant difference when LMWH (OR: 0.74; 95% CI: 0.49-1.11; I2: 56.9%) and warfarin were analyzed individually (OR: 0.75; 95% CI: 0.47-1.21; I2: 0%). We found higher odds of bleeding combining all treatment modalities (OR: 3.06; 95% CI: 1.64-5.72; I2: 64.4%) with the greatest occurrence in the warfarin group (OR: 5.42; 95% CI: 3.48-8.45; I2: 45.7%).. Primary VTE prophylaxis with LMWH reduces the occurrence of VTE among ambulatory patients with lung cancer, without apparent increase in bleeding risk. There is a measurable mortality benefit of anticoagulation strategies that remains elusive when the analysis is restricted to a single agent.

Topics: Anticoagulants; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Lung Neoplasms; Odds Ratio; Treatment Outcome; Venous Thromboembolism; Warfarin

Oral anticoagulants may improve the survival of people with cancer through both an antitumor effect and antithrombotic effect, yet increase the risk of bleeding.. To evaluate the efficacy and safety of oral anticoagulants in ambulatory people with cancer undergoing chemotherapy, hormonal therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation.. We conducted a comprehensive literature search in February 2016 that included a major electronic search of Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 1), MEDLINE (Ovid) and Embase (Ovid); handsearching of conference proceedings; checking of references of included studies; a search for ongoing studies; and using the 'related citation' feature in PubMed. As part of the living systematic review approach, we are running continual searches and will incorporate new evidence rapidly after it is identified. This update of the systematic review is based on the findings of a literature search conducted on 14 December 2017.. Randomized controlled trials (RCTs) assessing the benefits and harms of vitamin K antagonist (VKA) or direct oral anticoagulants (DOAC) in ambulatory people with cancer. These participants are typically undergoing systemic anticancer therapy, possibly including chemotherapy, target therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation.. Using a standardized form, we extracted data in duplicate on study design, participants, intervention outcomes of interest and risk of bias. Outcomes of interest included all-cause mortality, symptomatic venous thromboembolism (VTE), symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), major bleeding, minor bleeding and health-related quality of life (HRQoL). We assessed the certainty of evidence for each outcome using the GRADE approach (GRADE Handbook).. Of 8545 identified citations, including 7668 unique citations, 16 papers reporting on 7 RCTs fulfilled the inclusion criteria. These trials enrolled 1486 participants. The oral anticoagulant was warfarin in six of these RCTs and apixaban in the seventh RCT. The comparator was either placebo or no intervention. The meta-analysis of the studies comparing VKA to no VKA did not rule out a clinically significant increase or decrease in mortality at one year (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.87 to 1.03; risk difference (RD) 29 fewer per 1000, 95% CI 75 fewer to 17 more; moderate certainty evidence). One study assessed the effect of VKA on thrombotic outcomes. The study did not rule out a clinically significant increase or decrease in PE when comparing VKA to no VKA (RR 1.05, 95% CI 0.07 to 16.58; RD 0 fewer per 1000, 95% CI 6 fewer to 98 more; very low certainty evidence), but found that VKA compared to no VKA likely decreases the incidence of DVT (RR 0.08, 95% CI 0.00 to 1.42; RD 35 fewer per 1000, 95% CI 38 fewer to 16 more; low certainty evidence). VKA increased both major bleeding (RR 2.93, 95% CI 1.86 to 4.62; RD 107 more per 1000, 95% CI 48 more to 201 more; moderate certainty evidence) and minor bleeding (RR 3.14, 95% CI 1.85 to 5.32; RD 167 more per 1000, 95% CI 66 more to 337 more; moderate certainty evidence).The study assessing the effect of DOAC compared to no DOAC did not rule out a clinically significant increase or decrease in mortality at three months (RR 0.24, 95% CI 0.02 to 2.56; RD 51 fewer per 1000, 95% CI 65 fewer to 104 more; low certainty evidence), PE (RR 0.16, 95% CI 0.01 to 3.91; RD 28 fewer per 1000, 95% CI 33 fewer to 97 more; low certainty evidence), symptomatic DVT (RR 0.07, 95% CI 0.00 to 1.32; RD 93 fewer per 1000, 95% CI 100 fewer to 32 more; low certainty evidence), major bleeding (RR 0.16, 95% CI 0.01 to 3.91; RD 28 fewer per 1000, 95% CI 33 fewer to 97 more; low certainty evidence); and minor bleeding (RR 4.43, 95% CI 0.25 to 79.68; RD 0 fewer per 1000, 95% CI 0 fewer to 8 more; low certainty evidence).. The existing evidence does not show a mortality benefit from oral anticoagulation in people with cancer but suggests an increased risk for bleeding.Editorial note: this is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence, as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Female; Hemorrhage; Heparin; Humans; Lung Neoplasms; Male; Neoplasms; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Thromboembolism; Time Factors; Warfarin

Trapeziometacarpal osteoarthritis is associated with more pain and restrictions than other hand osteoarthritis due to the functional importance of the thumb. While the effectiveness of surgical and pharmacological interventions has been widely examined, there is a lack of specific evidence about conservative non-pharmacological trapeziometacarpal osteoarthritis therapies. The objective of this systematic review was to provide evidence-based knowledge on the effectiveness of physiotherapy and occupational therapy on pain, function and quality of life.. A literature search of Medline, CINAHL, PEDro, OTseeker, EMB Dare Cochrane Database of Systematic Reviews and Cochrane CENTRAL was performed. Randomized and quasi-randomized controlled trials and corresponding systematic reviews, observational studies, pragmatic studies and case-control studies were included. The risk of bias was assessed.. Physical and occupational therapy-related interventions, especially multimodal interventions, seem to be effective to treat pain in patients with trapeziometacarpal osteoarthritis. Pre-fabricated neoprene splints and custom-made thermoplastic splints may reduce pain equally. Single interventions seem not to be effective. Significant evidence for effectiveness on function and quality of life could not be found.. The sole Na. The SUV. Genetic variants of

Topics: AC133 Antigen; Acenaphthenes; Acer; Acrosome Reaction; Adult; Agaricales; Aged; Aged, 80 and over; Animals; Animals, Zoo; Anti-Bacterial Agents; Anticoagulants; Antifungal Agents; Antimanic Agents; Antioxidants; Aortic Valve; Area Under Curve; ATP Binding Cassette Transporter, Subfamily G, Member 2; Bacillus; Bacterial Toxins; Bacterial Typing Techniques; Base Composition; Beauveria; Binge Drinking; Biomarkers; Bipolar Disorder; Blood Coagulation; Blotting, Western; Brachytherapy; Calcium Channels, L-Type; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Wall; Cells, Cultured; Ceramics; Chi-Square Distribution; China; Chlorophyll; Chlorophyta; Chloroplasts; Cholesterol, HDL; Chromatography, High Pressure Liquid; Chromobacterium; Clostridium perfringens; Clozapine; Constriction, Pathologic; Coronary Artery Bypass; Corticotropin-Releasing Hormone; Cross-Sectional Studies; Cytochrome P-450 CYP2C9; Dental Porcelain; Dental Restoration Failure; Dental Stress Analysis; Designer Drugs; Diaminopimelic Acid; DNA Fingerprinting; DNA, Bacterial; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Dosage Calculations; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Elasticity Imaging Techniques; Epsilonproteobacteria; Equipment Design; Ericaceae; Excitatory Amino Acid Antagonists; False Negative Reactions; Fatty Acids; Female; Food Analysis; Fresh Water; Gene Expression Regulation, Neoplastic; Glutathione; Graft Occlusion, Vascular; Heart Valve Prosthesis Implantation; Heart Ventricles; HEK293 Cells; Hemolymph; Humans; Hyaluronan Receptors; Hydrogen Peroxide; Hydrothermal Vents; Indoles; Inflammation Mediators; Inhibitory Concentration 50; Insecta; International Normalized Ratio; Isotope Labeling; Itraconazole; Kidney; Kinetics; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lamotrigine; Lanthanoid Series Elements; Limit of Detection; Linear Models; Lipid Peroxidation; Liver; Liver Cirrhosis; Logistic Models; Lung Neoplasms; Lymph Node Excision; Lymphatic Metastasis; Male; Malondialdehyde; Mediastinum; Metronidazole; Mice; Mice, Nude; Mice, Transgenic; Microbial Sensitivity Tests; Microscopy, Fluorescence; Middle Aged; Monocytes; Monomeric GTP-Binding Proteins; Multivariate Analysis; Myocytes, Cardiac; Neoplasm Staging; Neoplastic Stem Cells; Neural Pathways; Nitrates; Nucleic Acid Hybridization; Octamer Transcription Factor-3; Odds Ratio; Oxidation-Reduction; Oxidative Stress; Peptidoglycan; Phantoms, Imaging; Pharmacogenetics; Pharmacogenomic Variants; Phenotype; Phospholipids; Photolysis; Photosynthesis; Phylogeny; Plant Extracts; Polychaeta; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Positron Emission Tomography Computed Tomography; Predictive Value of Tests; Preoperative Care; Prostatic Neoplasms; Pseudomonas aeruginosa; Pyrimidines; Pyrroles; Quorum Sensing; Radiology, Interventional; Radiopharmaceuticals; Radiotherapy Dosage; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Reference Values; Regression Analysis; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Rhizosphere; Risk Factors; RNA, Ribosomal, 16S; ROC Curve; Rutin; Saphenous Vein; Seawater; Selenium; Semen Preservation; Sensitivity and Specificity; Septal Nuclei; Sequence Analysis, DNA; Serum Albumin; Serum Albumin, Human; Shear Strength; Sodium Pertechnetate Tc 99m; Sodium-Hydrogen Exchangers; Soil Microbiology; SOXB1 Transcription Factors; Spain; Species Specificity; Sperm Motility; Spermatozoa; Spheroids, Cellular; Spores, Fungal; Stroke; Superoxide Dismutase; Swine; Tandem Mass Spectrometry; Technetium Compounds; Technetium Tc 99m Exametazime; Technetium Tc 99m Sestamibi; Temperature; Thiosulfates; Thrombosis; Thyroid Neoplasms; Transducers; Transfection; Transplantation, Heterologous; Treatment Outcome; Triazines; Tumor Burden; Urocortins; Uterine Cervical Neoplasms; Vacuoles; Valproic Acid; Ventral Tegmental Area; Vitamin K 2; Vitamin K Epoxide Reductases; Warfarin; Water Microbiology; Young Adult

Several basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect.. To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. We performed a comprehensive search for studies of anticoagulation in patients with cancer including 1. a February 2013 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE; 2. a handsearch of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with the 2003 issue); 3. checking of references of included studies; 4. use of the 'related citation' feature in PubMed; and 5. searching clinical trials.gov for ongoing studies.. Randomized controlled trials (RCTs) comparing vitamin K antagonist or other oral anticoagulants with no intervention or placebo in patients with cancer without clinical evidence of venous thromboembolism.. Using a standardized data form, we extracted data on risk of bias, participants, interventions and outcomes of interest that included all-cause mortality, venous thromboembolism, major bleeding, and minor bleeding.. Of 9559 identified citations, seven RCTs (eight reports) fulfilled the inclusion criteria. The oral anticoagulant was warfarin in six of these RCTs and apixaban in the seventh RCT. The comparator was either placebo or no intervention. The use of warfarin had no effect on mortality at six months (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.82 to 1.22), one year (RR 0.97; 95% CI 0.89 to 1.04), two years (RR 0.98; 95% CI 0.81 to 1.18), or five years (RR 0.92; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and did not show or exclude a beneficial or detrimental of effect (RR 0.15; 95% CI 0.02 to 1.20). Warfarin increased both major bleeding (RR 4.24; 95% CI 1.86 to 9.65) and minor bleeding (RR 3.19; 95% CI 1.83 to 5.55). We judged the quality of evidence as moderate for all outcomes.The study assessing the effect of apixaban did not show or exclude a beneficial effect or detrimental of apixaban on mortality at six months (RR 0.16; 95% CI 0.01 to 1.66); major bleeding (RR 0.62; 95% CI 0.06 to 6.63); and minor bleeding (RR 2.87; 95% CI 0.16 to 51.82). We judged the quality of evidence as low for all outcomes.. Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while the risk for bleeding is increased.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Humans; Lung Neoplasms; Neoplasms; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Thromboembolism; Time Factors; Warfarin

Several basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect.. To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. We performed a comprehensive search for studies of anticoagulation in patients with cancer including 1. a February 2013 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE; 2. a handsearch of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with the 2003 issue); 3. checking of references of included studies; 4. use of the 'related citation' feature in PubMed; and 5. searching clinical trials.gov for ongoing studies.. Randomized controlled trials (RCTs) comparing vitamin K antagonist or other oral anticoagulants with no intervention or placebo in patients with cancer without clinical evidence of venous thromboembolism.. Using a standardized data form, we extracted data on risk of bias, participants, interventions and outcomes of interest that included all-cause mortality, venous thromboembolism, major bleeding, and minor bleeding.. Of 9559 identified citations, seven RCTs (eight reports) fulfilled the inclusion criteria. The oral anticoagulant was warfarin in six of these RCTs and apixaban in the seventh RCT. The comparator was either placebo or no intervention. The use of warfarin had no effect on mortality at six months (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.82 to 1.22), one year (RR 0.97; 95% CI 0.89 to 1.04), two years (RR 0.98; 95% CI 0.81 to 1.18), or five years (RR 0.92; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and did not show or exclude a beneficial or detrimental of effect (RR 0.15; 95% CI 0.02 to 1.20). Warfarin increased both major bleeding (RR 4.24; 95% CI 1.86 to 9.65) and minor bleeding (RR 3.19; 95% CI 1.83 to 5.55). We judged the quality of evidence as moderate for all outcomes.The study assessing the effect of apixaban did not show or exclude a beneficial effect or detrimental of apixaban on mortality at six months (RR 0.16; 95% CI 0.01 to 1.66); major bleeding (RR 0.62; 95% CI 0.06 to 6.63); and minor bleeding (RR 2.87; 95% CI 0.16 to 51.82). We judged the quality of evidence as low for all outcomes.. Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while the risk for bleeding is increased.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Female; Hemorrhage; Heparin; Humans; Lung Neoplasms; Male; Neoplasms; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Thromboembolism; Time Factors; Warfarin

The effect of anticoagulant adjuvant anti-tumor therapy depends on the cancer type and stage and on the type of the used anticoagulant drug. A striking response rate was described in experiments involving human patients with lung cancer. The aim of this study is to review anticoagulant and fibrinolytic drugs as antitumor agents with focus on their clinical use. The first part of the review evaluates the results of clinical studies. The results of early clinical research are promising and observations suggest novel approaches to the experimental therapy of lung cancer. The second part of the review shortly describes the problem of thrombosis in patients with lung cancer (incidence of thromboembolic disease and its pathogenesis). The third part briefly describes the antimetastatic and antitumor attributes of anticoagulants and fibrinolytics.

Topics: Anticoagulants; Antineoplastic Agents; Carcinoma; Clinical Trials as Topic; Fibrinolytic Agents; Heparin; Humans; Lung Neoplasms; Thromboembolism; Thrombosis; Warfarin

Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect.. To evaluate the efficacy and safety of parenteral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. A comprehensive search included (1) an electronic search (February 2010) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) Issue 1, 2010, MEDLINE, EMBASE and ISI the Web of Science; (2) handsearch of conference proceedings; (3) checking of references of included studies; and (4) use of the 'related citation' feature in PubMed.. Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in patients with cancer but no therapeutic or prophylactic indication for anticoagulation.. Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all-cause mortality, symptomatic thromboembolism, major bleeding, minor bleeding and quality of life (QoL).. Of 8187 identified citations, nine RCTs enrolling 2857 patients fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, the effect of heparin therapy on mortality was not statistically significant at 12 months (risk ratio (RR) 0.93; 95% CI 0.85 to 1.02) but it was statistically significant at 24 months (RR 0.92; 95% CI 0.88 to 0.97). Heparin therapy was associated with a statistically and clinically important reduction in venous thromboembolism (RR 0.55; 95% CI 0.37 to 0.82). There were no statistically significant effects on major bleeding (RR 1.30; 95% CI 0.59 to 2.88), minor bleeding (RR 1.05; 95% 0.75 to 1.46) or QoL. The quality of evidence was high for symptomatic venous thromboembolism, moderate for mortality, major bleeding and minor bleeding, and low for QoL.. Heparin was associated with a significant reduction of death at 24 months but not 12 months. It was also associated with a reduction in venous thromboembolism but based on the RCTs in this review it had no significant effect on major bleeding, minor bleeding or QoL. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides and integrate the patient's values and preferences.

Topics: Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Survival Analysis; Time Factors; Venous Thromboembolism; Warfarin

A number of basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect.. To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. A comprehensive search for studies of anticoagulation in cancer patients including (1) a February 2010 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, ISI the Web of Science; (2) hand search of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with its 2003 issue); (3) checking of references of included studies; and (4) use of "related article" feature in PubMed.. Randomized controlled trials (RCTs) comparing vitamin K antagonist or other oral anticoagulants to no intervention or placebo in cancer patients without clinical evidence of venous thromboembolism.. Using a standardized data form we extracted data on risk of bias, participants, interventions and outcomes of interest that included all cause mortality, venous thromboembolism, major bleeding and minor bleeding.. Of 8187 identified citations, five RCTs fulfilled the inclusion criteria. Warfarin was the oral anticoagulant in all of these RCTs and it was compared to either placebo or no intervention. The quality of evidence was moderate for all outcomes. The effect of warfarin on reduction in mortality was not statistically significant at six months (Relative risk (RR) = 0.96; 95% CI 0.80 to 1.16), at one year (RR = 0.94; 95% CI 0.8 to 1.03) at two years (RR = 0.97; 95% CI 0.87 to 1.08) or at five years (RR 0.91; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and showed a RR reduction of 85% (P = 0.031). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85 to 9.68) and minor bleeding (RR = 3.34; 95% CI 1.66 to 6.74).. Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while increasing the risk for bleeding.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Thromboembolism; Time Factors; Warfarin

A number of basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect.. To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. A comprehensive search for studies of anticoagulation in cancer patients including (1) a February 2010 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, ISI the Web of Science; (2) hand search of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with its 2003 issue); (3) checking of references of included studies; and (4) use of "related article" feature in PubMed.. Randomized controlled trials (RCTs) comparing vitamin K antagonist or other oral anticoagulants to no intervention or placebo in cancer patients without clinical evidence of venous thromboembolism.. Using a standardized data form we extracted data on risk of bias, participants, interventions and outcomes of interest that included all cause mortality, venous thromboembolism, major bleeding and minor bleeding.. Of 8187 identified citations, five RCTs fulfilled the inclusion criteria. Warfarin was the oral anticoagulant in all of these RCTs and it was compared to either placebo or no intervention. The quality of evidence was moderate for all outcomes. The effect of warfarin on reduction in mortality was not statistically significant at six months (Relative risk (RR) = 0.96; 95% CI 0.80 to 1.16), at one year (RR = 0.94; 95% CI 0.8 to 1.03) at two years (RR = 0.97; 95% CI 0.87 to 1.08) or at five years (RR 0.91; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and showed a RR reduction of 85% (P = 0.031). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85 to 9.68) and minor bleeding (RR = 3.34; 95% CI 1.66 to 6.74).. Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while increasing the risk for bleeding.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Thromboembolism; Warfarin

Patients with cancer, including lung cancer are at an increased risk for venous thromboembolism and frequently are anticoagulated. Due to concerns of bleeding and drug-drug interactions, many clinical trials suggest the use of low-molecular-weight heparin (LMWH) rather than warfarin (coumadin) for patients requiring anticoagulation. We sought to evaluate, in a retrospective analysis, whether these recommendations were appropriate.. A pooled analysis of three lung cancer trials conducted by the NCIC Clinical Trials Group was performed to evaluate the risk of bleeding in patients receiving warfarin or LMWH; concomitant usage of nonsteroidal antinflammatories or aspirin. The Mantel-Haentzel test stratified by treatment group was used to analyze the prevalence of bleeding (all and > or =grade 3) according to LMWH, warfarin or nonsteroidal antiinflammatory drugs usage. Logistic regression was used to adjust for baseline characteristics including age, sex, performance status, creatinine, platelets.. Although bleeding was reported in a quarter of patients, only 2% experienced severe bleeding, with rates similar across the trials. In univariate analyses the risk of bleeding seemed higher with LMWH or warfarin usage, history of bleeding, thrombocytopenia, and increased age. However, in adjusted analyses only warfarin use was a significant risk factor (p = 0.073).. In this retrospective analysis, warfarin seemed to increase the risk of bleeding in lung cancer patients enrolled in clinical trials. Current recommendations in many clinical trials to preferentially use LMWH seem appropriate.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Lung Diseases; Lung Neoplasms; Male; Prognosis; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Venous Thromboembolism; Warfarin

A number of basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumour effect in addition to their antithrombotic effect.. To evaluate the effectiveness and safety of oral anticoagulation (including vitamin K antagonists and ximelagatran) as an intervention to improve survival of patients with cancer.. A comprehensive search for studies of anticoagulation in cancer patients including (1) a January 2007 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, ISI the Web of Science; (2) hand search of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with its 2003 issue); (3) checking of references of included studies; and (4) use of "related article" feature in PubMed.. Randomized clinical trials (RCTs) comparing vitamin K antagonist or ximelagatran to no intervention or placebo in cancer patients without clinical evidence of venous thromboembolism.. Using a standardized data form we extracted data on methodological quality, participants, interventions and outcome of interest that included all cause mortality, symptomatic deep venous thrombosis, symptomatic pulmonary embolism, major bleeding and minor bleeding.. Of 3986 identified citations five RCTs fulfilled the inclusion criteria. Warfarin was the oral anticoagulant in all of these RCTs and it was compared to either placebo or no intervention. The overall methodological quality of these RCTs was acceptable. The effect of warfarin on reduction in mortality was not statistically significant at six months (Relative risk (RR) = 0.96; 95% CI 0.80 to 1.16), at one year (RR = 0.95; 95% CI 0.86 to 1.05) at 2 years (RR = 0.97; 95% CI 0.87 to 1.08) or at five years (RR 0.91; 95% CI 0.83 to 1.01). In the subgroup of patients with small cell lung cancer (SCLC), warfarin reduced mortality at six months (RR = 0.69; 95% CI 0.50 to 0.96) but not at one year (RR = 0.88; 95% CI 0.77 to 1.01). This six month mortality benefit was statistically significant in the subgroup of extensive SCLC (RR = 0.65; 95% CI 0.45 to 0.93) but not in the subgroup of limited SCLC (RR = 0.68; 95% CI 0.36 to 1.28). One study assessed the effect of warfarin on venous thromboembolism and showed a RR reduction of 85% (p = 0.031). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85 to 9.68) and minor bleeding (RR = 3.34; 95% CI 1.66 to 6.74). Warfarin increased the risk of major bleeding (RR 5.46; 95% CI 3.04 to 9.81) and minor bleeding (RR 4.01; 95% CI 1.30 to 12.42) also in patients with SCLC. There was no evidence for a significant reduction in mortality in any other cancer subtype.. Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer. In patients with SCLC, the evidence suggests a survival benefit at six months from warfarin particularly when the disease is extensive. The decision for a patient with extensive SCLC to start warfarin for survival benefit should balance that benefit with the downsides of increased bleeding risk in light of patient values for these outcomes.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Thromboembolism; Warfarin

Basic research and clinical studies have generated the hypothesis that anticoagulation may improve survival in patients with cancer through an antitumour effect in addition to the antithrombotic effect.. To evaluate the efficacy and safety of heparin (including unfractionated heparin (UFH) and low molecular weight heparin (LMWH)) and fondaparinux to improve survival of patients with cancer.. A comprehensive search for studies of anticoagulation in cancer patients including (1) A January 2007 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI the Web of Science; (2) Hand search of the American Society of Clinical Oncology and of the American Society of Hematology; (3) Checking of references of included studies; and (4) Use of "related article" feature in PubMed.. We included randomized controlled trials (RCTs) in cancer patients without clinical evidence of venous thromboembolism comparing UFH, LMWH or fondaparinux to no intervention or placebo and RCTs comparing two of the three agents of interest.. Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all cause mortality, venous thrombosis, symptomatic pulmonary embolism, major bleeding and minor bleeding.. Of 3986 identified citations five RCTs fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin ( either UFH or LMWH). The overall methodological quality of the included studies was acceptable. Overall, heparin therapy was associated with a statistically and clinically significant survival benefit (hazard ratio (HR) = 0.77; 95% CI: 0.65 to 0.91). In subgroup analyses, patients with limited small cell lung cancer experienced a clear survival benefit (HR = 0.56; 95% CI: 0.38 to 0.83). The survival benefit was not statistically significant for either patients with extensive small cell lung cancer (HR = 0.80; 95% CI: 0.60 to 1.06) or patients with advanced cancer (HR = 0.84; 95%: 0.68 to 1.03). The increased risk of bleeding with heparin was not statistically significant (RR = 1.78; 95% CI: 0.73 to 4.38).. Heparin has a survival benefit in cancer patients in general, and in patients with limited small cell lung cancer in particular. Heparin might be particularly beneficial in cancer patients with limited cancer or a longer life expectancy. Future research should investigate the survival benefit of different types of anticoagulants (in different dosing, schedules and duration of therapy) in patients with different types and stages of cancers.

Topics: Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Survival Analysis; Warfarin

To evaluate the effectiveness and safety of oral anticoagulants in improving survival of cancer patients. We conducted in January 2007 a comprehensive search for relevant randomized clinical trials (RCTs). We extracted data on methodological quality, participants, interventions and outcomes using a standardized form. Five RCTs fulfilled the inclusion criteria and all compared warfarin to either placebo or no intervention. Their overall methodological quality was acceptable. The effect of warfarin on mortality was not statistically significant at 6 months (RR = 0.96; 95% CI 0.80-1.16), at 1 year (RR = 0.95; 95% CI 0.86-1.05), at 2 years (RR = 0.97; 95% CI 0.87-1.08) or at 5 years (RR 0.91; 95% CI 0.83-1.01). In the subgroup of patients with small cell lung cancer (SCLC), warfarin reduced mortality at 6 months (RR = 0.69; 95% CI 0.50-0.96) but not at 1 year (RR = 0.88; 95% CI 0.77-1.01). This 6 months mortality benefit was statistically significant in the subgroup of extensive SCLC (RR = 0.65; 95% CI 0.45-0.93) but not in the subgroup of limited SCLC (RR = 0.68; 95% CI 0.36-1.28). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85-9.68) and minor bleeding (RR = 3.34; 95% CI 1.66-6.74). The evidence suggests a survival benefit from warfarin in patients with extensive SCLC, but not in other patient groups. This survival benefit should be weighed against the increased risk for hemorrhage.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Survival Analysis; Warfarin

Activation of coagulation and of the fibrinolytic system has been identified in small cell and non-small cell cancers respectively. For the clinician this poses the diagnostic problem of a thrombosis, which is most often venous with or without pulmonary emboli, complicating the evolution of an already diagnosed cancer. The inverse is that these features may reveal an underlying neoplasm and amongst the most common of these would be bronchopulmonary cancer. Numerous laboratory studies have shown the existence of a state of hyper-coagulability, with disseminated intra-vascular coagulation, which is more or less compensated and is the more marked, the more advanced the cancer is. One should not fail to recognise that this state of hyper-coagulability may be aggravated by certain cytotoxic drugs. At the level of the tumour itself, there seems to be interactions between the cancer cells and the coagulation and fibrinolytic system: these interactions are very different according to the histological type as to whether they are small cell or non-small cell bronchopulmonary cancers.

Topics: Anticoagulants; Antineoplastic Agents; Blood Coagulation; Blood Coagulation Disorders; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Disseminated Intravascular Coagulation; Female; Fibrinolysis; Humans; Lung Neoplasms; Male; Middle Aged; Randomized Controlled Trials as Topic; Thromboembolism; Thrombosis; Warfarin

Studies of malignancy in experimental animal models have indicated that cause-effect relationships exist between coagulation activation and cancer progression. Evidence for coagulation activation in human malignancy together with favorable results from pilot clinical trials led to the establishment of a prospective, randomized therapeutic trial of warfarin in cancer. A statistically significant prolongation of survival was observed in patients with small cell carcinoma of the lung entered into this study. Demonstration of an initiator of coagulation activation together with coagulation factor intermediates and fibrin in situ associated with viable tumor cells in small cell carcinoma of the lung is consistent with the hypothesis that tumor-initiated thrombin formation might contribute to progression of this tumor type. These observations suggest novel experimental treatment strategies for small cell carcinoma of the lung. Warfarin anticoagulation may be of value in the treatment of certain other types of malignancy.

Topics: Anticoagulants; Carcinoma, Small Cell; Humans; Lung Neoplasms; Thrombin; Warfarin

Evidence indicates that progression of the Lewis lung carcinoma in mice and small cell carcinoma of the lung in humans is retarded by warfarin administration. This suggests that vitamin K-dependent pathways are of importance in the pathogenesis of these tumors. Available data were reviewed for these tumor types in an attempt to explore mechanisms and to gain insights that might guide the selection of other coagulation-reactive drugs for testing in future controlled clinical trials in small cell carcinoma of the lung. While many differences exist between the Lewis lung tumor and small cell carcinoma of the lung, both are rapidly growing malignancies of pulmonary origin that metastasize early to kill the host after a short time. Both are favorably influenced by combination chemotherapy and radiation therapy as well as anticoagulant treatment. Peripheral blood changes indicative of disseminated intravascular coagulation occur in each of these tumor types, and tumor cells from both are capable of interacting with the coagulation mechanism. While many details concerning the host-tumor interaction remain to be elucidated, the considerable and diverse information available for these tumor types provides a secure base for future investigation. It is postulated that certain drugs in addition to warfarin might reasonably be studied in controlled clinical trials of small cell carcinoma of the lung and that drugs other than warfarin might be effective for tumor types that are not responsive to this agent.

Topics: Animals; Anticoagulants; Antineoplastic Agents; Carcinoma, Small Cell; Clinical Trials as Topic; Disease Models, Animal; Humans; Lung Neoplasms; Mice; Warfarin

The recognition that the vast majority of patients with small cell lung cancer have distant metastatic disease at the time of diagnosis led to the use of systemic chemotherapy and consequent major improvements in survival in the early to mid-1970's. In the past five years, however, the pace of therapeutic advances has slowed. Recently evaluated treatment strategies, including more intensive induction chemotherapy, "late intensive" therapy of responding patients, alternation of chemotherapeutic regimens, integration of chest irradiation with drug therapy, large field irradiation, and reappraisal of the value of surgical resection, are discussed in this review. Advances in understanding of the cell biology of small cell lung cancer which may eventually lead to new forms of treatment are summarized.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Small Cell; Combined Modality Therapy; Humans; Immunotherapy; Lung Neoplasms; Neoplasm Staging; Prognosis; Retrospective Studies; Time Factors; Warfarin

Topics: Animals; Aspirin; Blood Vessels; Capillaries; Endothelium; Fibrin; Heparin; Lung Neoplasms; Microcirculation; Neoplasm Metastasis; Neoplasms; Platelet Aggregation; Warfarin

Topics: Animals; Anticoagulants; Female; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Heparin; Humans; Immunosuppression Therapy; Lung Neoplasms; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Peptide Hydrolases; Uterine Neoplasms; Warfarin

Topics: Animals; Anticoagulants; Antineoplastic Agents; Dicumarol; Drug Synergism; Drug Therapy, Combination; Ear Neoplasms; Endothelium; Factor XIII; Fibrinolysin; Fibrinolytic Agents; Heparin; Humans; In Vitro Techniques; Iodine Radioisotopes; Lung Neoplasms; Lymphatic Metastasis; Mice; Microcirculation; Neoplasm Metastasis; Neoplasms, Experimental; Neoplastic Cells, Circulating; Platelet Adhesiveness; Rabbits; Thrombosis; Warfarin

Topics: Animals; Blood Coagulation; Capillaries; Embolism; Heparin; Humans; Immunotherapy; Lung Neoplasms; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Thrombin; Warfarin

Topics: Animals; Benz(a)Anthracenes; Cell Movement; Culture Techniques; Ear; Fibrinolysin; Histological Techniques; Humans; Leukocytes; Lung Neoplasms; Lymphatic Metastasis; Mice; Motion Pictures; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Prothrombin Time; Rabbits; RNA; Thrombosis; Time Factors; Warfarin

Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first- and second-line treatment in adult patients with ALK + metastatic non-small cell lung cancer (NSCLC). The study investigated the drug-drug interaction (DDI) potential of ceritinib when coadministered with midazolam and warfarin as probe substrates for CYP3A and CYP2C9 activity, respectively.. This was a phase I, multicenter, open-label, single sequence, crossover DDI study in 33 adult patients with ALK + NSCLC or other advanced tumors. A single dose of a cocktail consisting of midazolam and warfarin was administered with and without concomitant administration of ceritinib. The primary objective was to evaluate the pharmacokinetics of midazolam and warfarin. Secondary objectives included pharmacokinetics, safety, tolerability, overall response rate (ORR), and duration of response (DOR) of ceritinib 750 mg once daily.. Ceritinib inhibited CYP3A-mediated metabolism of midazolam, resulting in a markedly increased AUC (geometric mean ratio [90% confidence interval]) by 5.4-fold (4.6, 6.3). Ceritinib also led to an increase in the AUC of S-warfarin by 54% (36%, 75%). The pharmacokinetics and safety profile of ceritinib in this study are consistent with previous reports and no new safety signals were reported. Among the 19 patients with NSCLC, efficacy (ORR: 42.1% and DCR: 63.2%) was similar to that reported previously in studies of pretreated patients with ALK + NSCLC.. Ceritinib is a strong CYP3A inhibitor and a weak CYP2C9 inhibitor. These findings should be reflected as actionable clinical recommendations in the prescribing information for ceritinib with regards to concomitant medications whose pharmacokinetics may be altered by ceritinib.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cross-Over Studies; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Drug Interactions; Female; Humans; Lung Neoplasms; Male; Midazolam; Middle Aged; Pyrimidines; Sulfones; Warfarin; Young Adult

The current study assessed the psychologic and neuropsychologic functioning of patients with small-cell lung cancer who were randomized in a large clinical trial to receive intensive doxorubicin, cyclophosphamide, etoposide (ACE)/cisplatin, cyclophosphamide, etoposide (PCE) chemotherapy and radiation therapy (RT) to the primary tumor and prophylactic whole-brain irradiation with (regimen I) or without (regimen II) warfarin.. Patients' emotional states and cognitive functioning were assessed using the Profile of Mood States (POMS) and Trail Making B Test (Trails B), respectively. Two hundred ninety-five patients completed the POMS and Trails B at pretreatment, 224 patients after the completion of the ACE course of chemotherapy (week 9), and 177 patients after the completion of the PCE chemotherapy and RT (week 17).. No differences on the POMS or Trails B measures were found between the two treatment arms as predicted, given that the only difference between the two treatment arms was the presence or absence of warfarin. Analysis of the POMS revealed that, overall, mean scores remained stable over the course of treatment; however, women showed a trend toward higher mean scores, which indicated a higher level of distress, compared with men at the pretreatment assessment. Examination of cognitive functioning, measured by the Trails B, revealed improved performance from baseline to post-ACE chemotherapy, which is consistent with a practice effect, but a significant worsening of Trails B scores post-RT compared with the pre-RT assessments, which is consistent with impaired cognitive functioning because of treatment (P < .0001).. Emotional state, measured by the POMS, did not differ between the groups or change significantly over time in this study of small-cell lung cancer patients treated with a combination of chemotherapy and RT plus or minus warfarin. However, the pattern of relatively stable POMS scores and poorer Trails B performance post-RT suggested that this combination of chemotherapy and RT had a negative impact on cognitive functioning.

Topics: Adult; Aged; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cisplatin; Cognition; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Doxorubicin; Emotions; Etoposide; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neuropsychological Tests; Trail Making Test; Warfarin

Studies by the Veterans Administration Cooperative Studies Program and Cancer and Leukemia Group B (CALGB) suggested that the addition of warfarin to chemotherapy might enhance response and/or survival in small-cell lung cancer (SCLC). This randomized study evaluated the effect of warfarin with chemotherapy and radiation therapy in limited-stage SCLC.. Patients were randomized to receive warfarin or no warfarin. All patients received three cycles of doxorubicin, cyclophosphamide, and etoposide (ACE). Cycles 4 and 5 (cisplatin, cyclophosphamide, and etoposide [PCE]) were given concurrently with radiation therapy. Three cycles of ACE were given after chemoradiation therapy, but were discontinued due to a high rate of pulmonary toxicity.. There were no significant differences in response rates, survival, failure-free survival, disease-free survival, or patterns of relapse between the warfarin-treated and control groups. In patients treated according to the initial design, an increase in failure-free survival seen with warfarin treatment approached significance (P = .07). Preamendment results, while not significant, did not have superimposable treatment survival curves. A landmark analysis at 8 months showed a median survival time after the landmark for complete responders of 33 months with warfarin treatment compared with < or = 13.75 months for complete or partial responders not treated with warfarin (P = .05). Differences between the complete responders in this preamendment population were not significant (P = .103).. Warfarin does not appear to improve outcome significantly in limited-stage SCLC. However, the differences in some variables between populations before the protocol amendment correspond to the favorable effects of anticoagulants observed in previous studies.

Topics: Adult; Aged; Amsacrine; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Disease-Free Survival; Etoposide; Female; Hemorrhage; Humans; Lung Neoplasms; Male; Middle Aged; Recurrence; Survival Analysis; Warfarin

Topics: Breast Neoplasms; Carcinoma, Small Cell; Double-Blind Method; Female; Humans; Lung Neoplasms; Prospective Studies; Thromboembolism; Warfarin

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Drug Evaluation; Drug Interactions; Female; Humans; Hypoprothrombinemias; Lung Neoplasms; Middle Aged; Ovarian Neoplasms; Sulfonylurea Compounds; Warfarin

Topics: Antineoplastic Agents; Carcinoma, Small Cell; Clinical Trials as Topic; Humans; Lung Neoplasms; Reproducibility of Results; Warfarin

The Cancer and Leukemia Group B (CALGB) conducted a prospective randomized trial to evaluate the role of warfarin and alternating chemotherapy in extensive small-cell lung cancer (SCCL). After stratification for sex and performance status, patients were randomly assigned to receive chemotherapy with methotrexate, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH), cyclophosphamide, and lomustine (CCNU) (MACC), or MACC plus warfarin (MACC + W), or mitomycin, etoposide, cisplatin, and hexamethylmelamine alternating with MACC (MEPH/MACC). Warfarin was given continuously to maintain a prothrombin time of one and one half to twice the control values. A total of 328 patients were enrolled, and 294 were evaluable. There was a statistically significant advantage in objective response rates (complete [CR] and partial responses [PR], respectively) for MACC + W (17% and 50%) as compared with MACC alone (8% and 43%) or MEPH/MACC (10% and 38%) (P = .012). Both failure-free survival (P = .054 Wilcoxon test) and overall survival (P = .098 Wilcoxon test) were higher on MACC + W (median, 6.6 months and 9.3 months, respectively), as compared with MACC (5.0 months and 7.9 months) and MEPH/MACC (5.0 months and 7.9 months). Toxicity was comparable among the three arms, except for increased hemorrhagic events on MACC + W, which were life-threatening in four patients (4%), and lethal in two others (2%). These data support the role of warfarin in the treatment of SCCL, but do not establish its mechanism of action. Warfarin deserves further studies in SCCL, particularly in patients with limited disease.

Topics: Altretamine; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cisplatin; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Etoposide; Female; Humans; Lomustine; Lung Neoplasms; Male; Methotrexate; Middle Aged; Mitomycin; Mitomycins; Prognosis; Random Allocation; Remission Induction; Warfarin

Evidence indicates that progression of the Lewis lung carcinoma in mice and small cell carcinoma of the lung in humans is retarded by warfarin administration. This suggests that vitamin K-dependent pathways are of importance in the pathogenesis of these tumors. Available data were reviewed for these tumor types in an attempt to explore mechanisms and to gain insights that might guide the selection of other coagulation-reactive drugs for testing in future controlled clinical trials in small cell carcinoma of the lung. While many differences exist between the Lewis lung tumor and small cell carcinoma of the lung, both are rapidly growing malignancies of pulmonary origin that metastasize early to kill the host after a short time. Both are favorably influenced by combination chemotherapy and radiation therapy as well as anticoagulant treatment. Peripheral blood changes indicative of disseminated intravascular coagulation occur in each of these tumor types, and tumor cells from both are capable of interacting with the coagulation mechanism. While many details concerning the host-tumor interaction remain to be elucidated, the considerable and diverse information available for these tumor types provides a secure base for future investigation. It is postulated that certain drugs in addition to warfarin might reasonably be studied in controlled clinical trials of small cell carcinoma of the lung and that drugs other than warfarin might be effective for tumor types that are not responsive to this agent.

Topics: Animals; Anticoagulants; Antineoplastic Agents; Carcinoma, Small Cell; Clinical Trials as Topic; Disease Models, Animal; Humans; Lung Neoplasms; Mice; Warfarin

VA Cooperative Study #75 was established to test in a controlled, randomized trial the hypothesis that warfarin anticoagulation would favorably affect the course of certain types of malignancy. No differences in survival were observed between warfarin-treated and control groups for advanced non-small cell lung, colorectal, head and neck and prostate cancers. However, warfarin therapy was associated with a significant prolongation in the time to first evidence of disease progression (P = 0.016) and a significant improvement in survival (P = 0.018) for patients with small cell carcinoma of the lung, including the subgroup of patients with disseminated disease at the time of randomization (P = 0.013). A trend toward improved survival with warfarin treatment was observed for the few patients admitted to this study with non-small cell lung cancer who had minimal disease at randomization. These results suggest that warfarin, as a single anticoagulant agent, may favorably modify the course of some, but not all, types of human malignancy, among which is small cell carcinoma of the lung. Further trials of warfarin may be indicated in patients with limited disease who have cell types that failed to respond when advanced disease was present.

Topics: Adenocarcinoma; Blood Coagulation; Carcinoma, Small Cell; Clinical Trials as Topic; Colonic Neoplasms; Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Neoplasm Metastasis; Prostatic Neoplasms; Random Allocation; Warfarin

In a controlled, randomized study, survival of patients with small cell carcinoma of the lung (SCCL) was prolonged on addition of warfarin sodium to combination chemotherapy plus radiation therapy. Median survival for 25 control patients was 24 weeks and for 25 warfarin-treated patients was 50 weeks. This difference could not be accounted for by differences between groups in performance status, extent of disease, age, or sex. The survival advantage associated with warfarin administration was observed both for patients with extensive disease and for those who failed to achieve complete or partial remission. The warfarin-treated group also demonstrated a significantly increased time to first evidence of disease progression. These results suggest that warfarin may be useful in the treatment of SCCL and also support the hypothesis that the blood coagulation mechanism may be involved in the growth and spread of cancer in man.

Topics: Antineoplastic Agents; Blood Coagulation; Carcinoma, Small Cell; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Lung Neoplasms; Random Allocation; United States; United States Department of Veterans Affairs; Warfarin

Topics: Animals; Anticoagulants; Blood Coagulation; Carcinoma 256, Walker; Cecal Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fibrinolysin; Fibrinolytic Agents; Heparin; Humans; Lung Neoplasms; Lymphoma; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Ovarian Neoplasms; Pelvic Neoplasms; Rabbits; Stomach Neoplasms; Swine; Thrombosis; Vena Cava, Superior; Warfarin

Topics: Administration, Oral; Anticoagulants; Antineoplastic Agents; Breast Neoplasms; Busulfan; Chlorambucil; Clinical Trials as Topic; Cyclophosphamide; Female; Hodgkin Disease; Humans; Leukemia, Myeloid; Lung Neoplasms; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Prognosis; Warfarin

Cisplatin is one of the key drugs that is frequently used for treating various types of malignancies. Although renal and digestive toxicities are well-known cisplatin-related toxicities, attention should also be paid to acute aortic thrombosis, a relatively rare but potentially fatal disorder caused by cisplatin. Additionally, D-dimer is mainly measured to detect venous thromboembolism or disseminated intravascular coagulation, whereas its usefulness for detecting aortic thrombosis remains unclear. Here, we report a case of squamous cell lung cancer treated with cisplatin-based chemotherapy, wherein acute aortic thrombosis was diagnosed based on elevated D-dimer levels.. A 65-year-old man with stage IV squamous cell lung cancer presented with elevated D-dimer levels during treatment with second-line chemotherapy with cisplatin and S-1. Contrast-enhanced computed tomography (CT) revealed an intramural thrombus, which had not been previously identified, extending from the abdominal aorta to the common iliac artery.. We diagnosed the patient as having acute aortic thrombosis caused by cisplatin.. The patient received intravenous administration of unfractionated heparin for 9 days followed by oral warfarin.. One month after initiating treatment, the patient's D-dimer levels decreased to the normal range, and contrast-enhanced CT revealed that the thrombi had nearly completely disappeared without any sequelae or organ damage.. Our findings revealed that cisplatin can cause acute aortic thrombosis and that regular measurements of D-dimer levels before and during chemotherapy may contribute to the early detection of acute aortic thrombosis.

Topics: Administration, Intravenous; Administration, Oral; Aged; Anticoagulants; Antineoplastic Agents; Aortic Diseases; Carcinoma, Squamous Cell; Cisplatin; Fibrin Fibrinogen Degradation Products; Heparin; Humans; Lung Neoplasms; Male; Neoplasm Staging; Thrombosis; Tomography, X-Ray Computed; Treatment Outcome; Warfarin

This report describes the case of a 66-year-old man with non-small cell lung cancer and venous thromboembolism (VTE). Unfractionated heparin (UFH) was initially used to control VTE before chemotherapy. However, switching UFH to warfarin or edoxaban, a novel oral anticoagulant (NOAC), failed. Chemotherapy was then administered to control the tumor which was thought to have been the main cause of VTE, which had been treated by UFH. After tumor shrinkage was achieved by chemotherapy, we were able to successfully switch from UFH to edoxaban. Controlling the tumor size and activity enabled the use of edoxaban as maintenance therapy for VTE.

Topics: Aged; Anticoagulants; Carcinoma, Non-Small-Cell Lung; Heparin; Humans; Lung Neoplasms; Male; Pyridines; Thiazoles; Tumor Burden; Venous Thromboembolism; Warfarin

A 65-year-old man was diagnosed with advanced non-small, non-squamous lung cancer. He was treated with chemotherapy containing bevacizumab as well as cisplatin and pemetrexed. After 2 courses of treatment, computed tomography revealed that his abdominal aortic artery was almost occluded by a thrombus; however, he had no ischemic symptoms. Heparin infusion and warfarin reduced the size of the arterial thrombus and the patient was subsequently treated with chemotherapy without bevacizumab. No thrombotic events occurred during the subsequent treatment. We later noticed a small organized abdominal arterial clot and calcification on a computed tomography scan taken before bevacizumab treatment. Atherosclerotic changes should be evaluated before the administration of bevacizumab.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Aortic Diseases; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Cisplatin; Heparin; Humans; Lung Neoplasms; Male; Pemetrexed; Thrombosis; Treatment Outcome; Warfarin

Background Anticoagulation in patients with malignancy and atrial fibrillation is challenging because of enhanced risks for thrombosis and bleeding and the frequent need for invasive procedures. Data on direct oral antagonists in such patients are sparse. Methods and Results The ENGAGE AF - TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48) trial randomized 21 105 patients with atrial fibrillation to edoxaban or warfarin. Patients with malignancy, defined as a postrandomization new diagnosis or recurrence of remote cancer, were followed up over a median of 2.8 years. Adjusted Cox proportional hazard models were used to evaluate the safety and efficacy of edoxaban versus warfarin. Over a median of 495 days (interquartile range, 230-771 days), 1153 patients (5.5%) were diagnosed with new or recurrent malignancy, most commonly involving the gastrointestinal tract (20.6%), prostate (13.6%), and lung (11.1%). Malignancy was associated with increased risk of death (adjusted hazard ratio [HR], 3.12; 95% confidence interval [CI], 2.78-3.50) and major bleeding (adjusted HR, 2.45; 95% CI, 2.07-2.89), but not stroke/systemic embolism (adjusted HR, 1.08; 95% CI, 0.83-1.42). Relative outcomes with higher-dose edoxaban versus warfarin were consistent regardless of malignancy status for stroke/systemic embolism ( HR , 0.60 [95% CI, 0.31-1.15] for malignancy versus HR , 0.89 [95% CI, 0.76-1.05] for no malignancy; interaction P=0.25) and major bleeding ( HR , 0.98 [95% CI, 0.69-1.40] for malignancy versus HR , 0.79 [95% CI, 0.69-1.05] for no malignancy; interaction P=0.31). There was, however, a significant treatment interaction for the composite ischemic end point (ischemic stroke/systemic embolism/myocardial infarction), with greater efficacy of higher-dose edoxaban versus warfarin in patients with malignancy ( HR , 0.54; 95% CI, 0.31-0.93) compared with no malignancy ( HR , 1.02; 95% CI, 0.88-1.18; interaction P=0.026). Conclusions In patients with atrial fibrillation who develop malignancy, the efficacy and safety profile of edoxaban relative to warfarin is preserved, and it may represent a more practical alternative.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Comorbidity; Embolism; Factor Xa Inhibitors; Female; Gastrointestinal Neoplasms; Hemorrhage; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Proportional Hazards Models; Prostatic Neoplasms; Pyridines; Stroke; Thiazoles; Warfarin

Asparagine endopeptidase (AEP), also called legumain, is highly expressed in various solid tumors, promoting cancer cell invasion, migration, and metastasis. It has been proposed to be a prognostic marker and therapeutic target for cancer treatment. However, an effective nonpeptide, small-molecule inhibitor against this protease has not yet been identified. Here we show that a family of xanthine derivatives selectively inhibit AEP and suppress matrix metalloproteinase (MMP) cleavage, leading to the inhibition of cancer metastasis. Through structure-activity relationship (SAR) analysis, we obtained an optimized lead compound (38u) that represses breast cancer invasion and migration. Chronic treatment of nude mice, which had been inoculated with MDA-MB-231 cells, with inhibitor 38u via oral administration robustly inhibits breast cancer lung metastasis in a dose-dependent manner, associated with blockade of MMP-2 by AEP. Therefore, our study supports that 38u might act as a potent and specific AEP inhibitor useful for cancer treatment.

Topics: Animals; Antineoplastic Agents; Breast; Breast Neoplasms; Cell Line, Tumor; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Female; Humans; Lung; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Invasiveness; Structure-Activity Relationship; Xanthine

We describe a case in which uncontrolled chronic disseminated intravascular coagulation (DIC) caused by an aortic aneurysm that was exacerbated by chemotherapy for lung cancer, showed dramatic improvement when warfarin, which was being administered for atrial fibrillation, was replaced by rivaroxaban, a direct oral anticoagulant (DOAC). The present case is interesting because a DOAC was effective in treating DIC due to an aortic aneurysm, whereas warfarin, another oral anticoagulant, was ineffective. In controlling DIC, it is important to inhibit activated coagulation factors such as thrombin and activated factor X, rather than the coagulation factors, which act as substrates.

Topics: Aged; Anticoagulants; Antineoplastic Agents; Aortic Aneurysm; Atrial Fibrillation; Disseminated Intravascular Coagulation; Humans; Lung Neoplasms; Male; Rivaroxaban; Warfarin

We report a case of increased prothrombin time-international normalized ratio (PT-INR) when crizotinib and warfarin were co-administered. A 74-year-old Japanese woman presented to the hospital with dyspnea, and was diagnosed with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). Three years after surgical resection of the tumor, the patient started crizotinib because of the recurrence of NSCLC. She received 2 mg/day warfarin due to a medical history of cerebral infarction and chronic atrial fibrillation. Before crizotinib initiation, the patient's PT-INR was 2.60. After 7 days of daily doses of crizotinib, the patient's PT-INR increased to 3.65. This case report provides the first evidence of a drug interaction between crizotinib and warfarin.

Topics: Aged; Anticoagulants; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Interactions; Drug Therapy, Combination; Female; Humans; International Normalized Ratio; Lung Neoplasms; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Prothrombin Time; Pyrazoles; Pyridines; Warfarin

Topics: Anticoagulants; Diagnosis, Differential; Humans; Incidental Findings; Lung Neoplasms; Male; Middle Aged; Pulmonary Embolism; Recurrence; Solitary Pulmonary Nodule; Thoracic Surgery, Video-Assisted; Tomography, X-Ray Computed; Warfarin

A 69-year-old man visited a clinic for left leg weakness. With suspicions of lung cancer and a metastatic brain tumor, he was referred to our hospital and was diagnosed with large cell neuroendocrine carcinoma, cT1bN0M1b (BRA), stage IV. After stereotactic radiosurgery for his brain metastasis, he was treated with chemotherapy containing cisplatin and irinotecan. A week after initiating chemotherapy, he suddenly developed severe right leg pain and adynamia. A computed tomography angiogram revealed occlusion of the right common femoral artery, and percutaneous thrombectomy was performed. The symptoms resolved completely, and he was discharged without any sequelae or recurrence. Acute arterial occlusion of the limbs during chemotherapy is uncommon and requires prompt diagnosis and treatment; hence, caution should be paid when it is clinically suspected.

Topics: Aged; Anticoagulants; Arterial Occlusive Diseases; Heparin; Humans; Lower Extremity; Lung Neoplasms; Male; Thrombectomy; Warfarin

A 66-year-old man with acute ischemic stroke in the setting of lung adenocarcinoma developed acute-onset deep vein thrombosis (DVT) of the lower limbs after changing to warfarin from a heparin combination. The diagnosis of warfarin-resistant DVT was established based on the laboratory data and clinical evaluation. Heparin administration resulted in good control of thrombin regulation. Cancer patients are at high risk of venous thromboembolism, and the combination of these 2 conditions is known as Trousseau's syndrome.. Our report suggests that heparin administration may provide good control of thromboembolic events, although there is no established medical treatment to extend the survival of patients with Trousseau's syndrome.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aged; Anticoagulants; Diffusion Magnetic Resonance Imaging; Humans; Lung Neoplasms; Male; Stroke; Tomography Scanners, X-Ray Computed; Venous Thrombosis; Warfarin

Pre-clinical studies suggest that oral anticoagulant agents, such as warfarin, may inhibit metastases and potentially prolong survival in cancer patients. However, few population-based studies have examined the association between warfarin use and cancer-specific mortality.. Using prescribing, cause of death, and cancer registration data from the UK Clinical Practice Research Datalink, four population-based cohorts were constructed, comprising breast, colorectal, lung, and prostate cancer patients diagnosed between 1 January 1998, and the 31 December 2010. Comparing pre-diagnostic warfarin users to non-users, multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for cancer-specific mortality.. Overall, 16,525 breast, 12,902 colorectal, 12,296 lung, and 12,772 prostate cancers were included. Pre-diagnostic warfarin use ranged from 2.4 to 4.7 %. There was little evidence of any strong association between warfarin use pre-diagnosis and cancer-specific mortality in prostate (adjusted HR 1.03, 95 % CI 0.84-1.26), lung (adjusted HR 1.06, 95 % CI 0.96-1.16), breast (adjusted HR 0.81, 95 % CI 0.62-1.07), or colorectal (adjusted HR 0.88, 95 % CI 0.77-1.01) cancer patients. Dose-response analyses did not reveal consistent evidence of reductions in users of warfarin defined by the number of prescriptions used and daily defined doses.. There was little evidence of associations between pre-diagnostic use of warfarin and cancer-specific mortality in lung, prostate, breast, or colorectal cancer patients.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Breast Neoplasms; Cohort Studies; Colorectal Neoplasms; Databases, Factual; Female; Humans; Incidence; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Proportional Hazards Models; Prostatic Neoplasms; Warfarin

We report a rare case of a pulmonary vein stump thrombus detected by a contrast-enhanced computed tomography for transient syncope 2 days after upper division segmentectomy of the left lung for metastatic pulmonary tumor. The thrombus disappeared without embolic events after anticoagulation with intravenous heparin followed by oral warfarin. Considering this case and previous reports, thoracic surgeons should be aware of pulmonary vein stump thrombus, a latent source of systemic embolization, after pulmonary resection, especially lobectomy or segmentectomy of the left upper lobe. This possible serious complication can occur at any time from the early postoperative period.

Topics: Aged; Anticoagulants; Female; Heparin; Humans; Lung Neoplasms; Pneumonectomy; Postoperative Complications; Pulmonary Veins; Tomography, X-Ray Computed; Venous Thrombosis; Warfarin

A middle-aged patient presented with dyspnoea, haemoptysis and weight loss following a recent admission for pulmonary embolus, diagnosed on CT pulmonary angiogram (CTPA). The patient was anticoagulated with warfarin to a therapeutic range 2-3. There was no relevant medical history. On examination, the pulse was 105 bpm and blood pressure was 70/50 mm Hg. Oxygen saturation was 94% on air. Repeat CTPA revealed extension of the clot burden, now a saddle embolus occluding pulmonary outflow. The patient underwent emergency surgical embolectomy, and histology of the excised clot revealed the underlying cause--a malignant, high-grade sarcoma of the pulmonary vasculature. The target international normalised ratio was increased to 3-4. Postoperatively, the patient developed a large malignant pericardial effusion which required urgent percutaneous drainage. The patient eventually underwent targeted chemotherapy, which extended patient survival. The patient passed away a year later from progressive right-sided heart failure as a result of cor pulmonale.

Topics: Anticoagulants; Early Detection of Cancer; Humans; Lung Neoplasms; Male; Middle Aged; Pulmonary Embolism; Recurrence; Sarcoma; Vascular Neoplasms; Warfarin

A 46-year-old woman presented with loss of consciousness and was diagnosed with acute cerebral embolism. She had undergone left upper lobectomy for primary lung cancer 6 months before this event. Transesophageal echocardiography and computed tomography showed a large mobile thrombus in the left upper pulmonary vein (LSPV). An emergent operation was performed through a median sternotomy. Cardiopulmonary bypass was performed and the heart was arrested, and the LSPV was incised. A fresh thrombus had formed in the stump of the LSPV and was removed successfully. The postoperative course was uneventful. During a 1 year of follow-up, there was no recurrence of the thrombus.

Topics: Acute Disease; Anticoagulants; Diagnosis, Differential; Echocardiography, Transesophageal; Female; Humans; Intracranial Embolism; Lung Neoplasms; Magnetic Resonance Imaging; Middle Aged; Pneumonectomy; Pulmonary Embolism; Pulmonary Veins; Thrombectomy; Thrombolytic Therapy; Tomography, X-Ray Computed; Venous Thrombosis; Warfarin

Cisplatin-based therapy is associated with various toxicities, including renal failure and neuropathy. However, acute arterial thrombosis is also a possible toxic effect of cisplatin, one that has been documented in a few cases worldwide. Here we present a rare case of ascending aortic thrombosis occurring 9 days after cisplatin-based chemotherapy in a 74-year-old male who was diagnosed with malignant pleural effusion suggestive of non-small cell lung cancer. The patient did not have any predisposing factor for the occurrence of an aortic thrombus before cisplatin-based chemotherapy. Thus, we suggest that the hypercoagulable state occurred secondary to cisplatin-based chemotherapy and was additive to the malignancy itself, causing aortic thrombosis. The patient was treated successfully with low-molecular-weight heparin and warfarin.

Topics: Aged; Anticoagulants; Aorta; Carcinoma, Non-Small-Cell Lung; Cisplatin; Heparin; Humans; Lung Neoplasms; Male; Pleural Effusion, Malignant; Thrombosis; Warfarin

Topics: Aged; Anticoagulants; Atrial Fibrillation; Biopsy, Fine-Needle; Diagnosis, Differential; Dyspnea; Female; Fluorodeoxyglucose F18; Humans; Hypertension; Lung Neoplasms; Multimodal Imaging; Positron-Emission Tomography; Pulmonary Artery; Pulmonary Embolism; Radiography, Thoracic; Sarcoma; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography; Vascular Neoplasms; Warfarin

It is well established that the blood coagulation system is activated in cancer. In addition, there is considerable evidence to suggest that clotting activation plays an important role in the biology of malignant tumors, including the process of blood-borne metastasis. For many years our laboratory has used experimental models of lung metastasis to study the events that follow the introduction of procoagulant-bearing tumor cells into circulating blood. This chapter focuses on the basic methods involved in assessing the anti-metastatic effects of anticoagulants and anti-platelet agents using rodent models of experimental metastasis. In addition, it summarizes our experience with these models, which collectively suggests that intravascular coagulation and platelet activation are a necessary prelude to lung tumor formation and that interruption of coagulation pathways or platelet aggregation may be an effective anti-metastatic strategy.

Topics: Animals; Anticoagulants; Antineoplastic Agents; Blood Coagulation; Cell Line, Tumor; Enoxaparin; Humans; Lung Neoplasms; Mice; Neoplasm Metastasis; Neoplasms, Experimental; Platelet Aggregation Inhibitors; Thromboplastin; Warfarin

The case of a patient who developed elevated International Normalized Ratio (INR) values after concomitant administration of warfarin and erlotinib is reported.. A 47-year-old Caucasian man with a history of atrial fibrillation, anxiety, and a 40-pack-year smoking history was diagnosed with advanced, moderately differentiated adenocarcinoma of the lung. Soon after being diagnosed with non-small-cell lung cancer, warfarin was initiated for the treatment of a venous thromboembolism. The patient's warfarin dosage was adjusted to reach a target INR of 2-3. His INR was relatively stable (2.1-3.2) for at least eight weeks before erlotinib was added to the chemotherapy regimen. The patient developed a well-disseminated rash and diarrhea soon after starting erlotinib. Seven days after the initiation of erlotinib therapy, the patient's INR value increased from 2.8 to 5.3, with no concurrent changes in warfarin dosage, other medications, or diet. After withholding two doses of warfarin, the patient's INR value increased to 9.1, and the patient developed an elbow hematoma. His anticoagulation was rapidly reversed with the administration of subcutaneous phytonadione. The patient elected to discontinue erlotinib nine days after its initiation. The next day, his INR value was 2.4. The patient returned to the hematology-oncology clinic for follow-up two days later, where his INR was found to be 0.9.. Concomitant administration of erlotinib and warfarin resulted in an increase in INR values in a 47-year-old man with advanced lung cancer.

Topics: Adenocarcinoma; Anticoagulants; Carcinoma, Non-Small-Cell Lung; Drug Interactions; Drug Therapy, Combination; Erlotinib Hydrochloride; Humans; International Normalized Ratio; Lung Neoplasms; Male; Middle Aged; Quinazolines; Thromboembolism; Warfarin

A 56-yr-old man with lung adenocarcinoma presented with subsegmental pulmonary thrombosis. Platelet count on presentation was 531 x 10(9)/L. The patient was anticoagulated with subcutaneous low molecular weight heparin (LMWH). Next day, oral anticoagulation was initiated with 5 mg of warfarin once daily with LMWH and LMWH was discontinued at third hospital day. On the third day of oral anticoagulation therapy, he complained of left leg swelling and prolonged painful penile erection of 24 hr-duration. His platelet count reached a nadir 164 x 10(9)/L at that time, and the patient had a deficiency of protein C and S, with an activity level of 16% and 20% of normal value. Warfarin was stopped and he underwent penile aspiration. The next day, left leg edema and penile erection was disappeared, but penile and glans penis necrosis was started. This case illustrates that processes underlying heparin-induced thrombocytopenia (HIT) may also underlie warfarin-induced skin necrosis.

Topics: Adenocarcinoma; Anticoagulants; Heparin; Humans; Lung Neoplasms; Male; Middle Aged; Necrosis; Penile Erection; Penis; Platelet Count; Protein C; Protein S; Pulmonary Artery; Thrombocytopenia; Thrombosis; Warfarin

Pulmonary embolism (PE) is a common complication in lung cancer patients with a high misdiagnosis rate and high mortality. This study was to investigate the clinical characteristics, diagnosis and treatment approaches for lung cancer accompanied by PE, thus to improve the diagnosis and treatment efficacy of this disease.. Clinical manifestations, comorbid conditions, risk factors, laboratory (indirect) and imaging examinations (direct) and treatment methods of 23 lung cancer patients with PE were retrospectively analyzed.. Among the 23 patients, 14(60.87%) had hypoxemia, all (100%) had elevated serum D-dimer, 11 (47.83%) had characteristic changes in electrocardiogram. Ten out of 12 cases (83.33%) examined by computed tomography angiography were found filling defect in the pulmonary artery; all two case receiving isotope perfusion scanning were detected segmental perfusion defect in the lung; one case undergoing MRI was found segmental filling defect in the pulmonary artery; and one case was discovered the direct sign of PE by pulmonary arteriography. The medium survival time (MST) of five cases who received symptomatic treatment was 13 days, of four cases who received thrombolysis therapy was 22.5 days, of 12 cases who underwent anticoagulation and chemotherapy was 93 days, and of two cases who were only given anticoagulant therapy were 70 days and 189 days respectively.. Diagnosis of lung cancer accompanied by PE mainly depends on direct examinations. Thrombolysis and anticoagulation therapy are recommended for those patients. In addition, chemotherapy may also be considered.

Topics: Adenocarcinoma; Adult; Aged; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Blood Gas Analysis; Echocardiography; Electrocardiography; Female; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Pulmonary Embolism; Retrospective Studies; Survival Rate; Tomography, Spiral Computed; Urokinase-Type Plasminogen Activator; Warfarin

A warfarin treated patient unexpectedly presented with an elevated international normalized ratio (INR). Repeat testing in two laboratories gave conflicting results. The chromogenic assay of factor X was used to determine the correct INR result. The patient had laboratory results consistent with a dysfibrinogenemia, which prevented detection of the endpoint with a photo-optical detection system. The chromogenic assay of factor X is recommended for monitoring patients on warfarin when the INR cannot be accurately determined due to interference with the fibrin endpoint in the INR.

Topics: Aged; Anticoagulants; Blood Coagulation; Chromogenic Compounds; Factor X; Female; Fibrin; Fibrinogen; Heart Failure; Humans; International Normalized Ratio; Lung Neoplasms; Prothrombin Time; Time Factors; Warfarin

Despite the literature indicating adverse interactions between warfarin and cytotoxic agents, whether such an interaction occurs when warfarin and gefitinib are used concomitantly is unknown. We analyzed the prevalence of the concomitant use of warfarin and gefitinib, and the incidence of prothrombin time-international normalized ratio (PT-INR) alterations or adverse interactions in concomitant users of warfarin and gefitinib.. We conducted a retrospective study of patients with non-small cell lung cancer treated at the Kitasato University Hospital who received concomitant warfarin and gefitinib between September 2002 and January 2007. Medical information, including the indication for warfarin use, warfarin dosing and dosing changes, and exposure to gefitinib were collected from computerized databases and medical records.. Twelve (4.1%) of 296 patients treated with gefitinib received warfarin. PT-INR elevation occurred in 6 patients (50.0%). Two (16.7%) of the 12 patients had liver metastases. Liver dysfunction was associated with PT-INR elevation (P = 0.0100).. As there is a possibility of PT-INR abnormalities occurring during the concomitant use of gefitinib and warfarin, clinicians should be aware of this interaction. Because of the potentially severe consequences of this interaction, close monitoring of PT-INR and warfarin dose adjustment are recommended for patients receiving warfarin and gefitinib, especially during the first 2 weeks in the beginning of warfarin therapy.

Topics: Aged; Anticoagulants; Antineoplastic Agents; Blood Coagulation; Carcinoma, Non-Small-Cell Lung; Drug Interactions; Female; Gefitinib; Humans; International Normalized Ratio; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Prothrombin Time; Quinazolines; Retrospective Studies; Time Factors; Warfarin

Topics: Aged; Anticoagulants; Follow-Up Studies; Heparin; Humans; Infarction; Kidney; Lung Neoplasms; Male; Pneumonectomy; Pulmonary Veins; Radiography; Risk Assessment; Thromboembolism; Treatment Outcome; Warfarin

The anticoagulant warfarin can produce a skin necrosis that is clinically indistinguishable from the skin necrosis caused by purpura fulminans associated with disseminated intravascular coagulation (DIC) and heparin-induced thrombocytopenia (HIT). The similar clinical and histologic findings observed in each of these skin necroses create a challenge for diagnosis and eventual treatment. The authors report a patient with significant risk factors for warfarin-induced skin necrosis, DIC, and HIT presenting with painful, purpuric patches beginning on her feet and extending proximally before becoming hemorrhagic bullae on her lower extremities.

Topics: Aged; Anticoagulants; Biopsy; Carcinoma, Non-Small-Cell Lung; Diagnosis, Differential; Disseminated Intravascular Coagulation; Fatal Outcome; Female; Humans; IgA Vasculitis; Lung Neoplasms; Mediastinal Neoplasms; Necrosis; Pulmonary Embolism; Warfarin

Gefitinib is a synthetic, oral anilinoquinazoline specifically designed to inhibit the epidermal growth factor receptor tyrosine kinase, and is the first targeted drug to demonstrate reproducible activity in non-small cell lung cancer patients who do not respond to platinum-based chemotherapy. In this report, we present two cases of an interaction between gefitinib and warfarin which has not been reported previously. Because of the potentially serious consequences of this interaction, close monitoring of the International Normalized Ratio and warfarin dosage adjustment are recommended for patients receiving warfarin together with gefitinib.

Topics: Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Administration Schedule; Drug Interactions; Drug Synergism; ErbB Receptors; Female; Gefitinib; Humans; Lung Neoplasms; Middle Aged; Protein Kinase Inhibitors; Quinazolines; Thrombosis; Warfarin

Topics: Aged; Anticoagulants; Arginine; Humans; International Normalized Ratio; Kidney; Kidney Function Tests; Liver; Lung Neoplasms; Partial Thromboplastin Time; Pipecolic Acids; Sulfonamides; Venous Thrombosis; Warfarin

One of the standard treatments for cancer-associated thrombosis has been initial therapy with unfractionated heparin (UFH) followed by long-term therapy with an oral anticoagulant (i.e., warfarin). However, characteristics associated with these two agents may make them suboptimal for many cancer patients. This article will explore some of the considerations and limitations when using UFH and warfarin in the cancer population and will also utilize case studies to emphasize the importance of individualized care.. UFH is an effective anticoagulant when doses are adjusted to maintain the activated partial thromboplastin time (aPTT) within a specified therapeutic range. However, due to the complex pharmacokinetics of this agent, patients must undergo frequent monitoring to maintain a therapeutic aPTT. In addition, UFH can be associated with serious adverse events including osteoporosis, heparin-induced thrombocytopenia, and bleeding. Similar to UFH, warfarin requires frequent monitoring and dose adjustments to maintain the International Normalized Ratio (INR) within the therapeutic range of 2.0 to 3.0. Warfarin also has numerous drug-herbal, drug-food, and drug-drug interactions, including interactions with many commonly used anti-tumor therapies. Complications related to UFH and warfarin in the treatment of cancer-associated thrombosis have gradually been minimized with the increased use of low molecular weight heparins (LMWHs), which are associated with reduced incidence of bleeding, heparin-induced thrombocytopenia, and drug interactions. In addition, LMWHs allow for convenient daily dosing without requiring routine monitoring and the option of home therapy.. When deciding on the optimal anticoagulant strategy, pharmacists must take into account the unique characteristics and needs of each individual patient as well as the specifics of the various anticoagulant therapies. Future strategies for the initial and long-term treatment of cancer-associated thrombosis may increasingly incorporate LMWHs because of factors related to safety and convenience.

Topics: Anticoagulants; Bone Neoplasms; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Fatigue; Female; Heparin; Heparin, Low-Molecular-Weight; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Thrombosis; Warfarin

Acute pulmonary thromboembolism is fatal if the diagnosis and treatments are delayed. Here we present a case of acute thromboembolism to the right and left pulmonary arteries after right lung lobar resection. A 52-year-old woman who admitted to our hospital with lung cancer was performed right upper lobectomy with mediastinal lymph node dissection (pT1N0M0, well differentiated adenocarcinoma). Two days after surgery, she complained sudden chest discomfort and dyspnea. The blood pressure and oxygen saturation were rapidly decreased. Because there was no lung edema or atelectasis in the chest portable roentgenogram and no ischemic change in the electrocardiogram, pulmonary thromboembolism was suspected and emergency chest computed tomography (CT) was performed. The CT showed left and right pulmonary arterial thromboembolism and immediate anti-coagulator therapy was started. Her condition was improved and chest CT, which was performed three days after the onset of the thromboembolism, showed decreased but still remained thrombus. The anti-coagulator therapy was continued and one month after the onset of the thromboembolism, thrombus was disappeared on chest CT. She is doing well 17 months after surgery. Early diagnosis and treatments are critical for the pulmonary thromboembolism.

Topics: Adenocarcinoma; Anticoagulants; Female; Heparin; Humans; Lung Neoplasms; Lymph Node Excision; Lymphatic Metastasis; Middle Aged; Pneumonectomy; Postoperative Complications; Pulmonary Embolism; Warfarin

The cause of cancer-associated venous limb gangrene is unknown but could paradoxically be due to warfarin.. To determine the pathogenesis of venous gangrene in a patient with cancer.. Case report.. University hospital in Ontario, Canada.. 66-year-old woman with metastatic lung cancer and deep venous thrombosis.. Levels of vitamin K-dependent factors, additional coagulation factors, and thrombin-antithrombin complexes (marker of thrombin generation).. During warfarin use, venous limb gangrene developed when the international normalized ratio (INR) reached 6.0 (therapeutic range, 2.0 to 3.0); at this time, the level of protein C (a vitamin K-dependent natural anticoagulant) was severely reduced, but thrombin-antithrombin complexes remained markedly elevated. The supratherapeutic INR was explained by the greatly reduced levels of factor VII, which correlated closely with protein C levels; therefore, the high INR was a surrogate marker for severely reduced protein C activity.. Warfarin may contribute to the pathogenesis of cancer-associated venous limb gangrene by leading to severe depletion of protein C while at the same time failing to reduce thrombin generation.

Topics: Aged; Anticoagulants; Antigen-Antibody Complex; Blood Coagulation Disorders; Blood Coagulation Factors; Female; Gangrene; Humans; Lung Neoplasms; Protein C Deficiency; Thrombin; Thrombocytopenia; Venous Thrombosis; Warfarin

Topics: Aged; Anticoagulants; Antigen-Antibody Complex; Blood Coagulation Disorders; Blood Coagulation Factors; Female; Gangrene; Humans; Lung Neoplasms; Protein C Deficiency; Thrombin; Thrombocytopenia; Venous Thrombosis; Warfarin

Topics: Anticoagulants; Carcinoma, Small Cell; Humans; Lung Neoplasms; Neoplasms; Thromboembolism; Warfarin

CYP2C9 is involved in the metabolism of warfarin and a wide array of other therapeutic agents. It also appears to play a role, along with other cytochrome P450 enzymes, in the metabolism of benzo[a]pyrene, a carcinogen in tobacco smoke. A relatively common allelic variant (termed R144C, Cys144 or more recently CYP2C9*2) has been described that results in the substitution of cysteine for arginine at residue 144 and appears to reduce enzyme activity. We therefore examined the possible association between the presence of the CYP2C9*2 variant allele and risk of lung cancer using peripheral blood DNA from 329 incident cases of lung cancer (152 African-American and 177 Caucasian) and 700 (239 African-American and 461 Caucasian) population controls in Los Angeles County, California. Among the population controls the frequency of the CYP2C9*2 variant allele was lower (p = 0.00002) among African-Americans (0.036) than among Caucasians (0.100). The presence of the CYP2C9*2 variant allele was not associated with a decreased risk of lung cancer; slight but nonstatistically significant elevations in risk were observed for both African-Americans [odds ratio (OR) 1.22, 95% confidence interval (CI) 0.48-3.11] and Caucasians (OR = 1.55, 95% CI 0.96-2.48). The ORs were slightly and nonsignificantly elevated for all histologic types without substantive variation. The association also did not vary materially according to smoking history or whether subjects had the homozygous deletion of the GSTM1 gene. We found no support for the hypothesis that the CYP2C9*2 variant allele decreases the risk of lung cancer. The role of P450s, including CYP2C9, in benzo[a]pyrene metabolism is not fully defined, and CYP2C9 catalyses detoxication as well as activation steps. Thus it is not inconceivable that diminished CYP2C9 activity could increase metabolic activation of benzo[a]pyrene to carcinogenic intermediates. Nonetheless, the small increased risk associated the CYP2C9*2 variant allele in our data is consistent with chance and should not be overinterpreted.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Alleles; Aryl Hydrocarbon Hydroxylases; Benzo(a)pyrene; Black People; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cohort Studies; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System; Genetic Variation; Genotype; Humans; Los Angeles; Lung Neoplasms; Middle Aged; Polymorphism, Genetic; Reference Values; Risk Factors; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases; Warfarin; White People

Urokinase-type plasminogen activator has been administered by other investigators to patients with small cell carcinoma of the lung (SCCL) in an attempt to induce lysis of fibrin that is known to exist in the connective tissue stroma of this tumour type and that may support tumour growth. To study the fate of infused urokinase in this disease, a biopsy of a scalp metastasis was obtained from a patient with SCCL (entered on a phase I clinical trial of urokinase plus combination chemotherapy) immediately following urokinase infusion during the fourth course of therapy a time when this tumour mass had decreased to approximately 25% of its original size. Immunohistochemical procedures revealed abundant stromal fibrin in accord with previous observations from this laboratory. By contrast, urokinase, that is not a feature of small cell tumour cells, was present on the tumour cells in this specimen. Urokinase infusion was associated with a rapid increase in the amount of this enzyme associated with isolated peripheral blood monocytes. These results are consistent with uptake of infused urokinase onto monocytes and possibly tumour cells. It is postulated that substantial tumour fibrinolysis may not accompany such therapy and that urokinase, or its amino terminal fragment that bears the growth factor domain of this molecule, may bind to and alter the growth of the tumour cells.

Topics: Aged; Carcinoma, Small Cell; Drug Therapy, Combination; Humans; Immunohistochemistry; Infusions, Intravenous; Lung Neoplasms; Male; Monocytes; Urokinase-Type Plasminogen Activator; Warfarin

Tumor cells interact with the hemostatic system in various ways and may thus influence malignant growth and spread. MC28 fibrosarcoma cells possess a potent procoagulant activity (PCA) and form lung tumors following intravenous injection. The aim of this work was to study the relationship between PCA, intravascular coagulation and lung seeding in the MC28 model. MC28 cells were injected into control, warfarinized and heparinized hooded Lister rats. Coagulation changes were monitored by thromboelastography (TEG) and Sonoclot analysis (SA), lung fibrin formation by light and electron microscopy, tumor seeding by macroscopic counting and tumor cell and platelet deposition in the lungs by radiolabelling. PCA was measured by chromogenic assay. MC28 PCA was characterized as a tissue factor-factor VIIa complex that probably arose during cell culture or disaggregation of solid tumors. Injection of tumor cells caused marked coagulopathy and was rapidly (within 30 min) followed by fibrin deposition in the lungs and accumulation of radiolabelled platelets. Heparin and warfarin significantly reduced lung seeding (p < 0.001) and reduced retention of radiolabelled tumor cells in the pulmonary circulation (p < 0.01). Inhibition of cellular PCA by prior treatment with concanavalin A markedly reduced intravascular coagulation and lung seeding. We conclude that MC28 cells cause intravascular coagulation as a direct result of their procoagulant activity. The data suggest that tumor cells form complexes with platelets and fibrin which are retained in the lungs long enough for extravasation and seeding to occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Cell Adhesion; Concanavalin A; Culture Media, Serum-Free; Cysteine Endopeptidases; Disseminated Intravascular Coagulation; Fibrin; Fibrosarcoma; Heparin; Injections, Intravenous; Lung; Lung Neoplasms; Macrophage Activation; Male; Neoplasm Proteins; Neoplasm Transplantation; Neoplastic Cells, Circulating; Pulmonary Circulation; Rats; T-Lymphocytes; Tumor Cells, Cultured; Warfarin

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Humans; Lung Neoplasms; Warfarin

In prior Cancer and Leukemia Group B (CALGB) studies, combined chemotherapy and thoracic irradiation was superior to chemotherapy alone in limited-disease (LD) small-cell lung cancer (SCLC). A combined modality pilot study was performed to test the feasibility of adding warfarin to aggressive chemoradiotherapy for LD SCLC.. Combination chemotherapy with doxorubicin 45 mg/m2 intravenously (IV) on day 1, cyclophosphamide 800 mg/m2 IV on day 1, and etoposide (ACE) 80 mg/m2 on days 1 to 3 was given every 21 days for the first three courses. The fourth and fifth courses substituted cisplatin 33 mg/m2 IV on days 1 to 3 for the doxorubicin, with concurrent chest irradiation to a total of 4,000 cGy given in 20 fractions during a 4-week period followed by a boost of 1,000 cGy in five fractions during a 1-week period. Prophylactic cranial irradiation, 3,000 cGy was given concurrently in 10 fractions during a 2-week period. Courses 6 to 8 again used ACE chemotherapy, but courses 4 to 8 were given on a 28-day schedule with dose adjustment for hematologic or renal toxicity. Warfarin was given throughout the treatment period titrated to achieve a prothrombin time (PT) of 1.5 to 2 times the control. Patients with histologically proven limited-stage SCLC, good performance status, and normal renal, hematologic, and hepatic functions were eligible.. Sixty-one of 66 patients entered onto the study were eligible and assessable. Fifty-four (89%) (95%) confidence interval [CI], 78% to 95%) experienced an objective response, 35 (57%) achieved a complete response (CR) (95% CI, 44% to 70%), and 17 (28%) achieved a partial response (95% CI, 16% to 39%). Median durations were CR, 26.3 months; failure-free survival, 11.8 months; and survival, 18 months. Forty-one percent of the patients were alive at 2 years, 33% were alive at 3 years, and 25% were alive at 4 or more years. Median follow-up for survivors is 5 years (range, 3.5 to 5.9 years). Severe or life-threatening myelosuppression occurred in 90%, infection occurred in 34%, fever without documented infection occurred in 26%, and pulmonary toxicity occurred in 6%. Another 6% of patients experienced severe or life-threatening hemorrhages. There were four treatment-related fatalities. The pulmonary toxicities have been associated with the resumption of ACE chemotherapy after chest irradiation.. These highly encouraging response and survival results compare favorably with any prior CALGB group study. Although they are somewhat more toxic, they are comparable to the best published results. A randomized study that examines the role of warfarin is underway.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Combined Modality Therapy; Female; Humans; Lung Neoplasms; Male; Middle Aged; Pilot Projects; Survival Analysis; Treatment Outcome; Warfarin

Peri-tumour fibrin is a consistent feature of tumour stroma and is deposited shortly after tumour cell inoculation. Since there are several ways in which fibrin may be beneficial to tumour growth, it is possible that the ability of normal or malignant tissue to generate fibrin may influence metastasis. Many normal tissues and tumour cells possess a procoagulant activity that is due to a complex of tissue factor and factor VII. We have measured this tissue procoagulant activity in normal rats, rats stabilised on Warfarin and similarly anticoagulated animals injected with factor VII. The effect of Warfarin and factor VII administration on pulmonary seeding following injection of MC28 fibrosarcoma cells was also assessed. Procoagulant activity in adrenal, lung and colon was significantly reduced by Warfarin (P less than 0.001). Administration of factor VII significantly increased lung and adrenal tissue procoagulant activity in anticoagulated rats (P less than 0.02). Warfarinised rats had significantly slower primary tumour growth (P less than 0.001) and fewer lung deposits than control animals (P less than 0.001). Injection of factor VII restored pulmonary seeding to control levels (P less than 0.001). Warfarin did not affect the ability of the cells to adhere in vitro and did not reduce the number of tumour cells physically trapped in the lungs after intravenous injection. It is concluded that the procoagulant activity of normal tissues may influence their ability to support tumour growth and that the antimetastatic effect of Warfarin may be at least partly due to a reduction in the availability of the factor VII required for this activity.

Topics: Adrenal Glands; Animals; Cell Adhesion; Colon; Factor VII; Factor X; Fibrosarcoma; Liver; Lung; Lung Neoplasms; Neoplasm Seeding; Neoplasms, Experimental; Rats; Thromboplastin; Warfarin

Topics: Carcinoma, Small Cell; Drug Evaluation, Preclinical; Humans; Lung Neoplasms; Tumor Cells, Cultured; Warfarin

Among patients with various malignancies, three to 15 per cent may have associated idiopathic thrombosis. In a two-year period, we saw three patients with signs and symptoms demonstrating the association of neoplasia and coagulopathy. Their clinical courses and eventual outcomes are summarized. All had thrombophlebitis of multiple sites. There were difficulties in demonstrating their underlying occult malignancies, and all three patients showed resistance to oral anticoagulation drugs. Current hypotheses concerning the pathophysiology of coagulopathy associated with cancer are discussed, and recommendations for management of such patients were presented.

Topics: Adenocarcinoma; Adult; Blood Coagulation; Female; Heparin; Humans; Lung Neoplasms; Male; Middle Aged; Thrombophlebitis; Warfarin

Coumarin anticoagulants inhibit metastasis in several animal models, but the mechanism of this effect is uncertain. In order to determine the role of cytotoxic and/or cytostatic actions of coumarins on the tumour cells, we have studied the effects of warfarin on tumour cell growth in a model in which tumour metastasis is inhibited by this drug. Clonogenic assay, growth curve analysis and thymidine labelling index revealed that warfarin had no effects on Mtln3 mammary carcinoma cell growth in vitro at concentrations below 1 mM. The growth rate of subcutaneously implanted Mtln3 tumour deposits in female F344 rats, assessed by weight and by stathmokinetic analysis of the tumour tissue, was identical in warfarin-treated and control animals. Spontaneous metastasis from such tumours to the lungs was, however, significantly reduced in warfarin-treated animals (median 0 pulmonary tumours per animal in warfarin treated, eight tumours per animal in control animals; P less than 0.05, Mann-Whitney). The mean plasma warfarin concentration in warfarin treated rats was 1.63 microM. These results suggest that warfarin treatment of the host animal can inhibit tumour metastasis without having any direct or indirect effect on the growth rate of the tumour cells.

Topics: Adenocarcinoma; Animals; Female; Lung Neoplasms; Mammary Neoplasms, Experimental; Neoplastic Stem Cells; Rats; Rats, Inbred F344; Tumor Cells, Cultured; Warfarin

The effect on long-term survival of immunomodulation adjuvant to various cytotoxic chemotherapy regimens in non-small cell lung cancer (NSCLC) was evaluated in 669 patients followed up between 1974 and 1987. Four hundred seventeen patients were treated only by cytotoxic chemotherapy and served as controls. Two hundred fifty-two patients received warfarin (W), levamisole (L) and tranexamic acid (T) for adjuvant immunomodulation. These drugs, especially when given in combination (W + L + T), led to a significant (p less than 0.05) enhancement of survival in patients with advanced NSCLC, independent of the cytotoxic regimen used.

Topics: Adjuvants, Immunologic; Carcinoma, Non-Small-Cell Lung; Combined Modality Therapy; Female; Humans; Levamisole; Lung Neoplasms; Male; Middle Aged; Tranexamic Acid; Warfarin

In order to study the interactions between UFT and anticoagulants, the plasma and tissue concentrations of 5-FU, uracil and FT-207 were examined in patients with lung cancer. Higher plasma concentrations of 5-FU and uracil were observed in the patients who were given warfarin and ticlopidine beforehand, whereas the concentrations of FT-207 were almost the same in the patients who were given anticoagulants as in those who were not. This may be interpreted as an inhibition of dihydrouracil dehydrogenase, the common metabolizing enzyme of 5-FU and uracil, by anticoagulants. With regard to the tissue concentrations, higher levels of 5-FU and uracil in the tumor and lymph nodes were obtained after anticoagulants were given beforehand. Concentrations of FT-207 in these tissues, however, were almost the same in the patients who were given anticoagulants as in those who were not. We thus concluded that an increase of 5-FU in tumor cells and lymph nodes can be achieved after elevating the plasma concentrations of ordinary oral doses of UFT by using anticoagulation therapy beforehand.

Topics: Aged; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Drug Interactions; Drug Therapy, Combination; Humans; Lung Neoplasms; Postoperative Care; Tegafur; Ticlopidine; Uracil; Warfarin

Interactions between fluorinated Pyrimidine derivatives and anticoagulants were studied experimentally and clinically, using transplanted tumor tissues of Donryu rats and tissues from lung cancer patients. In rats, which were given 5-FU, uracil, tegafur and UFT respectively, the higher tumor concentrations of 5-FU and uracil were observed when given warfarin and ticlopidine beforehand, on the other hand, the concentrations of tegafur were almost the same between rats with and without anticoagulants. In patients with lung cancer, who were given UFT and anticoagulants, the higher concentrations of 5-FU and uracil in plasma, tumor and lymph nodes were observed than those who were given UFT alone. The 5-FU concentrations in normal lung tissues were about a half of those in tumor. These results suggest a existence of the synergistic effects between fluorinated pyrimidine derivatives and anticoagulants in plasma and tissue concentrations of 5-FU.

Topics: Animals; Anticoagulants; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Synergism; Fluorouracil; Humans; Lung Neoplasms; Neoplasm Transplantation; Pyrimidines; Rats; Rats, Inbred Strains; Tegafur; Ticlopidine; Uracil; Warfarin

Topics: Antineoplastic Combined Chemotherapy Protocols; Dihydrouracil Dehydrogenase (NAD+); Drug Interactions; Drug Synergism; Humans; Lung Neoplasms; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Tegafur; Uracil; Warfarin

Mouse Lewis lung (LL) carcinoma cells possess a factor X activator (procoagulant) that is inhibited in vivo by warfarin treatment or diet-induced vitamin K deficiency. This inhibition suggests that vitamin-K-dependent proteins are involved in LL cell activation of factor X. A LL primary tumor clone (LL13) was isolated which contained a warfarin-sensitive vitamin-K cycle of metabolism and expressed factor X procoagulant activity. LL13 cells exposed to media containing warfarin or deficient in vitamin K grew as well as cells in normal media, and activated factor X to similar extents. In contrast, administration of warfarin to mice bearing LL13 cells inhibited factor X procoagulant activity as well as the vitamin K cycle of metabolism in the primary tumors. In relation to LL13 cells grown in media containing fetal bovine serum, those incubated for 20 hr in media containing mouse serum or the sera from LL13-bearing mice exhibited 9- to 10-times higher levels of factor X procoagulant activity. However, LL13 cells exposed to media containing the sera of warfarin-treated LL-13-bearing mice or to barium-sulfate-adsorbed normal mouse serum activated factor X much less efficiently. Collectively, these data suggest that inhibition of vitamin K function in LL cells does not affect the extent of factor X activation and thus the intrinsic factor X procoagulant is not a vitamin-K-dependent protein. They further suggest that both a warfarin-sensitive (vitamin-K-dependent) protein present in normal mouse serum and a LL13 cell component participate in factor X procoagulant activity.

Topics: Animals; Biotransformation; Blood Coagulation Factors; Cell Line; Culture Media; Factor X; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Vitamin K; Vitamin K Deficiency; Warfarin

The platelet-secreted protein thrombospondin (TSP) potentiates tumor cell metastasis. Human TSP injected i.v. into mice 5 min prior to i.v. injection of T241 sarcoma cells potentiates lung tumor colony formation. Several lines of evidence suggest that the TSP-enhancing effect involves both TSP-mediated tumor cell adhesion and the host's hemostatic system: TSP potentiates the initial, rapid sequestering of tumor cells in the lung; TSP promotes the adhesion of tumor cells in vitro; the effect of TSP on tumor cell metastasis is dependent on the presence of platelets and a normal plasma clotting system, since TSP does not potentiate lung tumor colony formation in either thrombocytopenic mice or mice anticoagulated with Coumadin. Our results suggest a central role for TSP in the metastatic process.

Topics: Animals; Blood Coagulation; Blood Platelets; Cell Adhesion; Glycoproteins; Humans; Lung; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Neoplastic Cells, Circulating; Neuraminidase; Sarcoma, Experimental; Stimulation, Chemical; Thrombospondins; Warfarin

Warfarin inhibits metastasis in animal models by mechanisms that remain unclear. A better understanding of this phenomenon may clarify processes underlying metastasis in human cancer. We have studied the effects of warfarin on metastasis in a rat model by intravenous injection of Mtln3 mammary carcinoma cells and subsequent counting of pulmonary seedlings. To determine whether warfarin acts principally on the tumour cells or the host, we pretreated either cells or animals with warfarin before intravenous injection of 10(4) Mtln3 cells. Pretreatment of tumour cells had no effect, whilst pretreatment of the host reduced median seedlings from 67 to 4.5 per animal (P less than 0.005). To determine whether warfarin was acting via its anticoagulant action, we reversed warfarin anticoagulation by intravenous injection of coagulation factors II, VII, IX and X. Restoration of coagulation for 12 h immediately after injection of cells completely reversed the warfarin effect (P less than 0.001), but if the injection of factors was delayed for 12 h it had no effect (P = 0.1753). We conclude that warfarin acts principally on the host, not the tumour cell, and that it acts via its effect on coagulation. The restriction of the effect to the first 12 h after tumour cell injection suggests a mechanism involving intravascular processes such as tumour cell survival or endothelial adhesion.

Topics: Animals; Blood Coagulation; Female; Lung Neoplasms; Mammary Neoplasms, Experimental; Rats; Rats, Inbred F344; Warfarin

The effect of anticoagulant drugs on formation of experimental tumor metastases after i.v. inoculation of BL6 melanoma or Lewis lung carcinoma (3LL) cells was studied in mice with stimulated or depressed natural killer (NK) cell activity. When mice were treated with anticoagulants (warfarin or heparin) or when NK cell activity was stimulated by polyinosinic-polycytidylic acid, significant antimetastatic effects were observed; these effects were substantially augmented when the treatments were combined. However, when NK reactivity of mice was suppressed by anti-asialo GM1 serum or cyclophosphamide, the antimetastatic effects of warfarin and heparin were diminished or completely abrogated. In some experiments, the anticoagulants had a partial effect in mice treated with cyclophosphamide or anti-asialo GM1 serum and reduced at least to control levels the number of metastases in these mice. This limited antimetastatic effect of the anticoagulants was mostly due to the action of residual NK cells, since it was completely abrogated in mice whose NK cell activity was more completely suppressed by two injections of anti-asialo GM1 serum. In addition, the low NK reactivity of 3-week-old C57BL/6 or beige mice was sufficient to support the antimetastatic effects of the anticoagulants, effects that completely disappeared after these mice were treated with anti-asialo GM1 serum. Augmentation or abrogation of the antimetastatic effects of heparin after polyinosinic-polycytidylic acid or anti-asialo GM1 treatments, respectively, was observed in athymic nude and allogeneic BALB/c mice that received i.v. injections of B16F1 melanoma cells, indicating that the antimetastatic effects of anticoagulants depend on the presence of active NK rather than T-cells. Furthermore, adoptive transfer of NK-competent but not NK-depleted syngeneic spleen cells restored the antimetastatic effect of heparin in cyclophosphamide-treated mice. Warfarin treatment increased the elimination of radiolabeled BL6 melanoma cells from the lungs of normal mice, and the rate of tumor cell elimination was further potentiated when NK cell activity was stimulated by polyinosinic-polycytidylic acid. In contrast, after anti-asialo GM1 treatment, warfarin had no effect on the survival of i.v. administered tumor cells. Covering of YAC-1 or 3LL tumor cells with fibrin after in vitro exposure with fibrinogen and thrombin substantially protected them from the in vitro cytotoxic action of NK or lymphokine-activate

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Combined Modality Therapy; G(M1) Ganglioside; Glycosphingolipids; Heparin; Immune Sera; Immunotherapy; Killer Cells, Natural; Lung Neoplasms; Lymphoma; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Warfarin

To evaluate coagulable state, beta-thromboglobulin (beta-TG) levels have been followed sequentially in 70 postoperative patients with lung cancer. Nineteen out of them were treated with warfarin plus ticlopidine at a dosage enough to prolong the thrombo-test time to approximately 20% of normal value. There was a significant rise in beta-TG compared with control subjects and beta-TG was correlated with stages of disease. Serial beta-TG determinations revealed that beta-TG and CEA levels fairly paralleled with each other which suggested beta-TG might be useful in following tumor progression or response to therapy in postoperative period. As to the relation between beta-TG levels and five-year survivals, patients whose beta-TG were under 50 ng/ml showed more favorable prognoses than those who had higher levels. Long term anticoagulation with warfarin plus ticlopidine reduced the beta-TG levels of 19 stage 3 or 4 patients, especially in stage 4 the rate of reduction was marked. Nineteen patients with anticoagulant-treated group demonstrated a more prolonged time from beginning of treatment to first evidence of disease progression than 18 non-treated patients. Also anticoagulant-treated group had a more prolonged clinical course than non-treated group after disease progression. These results might be associated with disease stabilization which achieved with anticoagulant therapy. Survival at 30 months after initiation of treatment was 74% in the treated group and 64% in the nontreated group. Although there was no statistical difference in two groups, survival of treated group exceeded that of the non-treated group throughout the observation period. In stage 4 patients, however, the difference between two groups was statistically significant.

Topics: Adult; Aged; Anticoagulants; beta-Thromboglobulin; Blood Coagulation Disorders; Female; Humans; Lung Neoplasms; Male; Middle Aged; Postoperative Complications; Thiophenes; Ticlopidine; Warfarin

This study reports an increased susceptibility to warfarin anticoagulation in mice bearing an experimental tumour, the Lewis lung carcinoma. In these animals, following a single i.v. injection of warfarin, the prothrombin complex activity decreased normally but recovered far slower than in controls, while the rate of degradation of the clotting factors was not modified. At the level of the vitamin K-dependent liver carboxylase, it was possible to demonstrate an increase in the endogenous substrate (reflecting an impairment of the carboxylase vitamin K dependent system). This abnormality was reversed by vitamin K administration and can be reasonably ascribed to a vitamin K deficiency in association with tumour growth.

Topics: Animals; Blood Coagulation; Carbon-Carbon Ligases; Ligases; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Prothrombin; Vitamin K Deficiency; Warfarin

Microsomes isolated from Lewis lung (LL) primary tumors raised in C57BL/6 mice have been shown to (i) contain a 4-hydroxycoumarin (warfarin)-sensitive cycle of vitamin K metabolism which is at least qualitatively similar to that of liver, and (ii) catalyze the incorporation of NaH14 CO3 into endogenous protein in a vitamin-K hydroquinone-dependent reaction to produce gamma-carboxyglutamate. As in liver microsomes, LL microsomal reduction of vitamin K 2,3-epoxide to vitamin K was greatly enhanced by exogenous dithiols such as dithiothreitol, but under identical conditions the former was 10-fold faster. The R(+) and S(-) warfarin enantiomers were highly and equally effective inhibitors of both the liver and tumor vitamin K 2,3-epoxide reductases-the average I50 against the tumor enzyme was 0.25 microM. Partially purified reductases isolated by centrifugation of sodium-cholate-treated liver and LL tumor microsomes over a discontinuous sucrose gradient were also inhibited by the sulfhydryl reagent N-ethylmaleimide following their reduction by dithiothreitol. Like the activity of the epoxide reductase, that of the gamma-carboxylase was much lower in tumor than in liver microsomes and was only detectable in microsomes isolated from tumor-bearing mice previously administered S(-) warfarin. In view of the reported inhibition of LL tumor metastasis by warfarin and diet-induced vitamin-K deficiency, vitamin-K-dependent proteins may play a role in the spread and/or subsequent growth of LL cells.

Topics: Animals; Dithiothreitol; Liver; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Microsomes; Mixed Function Oxygenases; Neoplasm Metastasis; Neoplasm Proteins; Vitamin K; Vitamin K Epoxide Reductases; Warfarin

Lung metastasis is a frequent cancer complication resulting in significant mortality. This study evaluates the effect of coumadin and cytoxan alone and in combination on lung metastases in rats challenged with Morris hepatoma 3924A. Seventy-seven male American Cancer Institute (ACI) rats weighing 200 g were studied. Thirty-seven rats received coumadin orally for six days, which resulted in a prothrombin time 2 times that of controls (30 sec). All rats received 1 X 10(5) clumped Morris hepatoma cells via tail vein injection. Animals were divided into four groups: Group I (controls, n = 20) received no antitumor treatment; group II rats (n = 20) received 25 mg/kg cytoxan intraperitoneally at the time of tumor challenge; group III animals (n = 19) received coumadin alone; while group IV (n = 18) received both coumadin and cytoxan. Rats were evaluated for number of lung metastases and lung weight at 3 weeks postinjection. Data was subjected to statistical analysis by the Student's test. The mean number of lung metastases were 580 +/- 45 in group I, 350 +/- 310 in group II, 330 +/- 263 in group III, and 200 +/- 161 in group IV (P less than .005 [IV] v [I], P less than .05 [IV] v [II], [III]), (P less than .05 [II] v [I]), (P less than .05 [III] v [I]). Mean lung weights were 2.597 g +/- 1.65 in group I, 2.049 g +/- 0.75 in group II, 1.898 g +/- 0.80 in group III, and 1,677 g +/- 0.31 in group IV. (P less than .025 [IV] v [I], P less than .05 [IV] v [II]).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Drug Synergism; Liver Neoplasms, Experimental; Lung; Lung Neoplasms; Male; Organ Size; Rats; Rats, Inbred ACI; Warfarin

Two patients with Trousseau's syndrome experienced frequently recurring concomitant arterial and venous thrombotic events that resulted in sequential amputation and loss of the lower extremities. Serial examination of the blood in the patients demonstrated that these devastating thrombotic events were preceded by severe disseminated intravascular coagulopathy that occurred within an interval of a few hours. Warfarin therapy was without effect in preventing the occurrence of these events. Both patients demonstrated the absolute need for intravenous heparin, which effectively prevented the thrombotic events; when it was discontinued, the immediate consequences were disastrous and resulted in death. Techniques for long-term outpatient heparin therapy are discussed.

Topics: Blood Coagulation Tests; Carcinoma, Bronchogenic; Disseminated Intravascular Coagulation; Heparin; Humans; Lung Neoplasms; Male; Middle Aged; Platelet Count; Recurrence; Syndrome; Thrombosis; Time Factors; Warfarin

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Interactions; Etoposide; Humans; Lung Neoplasms; Male; Prothrombin Time; Vinblastine; Vindesine; Warfarin

Fibrinopeptide A (FPA) levels have been followed sequentially in a three-year study of 50 patients with advanced carcinoma. Evidence for activation of blood coagulation was found in 26 of 43 subjects (60%) at the time of entry into the study. Serial FPA determinations revealed an upward trend which paralleled the progression of clinical disease. Persistent elevation of the FPA level suggested treatment failure and a poor prognosis. Anticoagulation with sodium warfarin significantly reduced the FPA level in subjects with cancer. Short-term anticoagulation with heparin decreased FPA levels in two patients with thromboembolic disease but failed to reduce FPA to the normal range in any of the three patients with cancer so tested. These data suggest that most patients with advanced cancer have evidence for activation of blood coagulation and suggest that serial FPA determinations may be useful in following tumor progression or response to therapy in patients with cancer.

Topics: Aged; Blood Coagulation; Fibrinogen; Fibrinopeptide A; Heparin; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Prognosis; Prothrombin Time; Warfarin

Chronic vitamin K deficiency, either dietary or pharmacologically induced with warfarin, depressed significantly the growth of lung secondaries in a spontaneously metastasizing murine tumor, the Lewis Lung Carcinoma. This effect was associated with a marked depression of the procoagulant activity of cancer cells, which could contribute to fibrin deposition around the tumor. Cellular anticoagulation may thus be an important mechanism in the antimetastatic effect of warfarin.

Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms, Experimental; Vitamin K Deficiency; Warfarin

Topics: Animals; Colonic Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Neoplasm Metastasis; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Rectal Neoplasms; Warfarin

Activation of blood coagulation, as characterized by the occurrence of disseminated intravascular coagulation, increased levels of plasma FPA, and the local deposition of fibrin, is common in both experimental animals and patients with malignant tumors. Many mechanisms have been proposed for the mediation of this response to tumors, including tumor-associated proteases, platelet adherence to tumors, surface activation of blood coagulation by tumor cells, and activation of coagulation by tissue factor derived from either tumor tissue or reactive leukocytes. We have investigated the hypothesis that MTF generation may contribute to increased fibrin generation in cancer patients. Plasma FPA levels and in vitro unstimulated MTF generation were measured simultaneously in samples obtained from 35 patients with lung cancer. FPA levels were significantly elevated in these patients as compared to a group of 20 normal volunteers (p = 0.03). Although unstimulated MTF generation showed considerable variability in both the patients and the normal volunteers, a high degree of correlation was observed between simultaneous levels of FPA and MTF regardless of whether MTF was expressed per cell (r = 0.83), per monocyte (r = 0.95), or per volume of peripheral blood (r = 0.96). MTF generation was also significantly decreased in a group of patients receiving sodium warfarin (p less than 0.001). These results suggest a potential role for MTF generation in the activation of blood coagulation in neoplasia and also suggest the possibility that inhibition of MTF generation by warfarin may be partially responsible for the decreased FPA values previously reported in anticoagulated cancer patients.

Topics: Aged; Blood Coagulation Disorders; Cells, Cultured; Fibrinopeptide A; Humans; Lung Neoplasms; Middle Aged; Mitogens; Monocytes; Reference Values; Warfarin

Topics: Animals; Blood Coagulation Factors; Factor X; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms, Experimental; Vitamin K; Vitamin K Deficiency; Warfarin

Topics: Animals; Carrageenan; Lung Neoplasms; Macrophages; Male; Mice; Neoplasms, Experimental; Silicon Dioxide; Warfarin

Topics: Animals; Blood Coagulation; Factor X; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Warfarin

The distribution of adriamycin (AM) in C57Bl/6 mice bearing intramuscular Lewis lung carcinoma under the influence of combined treatment with warfarin (W) was investigated by a fluorimetric procedure. AM was injected IV at the dose of 7.5 mg/kg 14 days after tumor transplantation and W was given in the drinking water for 96 h, starting 24 h before AM.. No substantial modifications in the serum and tissue distribution of AM fluorescence were observed under combined short-term treatment with W.

Topics: Animals; Carcinoma; Doxorubicin; Drug Therapy, Combination; Kinetics; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Myocardium; Neoplasms, Experimental; Warfarin

The effect has been examined of various host treatments (C. parvum injection, immunization, thoracic irradiation, cyclophosphamide injection, and anticoagulation) on both lung colony formation and clearance of radioactive cells from the lungs after i.v. injection of tumour cells. Two tumour-host models have been used: the non-immunogenic KHT tumour in C3H/Km mice, and the immunogenic EMT6 tumour in BALB/c/Ka mice. Even for the at most weakly immunogenic KHT tumour, the number of artificial pulmonary metastases could be modified by a factor of up to 10(4) by different host treatments before i.v. inoculation of tumour cells. For all pretreatments except immunization, the shape of the curve of loss of radioactivity from the lungs vs time was biphasic, with an initial steep portion representing intravascular death of the tumor cells, followed 1--2 days after tumour-cell injection by a shallow exponential curve. It was concluded that the shallow slope represented spontaneous death of tumour cells in the perivascular tissues. Essentially all the injected tumour cells lodged initially in the lungs, and this was unaffected by the different host treatments. Furthermore, except for specific immunization, cell death in the perivascular tissues was also unaffected by host treatment. However, the survival of the tumour cells during the 24 h after injection (before they became extravascular) was extremely dependent on the particular host pretreatment. It would appear from these studies that host treatments such as C. parvum injection or anticoagulation can markedly affect the number of blood-borne pulmonary metastases, but they will only be effective if given before the tumor cells arrive in the lung vasculature.

Topics: Animals; Antigens, Neoplasm; Cell Survival; Cyclophosphamide; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred Strains; Neoplastic Cells, Circulating; Propionibacterium acnes; Sarcoma, Experimental; Warfarin

Heparin and warfarin inhibit the intravascular survival of B16 melanoma cells in syngeneic C57B1/6J mice in a dose-related manner. The anticoagulant properties of these drugs appear to mediate their inhibitory effects on the survival of intravascular tumor cells. Despite the administration of large doses of heparin, a constant fraction of tumor cells survive to form lung tumors. These data indicate that coagulation dependent and coagulation independent populations of B16 cells normally survive following the intravenous injection of tumor cells.

Topics: Animals; Blood Coagulation; Cell Line; Cell Survival; Heparin; Lung Neoplasms; Male; Melanoma; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Prothrombin Time; Warfarin

A study was made of the effect of various cytotoxic drugs on the ability of i.v.-injected KHT sarcoma cells to form lung colonies in syngeneic C3H mice. Some enhancement of the number of lung colonies following an i.v. injection was seen following pretreatment of the mice with actinomycin D and mithramycin, while pretreatment with vinblastine, bleomycin, methotrexate, cytosine arabinoside, or 5-fluorouracil had little or no effect on lung colony formation. Pretreatment of the mice with cyclophosphamide, however, greatly increased lung colony formation (by a factor of approximately 100). This enhancement in lung colony formation was maximal when the drug was given 24 hr prio to the injection of tumor cells, but was seen as early as 2 hr and persisted as long as 8 weeks prior to the tumor cell injection. The degree of enhancement of lung colony formation was related to the dose of cyclophosphamide and was present in weaning as well as adult mice. This enhancement was not significantly reversed by anticoagulation with either aspirin or warfarin. Immunosuppression by whole-body irradiation did not affect the number of lung colonies seen in cyclophosphamide-treated mice. The mechanism by which cyclophosphamide enhances metastatic tumor growth within the lung is not known. The major effect, however, does not appear to be mediated either by specific immunological or clotting factors.

Topics: Age Factors; Animals; Antineoplastic Agents; Aspirin; Cyclophosphamide; Dactinomycin; Dose-Response Relationship, Drug; Female; Immunosuppression Therapy; Lung Neoplasms; Mice; Mice, Inbred C3H; Neoplasm Metastasis; Neoplasm Transplantation; Plicamycin; Radiation Effects; Sarcoma, Experimental; Warfarin

Topics: Acute Disease; Adolescent; Adult; Aged; Aneurysm; Child; Chronic Disease; Disseminated Intravascular Coagulation; Embolism, Amniotic Fluid; Female; Fetal Death; Fibrinolysis; Hemangioma; Heparin; Humans; Iliac Artery; Infusions, Parenteral; Lung Neoplasms; Lymphatic Metastasis; Male; Melanoma; Middle Aged; Pregnancy; Sepsis; Streptococcal Infections; Syndrome; Thrombophlebitis; Thumb; Warfarin

Topics: Administration, Oral; Animals; Blood Coagulation; Female; Idoxuridine; Injections, Intravenous; Iodine Isotopes; Leukemia, Experimental; Lung Neoplasms; Mice; Mice, Inbred C3H; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasm Transplantation; Neoplastic Cells, Circulating; Sarcoma, Experimental; Transplantation, Homologous; Vitamin K; Warfarin

Topics: Adenocarcinoma; Animals; Aspirin; Heparin; Lung Neoplasms; Mice; Neoplasm Metastasis; Neoplasms, Experimental; Neoplastic Cells, Circulating; Sodium Chloride; Warfarin

Topics: Animals; Female; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Neoplasm Metastasis; Prothrombin Time; Sarcoma; Time Factors; Warfarin

Long-term oral administration of sodium warfarin significantly reduced the incidence of spontaneous metastases in the lungs from 83 percent in controls to 8 percent in treated C57/BL/6N mice. The size and weight of primary tumors in mice treated with warfarin were less than in control mice. Length of survival was unaffected.

Topics: Animals; Female; Lung Neoplasms; Methylcholanthrene; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Warfarin

Topics: Adenocarcinoma; Heparin; Humans; Lung Neoplasms; Male; Middle Aged; Thrombophlebitis; Warfarin

Topics: Animals; Carcinoma 256, Walker; Lung Neoplasms; Neoplasm Metastasis; Rats; Warfarin