Clara P. W. Klerk

The Effect of Low Molecular Weight Heparin on Survival in Patients With Advanced Malignancy

PURPOSE Studies in cancer patients with venous thromboembolism suggested that low molecular weight heparin may prolong survival. In a double-blind study, we evaluated the effect of low molecular weight heparin on survival in patients with advanced malignancy without venous thromboembolism. METHODS Patients with metastasized or locally advanced solid tumors were randomly assigned to receive a 6-week course of subcutaneous nadroparin or placebo. The primary efficacy analysis was based on time from random assignment to death. The primary safety outcome was major bleeding. RESULTS In total, 148 patients were allocated to nadroparin and 154 patients were allocated to placebo. Mean follow-up was 1 year. In the intention-to-treat analysis the overall hazard ratio of mortality was 0.75 (95% CI, 0.59 to 0.96) with a median survival of 8.0 months in the nadroparin recipients versus 6.6 months in the placebo group. After adjustment for potential confounders, the treatment effect remained statistically significant. Major bleeding occurred in five (3%) of nadroparin-treated patients and in one (1%) of the placebo recipients (P = .12). In the a priori specified subgroup of patients with a life expectancy of 6 months or more at enrollment, the hazard ratio was 0.64 (95% CI, 0.45 to 0.90) with a median survival of 15.4 and 9.4 months, respectively. For patients with a shorter life expectancy, the hazard ratio was 0.88 (95% CI, 0.62 to 1.25). CONCLUSION A brief course of subcutaneous low molecular weight heparin favorably influences the survival in patients with advanced malignancy and deserves additional clinical evaluation.

Validity of bioluminescence measurements for noninvasive in vivo imaging of tumor load in small animals

A relatively new strategy to longitudinally monitor tumor load in intact animals and the effects of therapy is noninvasive bioluminescence imaging (BLI). The validity of BLIf or quantitative assessment of tumor load in small animals is critically evaluated in the present review. Cancer cells are grafted in mice or rats after transfection with a luciferase gene--usually that of a firefly. To determine tumor load, animals receive the substrate agent luciferin intraperitoneally, which luciferase converts into oxyluciferin in an ATP-dependent manner Light emitted by oxyluciferin in viable cancer cells is captured noninvasively with a highly sensitive charge-coupled device (CCD) camera. Validation studies indicate that BLI is useful to determine tumor load in the course of time, with each animal serving as its own reference. BLI is rapid, easy to perform, and sensitive. It can detect tumor load shortly after inoculation, even when relatively few cancer cells (2500-10,000) are used. BLI is less suited for the determination of absolute tumor mass in an animal because of quenching of bioluminescence by tissue components and the exact location of tumors because its spatial resolution is limited. Nevertheless, BLI is a powerful tool for high-throughput longitudinal monitoring of tumor load in small animals and allows the implementation of more advanced orthotopic tumor models in therapy intervention studies with almost the same simplicity as when measuring traditional ectopic subcutaneous models in combination with calipers.

Prevention of catheter-related venous thrombosis with nadroparin in patients receiving chemotherapy for hematologic malignancies: a randomized, placebo-controlled study.

Summary.  Background: Hemato‐oncology patients treated with intensive chemotherapy usually require the placement of a central venous catheter (CVC). CVCs are frequently complicated by catheter‐related central venous thrombosis (CVT), which has been associated with an increased risk of pulmonary embolism and catheter‐related infection. Objectives: To determine the efficacy and safety of thromboprophylaxis with s.c. low‐molecular‐weight heparin (nadroparin) administered once daily in a randomized placebo‐controlled, double‐blind trial in patients with hematologic malignancies. Patients and methods: Consecutive patients with hematologic malignancies requiring intensive chemotherapy including autologous stem cell transplantation were eligible. The patients were randomized to receive nadroparin 2850 antifactor Xa units once daily or placebo s.c. for 3 weeks. Venography was performed on day 21 after CVC insertion. Secondary outcomes were bleeding and catheter‐related infection. Results: In total, 113 patients were randomized to nadroparin or placebo, and 87 patients (77%) underwent venography. In total, 11 venographically proven catheter‐related CVTs were diagnosed. The frequency of catheter‐related CVT was not significantly different between study groups, namely four catheter‐related CVTs in the placebo group [9%; 95% CI: 0.002–0.16] vs. seven catheter‐related CVTs in the nadroparin group (17%; 95% CI: 0.06–0.28). In addition, no difference in the incidence of catheter‐related infection or bleeding was observed between the groups. Conclusion: This study showed that the actual risk for catheter‐related CVT in patients with hematologic malignancies is lower than suggested in earlier studies in cancer patients. Although prophylactic administration of nadroparin appeared to be safe in this group of patients with a high risk of bleeding, it cannot be recommended for the prevention of catheter‐related CVT or catheter‐related infection in patients with hematologic malignancies.

Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung

Abstract Cancer progression is facilitated by blood coagulation. Anticoagulants, such as Hirudin and low molecular weight heparins (LMWHs), reduce metastasis mainly by inhibition of thrombin formation and L- and P-selectin-mediated cell-cell adhesion. It is unknown whether the effects are dependent on cancer cell type. The effects of anticoagulants on tumor development of K1735 and B16 melanoma cells and CT26 colon cancer cells were investigated in mouse lung. Tumor load was determined noninvasively each week up to day 21 in all experiments using bioluminescence imaging. Effects of anticoagulants on tumor development of the three cell lines were correlated with the fibrin/fibrinogen content in the tumors, expression of tissue factor (TF), protease activated receptor (PAR)-1 and -4 and CD24, a ligand of L- and P-selectins. Hirudin inhibited tumor development of B16 cells in lungs completely but did not affect tumor growth of K1735 and CT26 cells. Low molecular weight heparin did not have an effect on K1735 melanoma tumor growth either. TF and PAR-4 expression was similar in the three cell lines. PAR-1 and CD24 were hardly expressed by K1735, whereas CT26 cells expressed low levels and B16 high levels of PAR-1 and CD24. Fibrin content of the tumors was not affected by LMWH. It is concluded that effects of anticoagulants are dependent on cancer cell type and are correlated with their CD24 and PAR-1 expression.

The prognostic value of the D‐dimer test in cancer patients treated with and without low‐molecular‐weight heparin

adsorption of the rFVIII protein to the inner surface of the tubing and bag. This effect is slightly different for the sucroseformulated product evaluated here compared with the albumin-formulated product studied by Hurst et al., and could be explained by the presence of albumin competing during the initial adsorption/saturation process. The results obtained under the above-mentioned experimental conditions suggest adequate stability when rFVIII-FS is delivered under in vitro conditions approximating continuous infusion. In a clinical situation, the minimal binding of protein to the infusion tubing at the start of continuous infusion would probably not alter the plasma FVIII concentration, as such patients would receive a bolus injection of FVIII prior to the initiation of continuous infusion. These results provide a preliminary basis for the use of Kogenate FS in clinical trials, and situations requiring prolonged and/or intensive hemostatic treatment. Conflicts of interest disclosure

Colon cancer metastasis in mouse liver is not affected by hypercoagulability due to Factor V Leiden mutation.

Clinical trials have shown life‐prolonging effects of antithrombotics in cancer patients, but the molecular mechanisms remain unknown due to the multitude of their effects. We investigated in a mouse model whether one of the targets of antithrombotic therapy, fibrin deposition, stimulates tumour development. Fibrin may provide either protection of cancer cells in the circulation against mechanical stress and the immune system, or form a matrix for tumours and/or angiogenesis in tumours to develop. Mice homozygous for Factor V Leiden (FVL), a mutation in one of the coagulation factors that facilitates fibrin formation, were used to investigate whether hypercoagulability affects tumour development in an experimental metastasis model. Liver metastases of colon cancer were induced in mice with the FVL mutation and wild‐type littermates. At day 21, number and size of tumours at the liver surface, fibrin/fibrinogen distribution, vessel density and the presence of newly formed vessels in tumours were analysed. Number and size of tumours did not differ between mice with and without the FVL mutation. Fibrin/fibrinogen was found in the cytoplasm of hepatocytes and cancer cells, in blood vessels in liver and tumour tissue and diffusely distributed outside vessels in tumours, indicating leaky vessels. Vessel density and angiogenesis varied widely between tumours, but a pre‐dominance for vessel‐rich or vessel‐poor tumours or vessel formation could not be found in either genotype. In conclusion, the FVL mutation has no effect on the development of secondary tumours of colon cancer in livers of mice. Fibrin deposition and thus inhibition of fibrin formation by anticoagulants do not seem to affect tumour development in this model.

Antithrombotic therapy and cancer.

Purpose of the reviewTo assess the current evidence from recent clinical trials investigating antithrombotic agents for the prophylaxis and treatment of venous thromboembolism in cancer patients and for the effects of these agents on cancer progression. Recent findingsA growing body of evidence supports the preventive use of antithrombotic strategies in subgroups of cancer patients. Moreover, in the long-term management of deep venous thrombosis in cancer patients, low-molecular-weight heparin seems to represent a valid alternative to vitamin K antagonists. Finally, several studies have claimed a direct anticancer activity and a positive impact on prognosis of some antithrombotic agents, eg, aspirin and low-molecular-weight heparin. SummaryAlthough recent evidence suggests low-molecular-weight heparin as a possible option in the management and prevention of venous thromboembolism in cancer patients, more evidence from large randomized, prospective, controlled trials is needed to determine the exact the magnitude of the risk-benefit ratio associated with its use. The promising results on the effects of antithrombotic agents in the prognosis of cancer patients deserve further evaluation to estimate the potential and the feasibility of this approach.

Prophylactic plasma levels of the low molecular weight heparin nadroparin does not affect colon cancer tumor development in mouse liver

a Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands b Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands c Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands d Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands