warfarin and Melanoma

Radiation optic neuropathy (RON) generally follows radiation therapy that exceed 50 Gy to the visual axis and occurs within three years of therapy. Currently, there are no universally accepted treatments or prophylaxis for RON. The review aimed to examine the efficacy of all treatments and prophylaxis for RON.. MEDLINE, Embase, the Cochrane Library, and gray literature were searched to December 2020. Studies on treatment(s) and/or prophylaxis of RON were included. Results were meta-analyzed using a random-effects model. Primary outcomes included the proportions of patients who experienced improvement, no change, or worsening of visual acuity (VA) for each treatment. Secondary outcome was the incidence of RON for studies on prophylaxis.. Overall, 50 studies (n = 5397) were included. Meta-analysis (n = 1752) showed significantly lower incidence of RON in patients who underwent intravitreal anti-VEGF prophylaxis compared to control (RR 0.64, 95%CI [0.48, 0.86]) for uveal melanoma. Intravitreal anti-VEGF injections (n = 68), hyperbaric oxygen therapy alone (n = 14), and pentoxifylline (n = 5) resulted in improved or stable vision ≤1 logMAR in 54.5%, 42.9%, and 40.0% of patients, respectively. Systemic corticosteroids (n = 82), anticoagulants (n = 12), and systemic bevacizumab (n = 7) showed improved or stable vision ≤1 logMAR in 17.1%, 33.3%, and 14.3% of patients, respectively. Overall risk of bias was low, but evidence was limited to retrospective studies.. Intravitreal anti-VEGF injections reduced incidence of RON in irradiated uveal melanoma patients. Systemic corticosteroids, systemic bevacizumab, and warfarin alone are likely ineffective treatments. Early hyperbaric oxygen therapy and intravitreal anti-VEGF injections were most effective among those investigated and require further investigation.

Topics: Adrenal Cortex Hormones; Angiogenesis Inhibitors; Anticoagulants; Bevacizumab; Humans; Intravitreal Injections; Melanoma; Optic Nerve Diseases; Pentoxifylline; Ranibizumab; Retrospective Studies; Uveal Neoplasms; Vascular Endothelial Growth Factor A; Warfarin

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Aspirin; Atrial Fibrillation; Brain Damage, Chronic; Case Management; Contraindications; Craniotomy; Decompression, Surgical; Diabetes Complications; Evidence-Based Medicine; Facial Neoplasms; Fibrin Tissue Adhesive; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Hypercholesterolemia; Hypertension; Infarction, Middle Cerebral Artery; International Normalized Ratio; Intracranial Embolism; Male; Melanoma; Middle Aged; Mohs Surgery; Paresis; Postoperative Complications; Preoperative Care; Prospective Studies; Retrospective Studies; Skin Neoplasms; Skin Transplantation; Thrombolytic Therapy; Warfarin

Additional carboxylation of glutamic acid by vitamin K-dependent gamma-carboxylase is a common posttranslational modification of many proteins, including some of blood clotting factors. Vitamin K-antagonists, such as warfarin, are often included in the therapy of malignant disease, decreasing the blood coagulation potential. Cancer procoagulant, a direct blood coagulation factor X activator from malignant tissue, is considered as a vitamin K-dependent protein, so it could serve as one of possible targets for the therapy with warfarin. However, there is still no experimental data demonstrating directly the presence of gamma-carboxyglutamic acid (Gla) in a cancer procoagulant molecule. The presence of Gla in cancer procoagulant isolated from human amnion-chorion membranes and from human malignant melanoma WM 115 cell line was analyzed directly, using specific anti-Gla monoclonal antibodies. There was no detectable amount of Gla in cancer procoagulant isolated from fetal or malignant tissue. Cancer procoagulant from human tissues does not contain Gla-rich domain. The finding indicates that cancer procoagulant is rather a poor target for warfarin therapy of malignant disease.

Topics: 1-Carboxyglutamic Acid; Amnion; Antibodies, Monoclonal; Anticoagulants; Cell Line, Tumor; Chorion; Cysteine Endopeptidases; Enzyme Activation; Factor X; Female; Humans; Melanoma; Neoplasm Proteins; Pregnancy; Warfarin

Optic neuropathy is a rare but important complication of radiotherapy used in the treatment of cancers of the head and neck, usually resulting in rapidly progressive blindness in one or both eyes. The case is presented of a 77-year-old woman with bilateral optic neuropathy resulting in blindness, secondary to radiotherapy for a melanoma of the nasal cavity. The onset of optic neuropathy occurred 9 months post-radiotherapy, at a cumulative dose of 6000 rad. The left eye was first involved, with the right eye becoming involved within 2 weeks. Despite treatment with oral anticoagulation and high dose intravenous methylprednisolone, there was progressive deterioration resulting in bilateral optic atrophy, with final visual acuities of perception of light in the right eye and no perception of light in the left eye. This case demonstrates that oral anticoagulation was ineffective in the treatment of progressive radiation-induced optic neuropathy.

Topics: Aged; Anticoagulants; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Magnetic Resonance Imaging; Melanoma; Methylprednisolone; Optic Nerve; Optic Nerve Diseases; Paranasal Sinus Neoplasms; Radiation Injuries; Radiotherapy; Visual Fields; Warfarin

Using an adapted assay that requires an enzyme aliquot that forms only 5 pmoles vitamin K, we were able to demonstrate vitamin K1 2,3 epoxide reductase activity in cultured B16 mouse melanoma cells. The enzyme uses dithiothreitol, but not NADH as a reducing cofactor and is sensitive to inhibition by warfarin (2% residual activity at 10 micrograms/ml warfarin). Incubation of B16 cells in culture with 30 micrograms/ml warfarin leads to an 45% residual reductase as compared to normally cultured B16 cells. Combined with the reported presence of vitamin K dependent carboxylase in B16 cells and the cytotoxicity of warfarin towards B16 cells this suggests an active vitamin K cycle in these melanoma cells that may be essential for survival.

Topics: Animals; Cattle; Melanoma; Mice; Microsomes, Liver; Mixed Function Oxygenases; Vitamin K; Vitamin K Epoxide Reductases; 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

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