Walter B. Forman

Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate: Final Report of VA cooperative study # 75

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.

Rationale and experimental design for the VA Cooperative Study of Anticoagulation (Warfarin) in the Treatment of Cancer.

Anticoagulants have been demonstrated to reduce tumor growth in certain experimental animal systems. Inhibition of clot formation interferes with tumor growth and spread while enhancement of coagulation promotes tumor growth and spread. The fact that the coagulation mechanism is commonly activated in human malignancy together with preliminary reports of therapeutic efficacy of anticoagulants suggests that the coagulation mechanism may be of pathophysiologic significance also in the growth of human tumors. A VA Cooperative Study has been established to test the hypothesis that warfarin anticoagulation will modify the course of malignancy in man. The purpose of this paper is to present the rationale and experimental design for this study with emphasis on management of anticoagulant administration in cancer patients. This paper serves as the basis for forthcoming reports of toxicity and therapeutic efficacy of warfarin in human malignancy. Cancer 44:732‐741, 1979.

Studies on the Nature of Antihemophilic Factor (Factor VIII): FURTHER EVIDENCE RELATING THE AHF-LIKE ANTIGENS IN NORMAL AND HEMOPHILIC PLASMAS

Normal human antihemophilic factor (AHF, factor VIII) and the protein antigenically related to it in hemophilic plasma both appeared in the void volume of columns of agarose (Sepharose 4B) during purification of these agents. On ultracentrifugation upon sucrose gradients, both agents had sedimentation characteristics similar to those of an S30 marker. After reduction, the polypeptide chains of purified normal AHF and of the nonfunctional agent from hemophilic patients had an apparent molecular weight of 200,000 as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. These observations suggest that AHF, purified as described, exists as a large molecule with subunits of molecular weight of approximately 200,000. Antisera to normal AHF and the nonfunctional agent from hemophilic plasma appeared to be directed against antigens of similar electrophoretic mobility and precipitating characteristics, present in normal and hemophilic plasma but deficient in severe von Willebrands disease plasma. Both antisera neutralized the AHF clot-promoting activity present in normal plasma, and this property was removed by absorption of the antisera with concentrates of normal or hemophilic plasma but to a greatly reduced extent by concentrates of von Willebrands disease plasma. These findings suggest that the antigen detected in normal plasma by the antisera appears on a molecule participating in the AHF clot-promoting reaction.

Esophageal carcinoma. A six-year review of the Cleveland Veterans Administration Hospital experience.

The records of 51 patients with esophageal carcinoma were reviewed. Twenty‐two patients underwent attempted curative resection with a mean survival of 7.7 months. Twenty patients underwent primary radiotherapy (mean survival, 4.3 months). Nine patients received palliative therapy alone (mean survival, 2.8 months). Surgical mortality was 27%, but symptomatic palliation was complete in 59% of the surgical patients. Only 5% of the radiotherapy group, and 11% of the palliative group were completely palliated. There is only one long‐term survivor (21+ months). Lesions in the middle third of the esophagus, and the presence of clinical evidence of metastatic disease were predictive of a shorter survival. Patients with metastatic disease at presentation had a mean survival of only 2.5 months from diagnosis. It is concluded that surgery should be considered a palliative, not curative procedure, and that it should be attempted only in those patients without clinical evidence of metastatic disease.

Two primary carcinomas of the lung: Adenocarcinoma and a metachronous squamous cell carcinoma. A case report and review of the literature

The case of a patient who underwent a left lower lobe lobectomy for adenocarcinoma of the lung and developed a metachronous squamous cell carcinoma of the right lung eight years later, is presented. The unusual nature of the case is emphasized utilizing a review of the literature. The criteria for diagnosing metachronous carcinomas are presented and a unified terminology for such cases is proposed. The requirement for life‐long follow‐up of any patient with cancer is emphasized.

Alveolar Macrophage Plasminogen Activator

Plasminogen activator is a neutral serine protease secreted by many different cells, including activated peritoneal macrophages, which can mediate both inflammation and fibrinolysis and perhaps cytolysis of tumor cells. Secretion of plasminogen activator by rabbit alveolar macrophages derived from normal animals and rabbits pretreated with bacillus Calmette-Guérin (BCG) to activate these macrophages was examined. Plasminogen activator was secreted into media of cultured alveolar macrophages, but was not present within the cells. Secretion, which was dependent upon the presence of viable cells, could be blocked by protein synthesis inhibitors and enhanced by concanavalin A and phorbol myristate acetate. The inhibition profile of rabbit alveolar macrophage plasminogen activator is consistent with that of a serine protease. Plasminogen activator is present in two forms with molecular weights of 28,000 and 45,000. Alveolar macrophage plasminogen activator was secreted in cultures from most rabbits (17 of 23) pretreated with BCG, but rarely in those from normal animals (2 of 14). Lavage fluids from many rabbits contained viable Bordetella bronchiseptica, but the presence of this organism showed no correlation with secretion of plasminogen activator. Rabbit alveolar macrophages secrete a plasminogen activator similar to that secreted by mouse peritoneal macrophages as described previously. Secretion is enhanced by activation of alveolar macrophage populations.