A ten-year follow-up on stage II malignant melanoma patients treated postsurgically with Newcastle disease virus oncolysate.

Newcastle disease virus oncolysate was examined as an adjunctive immunotherapeutic agent in the postsurgical management of 83 cases of Stage II malignant melanoma. At this time, all the patients have been under observation for at least 10 years, and over 60% are alive and free of recurrent disease. Older studies in the United States report postsurgical survival figures for Stage II cases of 5-15%. More contemporary studies indicate a 33% survival at 10 years. The unusual disease-free survival periods in the present study, including exceptional survivals in 21 patients with head and neck disease and six cases with cerebral metastases, suggest a unique role for the administration of Newcastle disease virus oncolysate in the management of Stage II malignant melanoma patients.

Malignant melanoma. Inflammatory mononuclear cell infiltrates in cerebral metastases during concurrent therapy with viral oncolysate.

Five patients with advanced malignant melanoma, treated with viral oncolysate, had solitary central nervous system metastases that were removed surgically. Histologic examination revealed striking and significant mononuclear inflammatory cell infiltrates, consisting of a mean of 60% plasma cells and a lesser proportion of lymphocytes at the edges of the lesions, within their supporting fibrovascular trabeculae, and among the tumor cells. Comparable inflammatory changes were not found in solitary metastatic malignant melanomas removed surgically from the brains of 19 patients not treated with viral oncolysate. Similarly, multiple metastatic malignant melanomas obtained postmortem from the brains of 12 patients not treated with viral oncolysate showed minimal inflammatory responses. Ultrastructural examination of material from a single treated patient revealed morphologic abnormalities of the blood-brain barrier, changes that were perhaps conducive to infiltration of the neoplasm by inflammatory cells. The authors suggest that administration of viral oncolysate enhances the inflammatory cell response to metastatic malignant melanoma in the brain.

A phase II study on the postsurgical management of Stage II malignant melanoma with a Newcastle disease virus oncolysate.

A Newcastle disease virus lysate of malignant melanoma cells was examined for its possible value in delaying the progression of malignant melanoma with palpable regional node disease (Stage II) to disseminated melanoma (Stage III). This Phase II study was carried out in a group of 32 patients following therapeutic lymphadenectomy. The patients were not prospectively randomized. In each patient, the viral oncolysate was administered subcutaneously at regular intervals over 3 years. The cumulated progressions to disseminated disease at 1, 2 and 3 years were 6%, 8% and 12% of the study group, respectively. These experienced losses were considerably lower than in the control group and in similar control groups described by other investigators. The results suggest that an oncolysate prepared with Newcastle disease virus is a helpful adjunct to surgery in the management of Stage II malignant melanoma.

Viral oncolysate in the management of malignant melanoma. I. Preparation of the oncolysate and measurement of immunologic responses.

Primary explants of human malignant melanoma were utilized in the preparation of oncolysates by Newcastle disease virus. The concentrated lysate, administered parenterally, was employed in an effort to augment antitumor immunologic responses in patients with metastatic melanoma. Observed cellular changes suggested a benefit, but humoral antibody measurements were not impressive.

Viral oncolysate in the management of malignant melanoma. II. Clinical studies.

Melanoma cell oncolysate, prepared with Newcastle disease virus, was administered as an immunostimulant to 13 patients with metastatic melanoma. The oncolysate was well tolerated. Six treated patients evidenced a decrease in the size of skin nodules or diseased lymph nodes. Visceral lesions were not favorably influenced to any marked degree. One case of fulminating disease showed a change to slow progression and survived a year longer than was otherwise expected. Another patient, whose melanoma could not be controlled by surgery or chemotherapy, has been in complete remission for 2 years. It appears that viral oncolysate might be particularly helpful to patients with early disease.

The pathogenesis of Vaccinia virus toxicity. II. An electron microscopic study.

The intravenous injection of mice with toxic doses of vaccinia virus, prepared in the Ehrlich ascites carcinoma, usually produces fatal intravascular coagulation, within 24 hours. Light and electron microscope studies demonstrate occlusion of the microcirculation of lungs and livers by fibrin. Fibrin deposition appears to be prevented in mice injected with heparinized virus preparations. However, in lieu of fibrin deposition, within the microcirculation widespread intravascular platelet aggregation occurs. Platelets within these aggregates are in various stages of degranulation, and some platelets have phagocytosed vaccinia virus. Platelet aggregation was not observed in mice receiving injections of heparinized material prepared from uninfected tumors. In mice surviving longer than 12 hours, hepatocytes and endothelial cells of pulmonary capillaries are the sites of viral replication. Although many hepatocytes are infected in mice surviving longer than 12 hours, it is postulated that hepatocyte necrosis is in part due to the congestive effects resulting from obstruction of liver and pulmonary capillaries. These studies suggest that vaccinia virus may trigger in vivo platelet aggregation, and that obstruction of the lung and liver microcirculation by these aggregates is the initial lesion of vaccinia virus toxicity.

The pathogenesis of Vaccinia virus toxicity. I. The role of virus-platelet interaction.

When mice are injected intravenously with a large dose of vaccinia virus, prepared in the Ehrlich ascites carcinoma of the mouse, there is a precipitous loss of plasma fibrinogen and blood platelets. Death occurs usually within 24 hours. A specific role of the virus in this toxic syndrome can be demonstrated when heparin is employed to circumvent intravascular coagulation and fibrinogen loss. Heparin does not prevent a profound thrombocytopenia from occurring, but it modifies the rate of platelet loss. Toxicity is prevented when heparinized virus preparations are pretreated with beta-propiolactone or specific antibody, although a mild thrombocytopenia occurs. Thrombocytopenia does not occur in mice injected with heparinized material prepared from uninfected tumors. These studies indicate that the basic mechanism of vaccinia virus toxicity is an early interaction between infectious virus and blood platelets, with marked thrombocytopenia and consequential pathophysiologic changes.

Ehrlich ascites tumor preservation for fifteen years--a simple method.

The Ehrlich ascites tumor was preserved for 15 years by adding to it an equal volume of 40% glycerol and placing the preparation directly into a freezer at -60 C.

Biological activity of a partially purified inhibitor of vaccinia virus hemagglutinin.

An inhibitor acting against vaccinia virus hemagglutinin, and producing a hemagglutinin-negative virus, was separated from tumorous ascitic plasma. The finding that the partially purified inhibitor was biologically active strengthens the evidence for a specific role of the inhibitor in altering the virus.