Gerald J. Vosika

Combination versus successive single agent chemotherapy in lymphocytic lymphoma.

Fifty‐three patients with advanced lymphocytic lymphoma were randomly assigned to treatment with the combination cyclophosphamide, vincristine, and prednisone (CVP) or the same agents used successively in maximal doses (C‐V‐P). Complete remissions occurred in 68% with CVP and 48% with C‐V‐P. For patients with nodular lymphoma, the complete remission rate was 81% with CVP and 46% with C‐V‐P. In patients with diffuse lymphoma a complete remission rate of 50% was obtained with both regimens. The median duration of response was longer for patients who obtained complete remission with CVP (37+ months) than for those entering remission with C‐V‐P (25+ months). More patients treated with CVP still survive. Current results suggest that CVP is a better induction regime than C‐V‐P in patients with nodular lymphoma. However, in patients with diffuse lymphocytic lymphoma, neither regimen results in more than 50% complete remissions or significant numbers of prolonged responses. More effective therapy is needed.

Combined chemotherapy with cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP) for patients with advanced Hodgkin's disease. An alternative program to MOPP

Thirty‐eight patients with advanced Hodgkins disease were treated with a combination of cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP). Complete remissions were obtained in 74% of patients. Response rates were similar for previously untreated and previously extensively irradiated patients. Fifty‐six percent of patients older than 50 and 50% of patients with bone marrow involvement responded. All patients with mixed cellularity Hodgkins disease responded compared with 74% of patients with nodular sclerosis. At the present time the median duration of complete remission is 27+ months. However, of the responders, 75% (21 of 28) remain in continuous complete remission for 14+ to 49+ months. Only five patients have relapsed but two have died from apparent sepsis without evidence of recurrent disease. The complete remission rate for CVPP is comparable to that for MOPP. CVPP is an easily administered, well‐tolerated alternative to MOPP chemotherapy for patients with advanced Hodgkins disease.

Comparison of tamoxifen and hypophysectomy in breast cancer treatment

The effectiveness of hypophysectomy and tamoxifen in treating advanced breast cancer was compared in a randomized study of 26 patients who had responded to prior oophorectomy or additive hormonal therapy. When patients failed to respond or relapsed from tamoxifen or hypophysectomy, the therapy was crossed over. In this designed sequence, the rate and duration of response observed with tamoxifen or hypophysectomy used as the first regimen were comparable. The results suggest that tamoxifen is effective in the posthypophysectomy phase and the sequence of hypophysectomy followed by tamoxifen in hormone‐dependent breast cancer is preferable to achieve a maximal control of the disease.

Vindesine for metastatic malignant melanoma. A phase II trial.

Sixteen patients, 13 of whom had received prior chemotherapy, were treated with vindesine for advanced malignant melanoma. Previous treatment included vinca alkaloids in six. Thirteen patients received vindesine, 4 mg/m2 and three received vindesine, 3 mg/m2 by weekly I.V. injection. There were two partial (12%) and no complete responses among all of the patients. Both responses occurred in subcutaneous lesions and lasted for 4 and 6 weeks, respectively. Fifteen patients could be evaluated for treatment-related toxicity. The most common side effect was modest leukopenia (less than 3000/microliter) in 10 patients (67%). The lowest leukocyte count recorded was 1100/microliter. Thrombocytopenia was not encountered. Neurotoxicity, manifest most commonly as mild or moderate peripheral paresthesiae, was seen in eight patients (53%).

Intralesional immunotherapy of malignant melanoma with mycobacterium smegmatis cell wall skeleton combined with trehalose dimycolate (P3).

The clinical efficacy of intralesional immunotherapy utilizing Mycobacterium smegmatis cell wall skeleton (CWS) and trehalose dimycolate attached to oil droplets was investigated in 15 patients with advanced malignant melanoma. Patients received 300 μg to 1050 μg of the CWS combined with one‐half that amount of trehalose dimycolate every 1 to 2 weeks for a total of 8 treatments. Therapy was continued if regression of injected lesions only occurred. Therapy was discontinued if regression of noninjected disease also occurred. Six of the 15 patients had regressionof at least one injected lesion. Four of these 6 patients also had regression of noninjected disease lasting 4+, 6, 16 and 18+ months. Response was highly related to immune status. Six (83%) of 7 patients who reacted to one of a battery of skin tests responded. All 8 patients who did not react to skin tests failed to respond to therapy. There was no correlation of response with sex, prior therapy, disease‐free interval or presence of visceral disease. Mycobacterial CWS and trehalose dimycolate is an effective immunotherapeutic agent. Additional studies of purified immunoadjuvants are warranted. Cancer 44:495‐503, 1979.

Phase I study of intradermal immunotherapy with oil-attached Mycobacterium smegmatis cell wall skeleton and trehalose dimycolate

SummaryThe clinical toxicity of intradermal immunotherapy with a nonviable mycobacterial vaccine consisting of oil-attached Mycobacterium smegmatis cell wall skeleton (CWS) and trehalose dimycolate (P3) was evaluated. Fifteen patients with advanced hypernephroma, lung cancer, or malignant melanoma were evaluated. Patients received one to ten separate intradermal injections in the subclavicular areas weekly for up to 8 weeks. Each separate injection usually contained 75 μg CWS and 37.5 μg P3.There were few systemic side effects. Mild fever occurred in 30% of 69 treatments. Severe local toxicity with ulceration and/or abscess formation occurred in seven patients. Regression of disease was observed in one patient to occur on two separate occasions following separate courses of therapy.Although intradermal CWS/P3 can be locally toxic, treatment with up to four separate injections of 75 μg CWS combined with 37.5 μg P3 every 1–2 weeks appears appropriate, from this study, for additional clinical trials.

Analysis of the genetic complexity and abundance classes of messenger RNA in human liver and leukemic cells

In an effort to determine the number of genes expressed as messenger RNA in disparate human tissues we have analyzed the genetic complexity of the polyribosome-associated poly(A)-containing RNA population obtained from liver and lymphoblastic leukemic cells. This was accomplished by measuring the kinetics of hybridization of mRNA to a complementary DNA probe synthesized by avian myeloblastosis virus reverse transcriptase in vitro. The results obtained from such an analysis revealed the presence of two major abundance classes of mRNA with a total genetic complexity of approximately 10,000 diverse mRNA species in both of these cell types. Diversity of mRNA species in these unrelated human cells was studied by heterologous hybridization reactions between the cDNA of one cell type and a vast excess of poly(A)-containing mRNA from another. These types of studies indicated that extensive homology (more than 80%) exists in the mRNA sequences of disparate human cell types and suggest that the vast majority of genetic information expressed as mRNA is required for the maintenance of cellular functions common to functionally different human tissues.

CCNU-adriamycin therapy in bronchogenic carcinoma.

Forty‐eight patients with advanced bronchogenic carcinoma were treated with a combination of CCNU and Adriamycin. There was an overall objective response rate of 38%. This consisted of 1 of 12 (8%) patients with epidermoid carcinoma, 5 of 15 (33%) with adenocarcinoma, 2 of 5 (40%) with large cell undifferentiated carcinoma and 10 of 16 (63%) with small cell undifferentiated carcinoma. The overall median survival time (MST) from initiation of therapy was 28 weeks. The MST was 18 weeks for patients with epidermoid carcinoma, 30 weeks for those with adenocarcinoma, 39 weeks for those with large cell carcinoma, and 30+ weeks for those with small cell carcinoma. Objective tumor response was associated with prolonged survival. There were no drug related deaths and toxicity was minimal.

Vindesine in bronchogenic carcinoma: a phase II trial.

Twenty-seven patients with advanced bronchogenic carcinoma were treated with vindesine, 3 mg/m2/week. Twenty-three patients were evaluable for response. Two of six patients with small-cell carcinoma and one of 17 patients with non-small-cell carcinoma had partial responses. Two other patients with non-small-cell carcinoma had minor responses. The duration of the responses was 2-4 months. Neurologic toxicity occurred in 14 patients and was mild except in two patients. There was a median hemoglobin fall of 2.2 g/dl and a median leukocyte nadir of 2800/microliter during vindesine therapy. Thrombocytopenia occurred in 2 patients and mild thrombocytosis occurred in 10 patients. Seven patients experienced phlebitis or cellulitis at the site of drug administration which could be prevented with small doses of intravenous methylprednisolone. These results suggest that vindesine is well tolerated and possesses some activity in patients with previously treated bronchogenic carcinoma.

Studies on the transformation of rat embryo cells of low passage by carcinogenic fluorenylhydroxamic acids and their acetate esters.

SummaryRat embryo cells of low passage subjected to a single treatment with certain carcinogenic fluorenylhydroxamic acids and their respective acetate esters showed signs of transformation in vitro, such as changes in phenotype, growth in soft agar and agglutination with concanavalin. A. In addition, certain changes in karyotype and loss of diploidy were observed. There was no evidence, either by electron microscopy or by assay of RNA-dependent DNA polymerase, for the presence of virus. None of these cell lines produced tumors after inoculation into the isologous host. The results of this study lead us to suggest that malignant transformation is a multistep process and that certain criteria of transformation of rat embryo cells are associated with the initial stage(s) in which the cells are transformed without being tumorigenic. The ultimate test for malignant transformation of rat embryo cells remains the production of tumors in a susceptible host after inoculation of treated cells.