Association of subacute motor neuronopathy with thymoma.

A case of subacute motor neuronopathy in association with thymoma is described. Subacute motor neuronopathy is marked by a painless, progressive, and asymmetric muscle weakness that usually affects the lower extremities. It is a rare paraneoplastic effect of tumors that has been described with both Hodgkin's and non-Hodgkin's lymphoma. This is the first case report of its association with thymoma.

Phase II evaluation of dibromodulcitol, ICRF-159, and maytansine for sarcomas.

Patients with objectively measurable soft tissue sarcomas, osteosarcomas, chondrosarcomas, and mesotheliomas were treated with dibromodulcitol (DBD) (180 mg/m2 p.o. days 1-10 q4 wks.). ICRF-159 (300 mg/m2 p.o. tid days 1-3 q4 wks), or maytansine (MAYT) (1.5 mg/m2 I.V. q3 wks.). Forty-five evaluable patients received DBD, 47 MAYT, and 37 ICRF-159. Only patients who had had their histopathologic diagnoses confirmed by a pathology reference panel were included in the final analysis. Two patients had objective partial responses: a patient with osteosarcoma who responded to DBD and a patient with fibrosarcoma who had a partial response of brief duration to ICRF-159. Approximately 70% of the patients treated with each drug were of ECOG performance status 0 or 1, and over half had moderate or worse toxicity. It seems unlikely that these drugs have significant therapeutic activity for common mesenchymal malignancies.

A Phase II study of autologous irradiated tumor cells plus BCG in patients with metastatic malignant melanoma.

Eighteen patients with surgically incurable metastatic malignant melanoma were treated with a mixture of irradiated (15,000 rads) autologous tumors cells (1-2 X 10(8)) and BCG (Glaxo, 2-4.5 X 10(6) organisms), which was injected intradermally (in five divided doses) every 2 weeks (X5). Four of 18 (22%) evaluable patients achieved objective remissions. It is concluded that this treatment regimen does not have general clinical application because the remissions were infrequent, of shor duration (median, 3 months) and occurred only in patients with minimal, nonvisceral tumor burdens.

Doxorubicin hydrochloride-associated renal failure.

Doxorubicin hydrochloride (Adriamycin) therapy was associated with renal failure in a 78-year-old man. The pathophysiologic findings in this patient were similar to those seen following administration of structural analogues of doxorubicin. Daunorubicin hydrochloride, particularly, is known to cause renal failure in experimental animals. Renal function should be monitored in patients receiving doxorubicin.

The phase II evaluation of Bacillus Calmette-Guerin plus megestrol acetate in patients with metastatic renal adenocarcinoma.

The case is reported of a patient with pulmonary metastases from a renal adenocarcinoma who experienced subjective improvement and objective tumor regression on Bacillus Calmette-Guerin (BCG) and megestrol acetate therapy. In a subsequent Phase II trial, no objective responses were noted among 15 patients treated with megestrol acetate (160 mg/day X 56 days) and BCG (five immunizing doses intradermally, every 2 weeks X 5). It is concluded that this treatment regimen is not clinically useful in patients with metastatic renal adenocarcinoma.

Randomized prospective trial of DTIC (NSC-45388) alone versus BCNU (NSC-409962) plus vincristine (NSC-67574) in the treatment of metastatic malignant melanoma.

Fifty patients with metastatic malignant melanoma were randomized to treatment with either DTIC (2 mg/kg/day X 10 iv) or the combination of BCNU (150 mg/m2 iv) plus vincristine (VCR) (2 mg/m2 iv on Day 1 only). Treatment failures were crossed over to the alternate therapy. Primary, secondary, and cumulative response rates to DTIC were 29%, 9%, and 22%, respectively. Primary, secondary, and cumulative response rates to BCNU plus VCR were 23%, 29%, and 25%, respectively. Five of 26 patients (19%) experienced objective regression from secondary therapy after failure to respond to primary therapy. DTIC produced gastrointestinal and hematologic toxic effects; BCNU plus VCR produced gastrointestinal, hematologic, and neurologic toxic effects. VCR administered at a dose of 2 mg/m2 resulted in excessive neurologic toxic effects in 12 of 21 patients; a maximum VCR dose of 2 mg/injection was well tolerated by 15 subsequent patients without an adverse effect upon response rate. An analysis of tumor burden and organ involvement in responders and nonresponders suggests that DTIC is the first-choice treatment for patients with limited tumor burdens and nonvisceral metastases; BCNU plus VCR is the first-choice treatment for patients with extensive tumor burdens and visceral-predominant disease. However, failure to respond to primary therapy does not preclude response to secondary therapy with the alternate regimen.

A clinical histologic, and immunologic study of a case of metastatic malignant melanoma undergoing spontaneous remission.

A patient with biopsy-proven dermal recurrent malignant melanoma who refused therapy, and who was observed to undergo clinical regression during the period of November 1972 through June 1974 was studied to define the histologic features of spontaneous remission, and to evaluate the immune response as measured by in vitro assays of lymphocyte cytotoxicity and serum effects during the course of regression. Biopsy of regressed areas showed the following histologic features: 1) absence of malignant melanoma cells in basal layers of epidermis with relative increase in basal layer clear cells; 2) dermal inflammatory reaction with lymphocytic infiltrate, melanophages, and degenerate malignant melanocytes; and 3) dermal reactive vascular proliferation and interstitial edema progressing to reparative dermal fibrosis. Using a microcytotoxicity assay with two established allogeneic melanoma cell cultures as target cells, a statistically significant (p less than 0.01) increase in lymphocyte cytotoxicity values was observed over the clinical time course of regression. No significant serum cytotoxic or serum blocking effects were detectable. These findings are consistent with an immunologic basis for the spontaneous remission of the dermal melanoma metastases present in this patient.

Sequential in vitro reactivity of lymphocytes from melanoma patients receiving immunotherapy compared with the reactivity of lymphocytes from healthy donors.

A microcytotoxicity technique was used to determine the sequential in vitro reactivity against melanoma cells of lymphocytes from melanoma patients receiving immunotherapy and from healthy donors. Lymphocytes were collected 2 weeks for 2-3 months and were stored in liquid nitrogen until use. Preliminary studies had indicated that freezing did not effect the reactivity of lymphocytes. Lymphocytes from 10 healthy donors tested against melanoma cells exhibited substantial reactivity which showed no consistent pattern over time. Lymphocytes from 9 melanoma patients exhibited increased reactivity after immunotherapy. Patterns of reactivity against melanoma cells and against bladder carcinoma cells were similar, indicating lack of specificity for melanoma antigens. Correlations with clinical course of the disease were not apparent.

Clinical and immunological significance of human melanoma cytotoxic antibody.

The activity of a complement-dependent cytotoxic antibody in the sera of 21 melanoma patients was investigated using a microcytotoxicity assay. Heat-inactivated sera were caused to react against mechanically dispersed fresh tumor cells in the presence of exogenous blood group AB complement. Cytotoxicity was evaluated relative to pooled normal sera as a control. Sera were cytotoxic against autochthonous tumor cells in 9 of 10 patients with localized or regional melanoma and in 1 of 11 patients with disseminated metastases. Cytotoxicity of sera was unrelated to size of tumor burden. Six of 7 antibody-positive sera (autochthonous system) were noncytotoxic to between 2 and 7 different allogeneic melanoma tumor cell preparations. Immunological reactivity of the cytotoxic antibody-positive and -negative groups was similar with respect to their capacity to be sensitized to dinitrochlorobenzene, produce positive skin tests to microbial antigens, and produce antibodies to typhoid vaccination; serum immunoglobulins were comparable. These results support the reported findings of the presence of cytotoxic antibody in the sera of melanoma patients without disseminated metastases.

Absorption, distribution, and excretion of 5-azacytidine (NSC-102816) in man.

Patients with advanced cancer were given 5-azacytidine labeled at position 4 with radioactive carbon (14C) by either the intravenous (iv) or subcutaneous (sc) route. Absorption of the drug from the sc injection site was rapid and peak plasma levels were attained within one-half hour. Within 2 hours, the plasma level of radioactivity was approximately equal to that noted in the patients treated iv. The plasma half-life after iv injection was 3.5 hours; after sc administration, the plasma half-life was 4.2 hours. Patients receiving the drug sc excreted less drug in the urine than did those receiving the drug iv. No radioactivity was detected in the expired carbon dioxide when the drug was given by either route. Drug uptake into tumor tissue was always greater than uptake into surrounding normal tissue. The highest concentrations of radioactivity in the tissues were achieved when the drug had been given iv. Traces of radioactivity were still detectable in the tissues for as long as 6 days after administration of the drug. The incorporation of radioactivity into tumor RNA but not into DNA was demonstrated. The maximum level of radioactivity detected in the spinal fluid was equivalent to 0.2 microg of 5-azacytidine per milliliter of fluid.

Phase I study of 5-azacytidine (NSC-102816) .

Thirty patients with various solid tumors were treated with 5-azacytidine. Total doses ranged from 1.0 to 24.0 mg/kg and were given over a minimal period of 8 days. The major toxic effect was hematologic with significant leukopenia and thrombocytopenia usually occurring 20-30 days after the start of therapy, especially at higher dose levels. The marrow depression lasted 1-5 weeks and was fully reversible. Nausea and mild diarrhea were common following injection of the drug. Serum glutamic oxaloacetic transaminase levels rose in several patients. No other evidence of hepatic toxicity was seen. Objective remissions were noted in seven of 11 patients with cancer of the breast, two of five with melanoma, and two of six with cancer of the colon.