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.

Improved survival in patients with poor-prognosis malignant melanoma treated with adjuvant levamisole: a phase III study by the National Cancer Institute of Canada Clinical Trials Group.

Five hundred forty-three patients with completely resected malignant melanoma who were considered to have a significant risk of developing recurrent disease were randomized to one of four study groups. One group received levamisole 2.5 mg/kg on 2 consecutive days weekly for 3 years, a second group received bacillus Calmette-Guérin (BCG) for 3 years. A third group alternated 8-week courses of BCG and levamisole for 3 years and a fourth group underwent clinical assessment at the same frequency as the three treatment groups. The median duration of follow-up is 8.5 years. The percentage of reduction in the death rate and the recurrence rate in the treatment groups compared with the control group was calculated using the Cox proportional hazards model and adjusted for age, sex, and stage as covariants. The patients treated with levamisole were estimated to have a 29% reduction in both the death rate (P = .08) and the recurrence rate (P = .09) compared with patients receiving no further treatment. Fifty-five patients discontinued levamisole early because of gastrointestinal intolerance or arthralgia, myalgia, fever, and immune leukopenia. The patients treated with BCG alternating with levamisole experienced a 10% reduction in the death rate and a 6% reduction in the recurrence rate, and the patients treated with BCG alone experienced a 4% reduction in the death rate and a 3% increase in the recurrence rate compared with the control group. The degree of improvement experienced by the patients that were treated by levamisole is of sufficient magnitude to warrant further investigation of this dose of levamisole as adjuvant treatment in patients with melanoma.

Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: We designed and conducted a randomized, double-blind, placebo-controlled trial to compare the response rates and survival of patients with metastatic melanoma who received carmustine (BCNU), dacarbazine (DTIC), and cisplatin with tamoxifen, or the same chemotherapy with placebo. PATIENTS AND METHODS: Eligible patients with metastatic melanoma received either BCNU 150 mg/m2 intravenously (i.v.) on day 1, DTIC 220 mg/m2 i.v. daily on days 1 to 3 and on days 22 to 24, and cisplatin 25 mg/m2 i.v. daily on days 1 to 3 and on days 22 to 24 with placebo every 6 weeks, or the same chemotherapy with tamoxifen 160 mg orally daily for 7 days before chemotherapy and 40 mg orally daily throughout the remainder of the treatment cycle. Patients were treated on protocol for up to three cycles depending on the type of response. Assuming that a minimum increase in response rate of 20% would be necessary to conclude that tamoxifen conferred a clinically important benefit, we designed the study with an 80% chance of detecting that difference at the 5% level (two-sided). RESULTS: Between February 1992 and January 1995, 211 patients were accrued, 199 of whom were considered assessable for response and toxicity. The overall response rate was 21% in the placebo group and 30% in the tamoxifen group (P = .187). Complete and partial responses were 3% and 27%, respectively, for the tamoxifen group and 6% and 14%, respectively, for the placebo group. Poor performance status and liver involvement were associated with a reduced likelihood to respond to treatment. Major toxicities were similar in both groups with no statistically significant difference in the rates of deep vein thrombosis, pulmonary thromboembolus, grade 4 neutropenia, or grade 4 thrombocytopenia. CONCLUSION: These results demonstrate that the addition of high doses of tamoxifen to this chemotherapy regimen does not increase the response rate compared with chemotherapy alone in unselected patients with metastatic melanoma.

Cutaneous malignant melanoma.

In Canada melanoma causes 400 deaths a year, often in young adult patients. Excessive ultraviolet radiation to unprotected skin is an important cause. Certain moles should be removed as a precautionary measure; an experienced clinician can recognize many melanomas. Both microstaging by the pathologist and clinical staging must be carried out before definitive treatment is planned. The only 'curative' treatment is surgical. Any patient so treated requires ten years of careful follow up. The results of chemotherapy for disseminated disease are poor.

Phase II study of trimetrexate in malignant melanoma: a National Cancer Institute of Canada Clinical Trials Group study.

The National Cancer Institute of Canada Clinical Trials Group carried out a phase II trial of trimetrexate given in a daily x 5 intravenous bolus schedule every 3 weeks in patients with measurable metastatic malignant melanoma who had not received previous chemotherapy. Significant hematologic toxicity was observed and was not obviously related to the dose of trimetrexate. No responses were seen in 18 patients. We did not find trimetrexate given as described to be effective in metastatic malignant melanoma.

Analysis of 29 cases of pancreatic pseudocyst treated surgically.

Twenty-nine cases of pancreatic pseudocyst requiring operative management were reviewed to determine the method of diagnosis and to analyse the results of internal and external drainage. Pain and the presence of an intra-abdominal mass were the two most common clinical features in the 29 patients. Serum amylase values were elevated in 50%. Diagnosis was confirmed by barium contrast roentgenography and abdominal ultrasonography in 60% of cases. Endoscopic retrograde cholangiopancreatography was a valuable diagnotic technique in four problem cases. The most common form of surgical treatment was internal drainage of the pseudocyst (18 patients). Th mortality resulting from internal drainage was 6% and there was an overall complication rate of 44%. External drainage was carried out in seven patients (six required emergency operation). The mortality associated with external drainage was 43% and the overall complication rate 86%.

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.

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.

Stereotactic fine-needle aspiration cytology of nonpalpable breast lesions: initial experience in a tertiary-care institution.

To assess the accuracy of stereotactic fine-needle aspiration cytology in the diagnosis of nonpalpable breast lesions, this procedure was performed in 226 consecutive patients, all women, immediately before needle localization and excision of the lesions. The patients were treated at a tertiary-care hospital between December 1989 and October 1991. The cytologic results (lesion benign, atypical, suspicious or malignant or insufficient material for interpretation) were compared with the histologic findings and the degree of suspicion (low, slight or high) on the basis of mammographic examination. The aspiration procedures were successful in only 159 patients (70.4%), and for 155 of these, histologic findings were available for correlation. The number of unsatisfactory specimens in this group was large: 65 of 155 (42%). When unsatisfactory specimens were included in the calculations and a cytologic finding of a suspicious or malignant lesion was treated as positive, the sensitivity of fine-needle aspiration cytology for malignancy was 23% (8/35) and the specificity 53% (63/120). The positive and negative predictive values were 89% (8/9) and 78% (63/81) respectively. A cytologic finding that the lesion was benign was unreliable in lesions for which the mammographic suspicion of malignancy was slight or high (4 of 30 malignant lesions with slight mammographic suspicion and 4 of 7 with high mammographic suspicion were classified as benign on the basis of the cytologic examination). Of the 24 cases with atypical cytologic findings, 10 involved malignancy.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Prophylactic node dissection for malignant melanoma.

The value of prophylactic node dissection was studied in 147 patients with nonsuperficial malignant melanoma of cutaneous origin; all had clinical stage I disease. Seventy-three patients had prophylactic node dissection and 74 did not. Survival rates were calculated by the actuarial method and were age and sex adjusted. Five-year crude survival rates for these two groups were 62 and 29%, respectively, and the adjusted rates were 70 and 33%, respectively. These significant differences (P less than 0.001) were maintained at 10 years. The difference in survival in the two groups cannot be explained on the basis of age, sex, year of operation, size or location of the primary tumour, or previous incisional biopsy. It is concluded that prophylactic node dissection contributed appreciably to increased survival in this study.

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.

A phase II study of weekly edatrexate (10-EDAM) in metastatic melanoma. A National Cancer Institute of Canada Clinical Trials Group study.

BACKGROUND: Phase I and II clinical trials have demonstrated acceptable toxicity and promising activity of Edatrexate (10-EDAM). The objective of this multicentre phase II study was to determine the efficacy and toxicity of this agent in patients with metastatic melanoma. PATIENTS AND METHODS: Sixteen previously untreated patients with metastatic melanoma received 10-EDAM, 80 mg/m2/week intravenously. Patients were evaluated for response and toxicity. RESULTS: There were no objective responses. The median dose intensity of 10-EDAM actually delivered was 56.25 mg/m2/week (70% of projected). Mucositis of any degree was encountered in 93.8% of patients. Grade 3 or 4 mucositis, skin rash, nausea, abdominal pain, neutropenia, thrombocytopenia, anemia and hyperbilirubinemia each were encountered in 1-2 patients. There was 1 toxic death due to 10-EDAM. CONCLUSION: 10-EDAM is an inactive agent in metastatic melanoma.