Nancy J. Crowley

Late recurrence of malignant melanoma. Analysis of 168 patients.

Analysis of 7104 patients with melanoma seen at Duke University identified 168 who experienced their first recurrence 10 or more years after diagnosis, for an incidence of 2.4%. This included patients with all stages of disease. There was no sex, age, or primary site predominance. The mean disease-free interval for cutaneous melanomas was 14.3 years versus 22.3 years for ocular primary melanomas. The prognosis following relapse was related to the site of recurrence. Survival after local or regional node recurrence was often prolonged; survival after distant metastases was usually limited. Patients with ocular primaries had the highest incidence of distant metastases, and the shortest subsequent survival. An additional 483 patients were identified who survived 10 or more years without evidence of recurrence; of these 651 patients with long disease-free intervals, 25% (168 of 651) developed recurrent disease. This demonstrates that a 10-year disease-free interval cannot be considered a cure, and emphasizes the importance of continued annual follow-up.

The role of elective lymph node dissection in the management of patients with thick cutaneous melanoma.

A retrospective search of patients seen at the Duke Melanoma Clinic from 1970 to 1986 identified 308 clinically Stage I patients, with 4.0 to 10.0 mm cutaneous melanomas. Five‐year and ten‐year survival was 56% and 43%, respectively. Elective lymph node dissection (ELND) was done in 116 patients (37.7%); there was no difference in disease‐free interval (DFI) or survival between these patients versus patients treated with wide excision only (P = 0.9). Thirty‐two patients (27.6%) had pathologically positive nodes on ELND. These patients had a shorter DFI (P = 0.05) and survival (P = 0.03) compared with patients with negative node dissections. When further divided by Breslows thickness, this difference persisted in patients with 4.0 to 6.0 mm lesions (P = 0.01). However, for thicker lesions (>6.0 mm), there was no difference in survival between the node‐negative and node‐positive groups (P = 0.9). the mean follow‐up was 7.1 years. Elective lymph node dissection was not done in 192 patients; 78 of these recurred first in the regional nodes. These 78 patients were compared with the 32 patients who had pathologically positive nodes by ELND to see if patient survival was improved by early removal of nodal disease. There was no difference in DFI (P = 0.5) or survival (P = 0.3) between these two groups. It is concluded that ELND may provide prognostic information for patients with thick cutaneous melanomas. However, there was no change in DFI or ultimate survival when patients were followed, and nodes removed when clinically positive. the authors do not recommend ELND for patients with thick melanomas because the risk of distant metastases outweighs any benefit of regional node dissection.

Modulation of in vitro autologous melanoma-specific cytotoxic T-cell responses by phorbol dibutyrate and ionomycin

Human melanoma-specific, HLA restricted, cytotoxic T-cell lines can be generated by in vitro stimulation and culturing of peripheral lymphocytes, or lymph node cells, with autologous or HLA-A region matched melanomas in the presence of a low concentration (5 U/ml) of IL-2. Stimulation is followed by a period of clonal expansion and differentiation into cytotoxic T-cells specific for melanoma. We investigated the effect of the PKC modulating drug phorbol dibutyrate combined with the calcium ionophore Ionomycin on growth and differentiation of the cell lines. The growth of the T-cell lines was substantially augmented in the presence of the drugs with increases of 10-fold or more in clonal expansion by 3 weeks of culture. The cell lines were IL-2 dependent for growth in the presence or absence of the drugs and the phenotypic distribution remained predominantly CD3+ T-cells of mixed CD4 and CD8 phenotypes. In spite of the increased rate of growth in the presence of the drugs, autologous melanoma-specific cytotoxicity was almost completely abrogated in those cultures. The cells were, however, nonspecifically lytic in the presence of concanavalin A. The melanoma-specific cytotoxic response was completely restored following culture with IL-2 alone. The results suggest that the human tumor-specific cytotoxic T-cell response can be induced and amplified in the presence of immune modulating drugs.