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A critical review of the date regarding node dissections for patients with melanoma does not support the use of elective lymph node dissection. Both randomized clinical trials and the majority of retrospective clinical trials demonstrate equivalent survival for patients with intermediate thickness melanomas treated with wide local excision and elective lymph node dissection versus wide local excision only, with the addition of a therapeutic node dissection if clinically indicated. These data support the concept that a positive node is not a predecessor of distant spread, but rather a manifestation of disseminated disease and an indicator of the host-tumor relationship.

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 Breslow's thickness, this difference persisted in patients with 4.0 to 6.0 mm lesions (P = 0.01). However, for thicker lesions (greater than 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.

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.

Melanoma-specific T-cells (CTLs) are specifically cytotoxic for autologous tumor, when assayed in vitro. To examine their effectiveness in vivo, we tested the ability of these human T-cells to inhibit growth of human melanoma xenografts by using a Winn assay. Nude mice receiving specific CTLs (n = 10) demonstrated a dramatic inhibition of tumor growth. All treated mice were tumor-free at day 50 and nine remained tumor-free at day 65, vs. control mice (n = 10) with average tumor volumes of 321 mm3 and 808 mm3, respectively. To control for the possibility that a non-specific response to the human T-cells could inhibit tumor growth, an additional group received allospecific CTLs. There was no inhibition of tumor growth in this group (n = 8), with the average tumor volume of 2,768 mm3 at day 40 vs. 1,882 mm3 in the control group (n = 10). We conclude that these tumor-specific CTLs can inhibit tumor growth in vivo and may prove useful in the adoptive immunotherapy of melanoma.

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.

• A total of 2468 patients with recurrent melanoma were subdivided on the basis of disease-free interval: group 1 had recurrences within 1 year (n=810), group 2 at years 1 to 3 (n=1001), group 3 at years 3 to 5 (n=363), group 4 at years 5 to 10 (n=329), and group 5 after 10 years (n=145). Ten-year survivals were 21%, 23%, 25%, 28%, and 35%, respectively. Patients who had recurrences within 1 year had a decreased median survival compared with those who had later recurrences, although the differences were not clinically significant (only 6 to 8 months). Survival was improved for the few patients who had recurrences longer than 10 years from diagnosis. However, for the majority of patients, who had recurrences between 1 and 10 years, the disease-free interval did not predict subsequent survival. The data support the hypothesis that malignant cells can exist in a state of relative quiescence for extended periods. Once disease reactivation occurs, however, the subsequent survival is relatively predictable and is independent of the initial period of tumor dormancy. (Arch Surg.1992;127:1303-1308)

Previous studies have demonstrated the presence of two functionally distinct intercellular adhesive systems operating among embryonic chick neural retina cells. These systems differ in their proteolytic sensitivity, protection by calcium against proteolysis, dependence on calcium for function, and in vitro morphogenetic potential. In this report we demonstrate that functional expression of the calcium-dependent adhesive system of embryonic chick neural retina cells is developmentally regulated between Days 7 and 16 of development, whereas the calcium-independent adhesive system is not. Age-dependent changes are described in terms of the ability to produce adhesive-competent cells bearing the calcium-dependent adhesive system and in terms of the responses of these cells during aggregation to perturbations with various drugs. Enzyme and ion combinations other than calcium and typsin are shown to yield calcium-dependent adhesive-competent cells. We also describe the protective effect of calcium on the histological and ultrastructural organization of trypsinized embryonic neural retina tissue. The possible role of the calcium-dependent adhesive system in retinal development is discussed.