Background Sentinel-node biopsy, a minimally invasive procedure for regional melanoma staging, was evaluated in a phase 3 trial. Methods We evaluated outcomes in 2001 patients with primary cutaneous melanomas randomly assigned to undergo wide excision and nodal observation, with lymphadenectomy for nodal relapse (observation group), or wide excision and sentinel-node biopsy, with immediate lymphadenectomy for nodal metastases detected on biopsy (biopsy group). Results No significant treatment-related difference in the 10-year melanoma-specific survival rate was seen in the overall study population (20.8% with and 79.2% without nodal metastases). Mean (±SE) 10-year disease-free survival rates were significantly improved in the biopsy group, as compared with the observation group, among patients with intermediate-thickness melanomas, defined as 1.20 to 3.50 mm (71.3±1.8% vs. 64.7±2.3%; hazard ratio for recurrence or metastasis, 0.76; P = 0.01), and those with thick melanomas, defined as >3.50 mm (50.7±4.0% vs. 40.5±4.7%; hazard ratio, 0.70; P = 0.03). Among patients with intermediate-thickness melanomas, the 10-year melanoma-specific survival rate was 62.1±4.8% among those with metastasis versus 85.1±1.5% for those without metastasis (hazard ratio for death from melanoma, 3.09; P<0.001); among patients with thick melanomas, the respective rates were 48.0±7.0% and 64.6±4.9% (hazard ratio, 1.75; P = 0.03). Biopsy-based management improved the 10-year rate of distant disease–free survival (hazard ratio for distant metastasis, 0.62; P = 0.02) and the 10-year rate of melanoma-specific survival (hazard ratio for death from melanoma, 0.56; P = 0.006) for patients with intermediate-thickness melanomas and nodal metastases. Accelerated-failure-time latent-subgroup analysis was performed to account for the fact that nodal status was initially known only in the biopsy group, and a significant treatment benefit persisted. Conclusions Biopsy-based staging of intermediate-thickness or thick primary melanomas provides important prognostic information and identifies patients with nodal metastases who may benefit from immediate complete lymphadenectomy. Biopsy-based management prolongs disease-free survival for all patients and prolongs distant disease–free survival and melanoma-specific survival for patients with nodal metastases from intermediate-thickness melanomas. (Funded by the National Cancer Institute, National Institutes of Health, and the Australia and New Zealand Melanoma Trials Group; ClinicalTrials.gov number, NCT00275496.)

Down-regulation of the immune system facilitates tumor progression at different stages of cutaneous melanoma. Sentinel nodes, the first lymph nodes on lymphatics draining directly from a primary melanoma are immune down-regulated by tumor-generated immune-suppressive cytokines including interleukin-10. To better understand the kinetics of sentinel node suppression, we investigated interleukin-10 expression by melanoma cells and tumor-associated macrophages and lymphocytes at different stages of primary melanoma evolution. We used reverse transcriptase in situ polymerase chain reaction to identify cellular sources of interleukin-10 mRNA in 39 melanomas. Interleukin-10 mRNA was identified in tumor cells of 2/6 melanomas in situ (33%), 17/21 invasive melanomas (81%) and 11/12 metastatic melanomas (92%). Higher interleukin-10 expression correlates with tumor progression, with differences between melanoma in situ, invasive melanoma and metastatic melanoma. In primary melanomas, the interleukin-10 mRNA content of tumor cells correlates with Clark level. There was significantly more interleukin-10 mRNA in vertical growth phase melanoma cells than in radial growth phase cells. In a logistic regression model, moderate to high interleukin-10 mRNA expression by tumor cells was significantly associated with vertical growth phase melanoma. Interleukin-10 mRNA was detected in melanoma-associated macrophages and lymphocytes. In invasive melanomas, the interleukin-10 mRNA reactivity of macrophages declined as Clark level increased. Alterations of immunity by interleukin-10 derived from melanoma cells and melanoma-associated macrophages and lymphocytes potentially facilitate evolution of the primary melanoma and render regional lymph nodes susceptible to metastases.

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A multicenter trial of isotretinoin in severe papulopustular rosacea in adult patients was undertaken to evaluate the efficacy and safety of this treatment. A 20-week course of therapy was instituted in 92 patients from 11 dermatology departments. At the end of the study period, isotretinoin was found to be highly effective in the clearing of refractory rosacea lesions.