Radiotherapy can be followed by recalcitrant skin ulcers. As low intensity laser irradiation has been demonstrated to have a beneficial effect on impaired wound healing, we investigated its efficacy and safety in three patients with chronic radiation ulcers. The three patients, previously mastectomized due to breast cancer, with recalcitrant radiation ulcers of the skin were treated with a 30 mW helium-neon laser (wavelength: 632.8 nm, intensity: 3 mW/cm2, dose: 30 J/ cm2) three times weekly. In all patients, complete wound closure was achieved within a period of 7, 5, and 8 weeks. One patient died 6 weeks after laser treatment due to tumor cachexia. Neither of the other patients showed recurrence of radiation ulcers or neoplasm during a follow-up of 36 months. Low intensity helium-neon laser irradiation has been shown to be effective in the induction of wound healing in radiotherapy-induced ulcers in three patients with breast cancer.

Based on evidence that granulocyte-macrophage colony stimulating factor (GM-CSF) induces a potent systemic antitumor immunity, we tested recombinant GM-CSF in advanced melanoma. Seven patients with histologically confirmed cutaneous melanoma metastases were treated with perilesional intracutaneous injections of recombinant GM-CSF and observed for a follow-up time of 5 y. All but two patients had a decrease in the total number of metastases. At the end of the 5 y follow-up three of the seven patients are still alive with only one patient receiving other than surgical therapy, and one patient died tumor free at the age of 93. The remaining three patients died from progressive melanoma. Perilesional intradermal GM-CSF therapy resulted in a mean survival time of 33 mo. The treatment was well tolerated and no side-effects other than local erythema at the injection sites and mild drowsiness were seen. Immunohistochemical analysis with staining for CD14 and GM-CSF receptor demonstrated an increased infiltration of monocytes into both injected and noninjected cutaneous melanoma metastases compared with lesions excised prior to the initiation of therapy. The same was true for CD4- and CD8-positive lymphocytes. This phenomenon, together with GM-CSF-induced leukocyte counts of more than 20,000 during therapy, support the possible impact of a systemic over a locally induced reaction by GM-CSF. To our knowledge this is the first report that intracutaneously injected GM-CSF results in long-lasting reduction of melanoma metastases.

Tumor invasion is the most reliable prognostic factor for primary stage I melanoma. "Thick" melanomas, with a Breslow thickness of more than 4 mm, tend to have a poor prognosis. Exceptions occur: some patients have no further recurrence of tumor. In an attempt to determine prognostic markers for "thick" clinical stage I melanomas, we investigated the volume-weighted mean nuclear volume of primary melanomas with tumor invasions > or = 4.0 mm in 32 patients. Seventeen of these patients developed melanoma metastases within a follow-up period of 60 mo; 15 patients who did not developed metastases and were comparable with regard to clinical and histological criteria were selected as a comparison group. Volume-weighted mean nuclear volume (Vv) is determined by a technique that permits an unbiased, efficient, shape- and orientation-independent, 3-dimensional estimation of nuclear size in tissues. This technique has been employed successfully in the prognostic assessment of stage I and II melanomas and was recently proven to be a sensitive marker for thin, high-risk melanomas. In our patients, Vv was determined by computer-assisted image analysis on Feulgen-stained sections by stereologic estimation of the Vv. The mean Vv (+/-SD) of primary melanomas with subsequent metastatic course was 794.99 +/- 209.18 micron3 (range: 409.48-1161.9 micron3), whereas primary melanoma lesions without subsequent metastases exhibited a mean Vv 640.54 +/- 205.07 micron3 (range: 206.7-927.48 micron3). This difference was found to be statistically significant (p = 0.0439). "Thick" melanomas with subsequent metastases thus exhibited a significantly higher Vv than did melanomas that did not metastasize.

A B S T R A C T PurposeThe combination of interferon alfa (IFN␣) and isotretinoin has shown a direct antiproliferative effect on human melanoma cell lines, but it remained unclear whether this combination is more effective than IFN␣ alone in patients with metastatic melanoma. We evaluated safety and efficacy of IFN␣ and isotretinoin compared with IFN␣ alone as adjuvant treatment in patients with primary malignant melanoma stage IIA and IIB. Patients and MethodsIn a prospective, randomized, double-blind, placebo-controlled trial, 407 melanoma patients in stage IIA (301 patients) and IIB (106 patients) were randomly assigned to either IFN␣ and isotretinoin (isotretinoin group; 206 patients) or IFN␣ and placebo (placebo group; 201 patients) after excision of the primary tumor. IFN␣ was administered three times a week at a dose of 3 million units subcutaneously for 24 months. Isotretinoin at a dose of 20 mg for patients Յ 73 kg, 30 mg for patients greater than 73 kg, or placebo daily for 24 months. ResultsA scheduled interim analysis revealed no significant differences in survival rates, with the isotretinoin group and the placebo group showing 5-year disease-free survival rates of 55% (95% CI, 46% to 65%) and 67% (95% CI, 59% to 75%), respectively, and overall 5-year survival rates of 76% (95% CI, 67% to 84%) and 81% (95% CI, 74% to 88%), respectively. The trial was stopped for futility. ConclusionThe addition of isotretinoin to an adjuvant treatment of low-dose IFN␣ in patients with stage IIA and IIB melanoma had no significant effect on disease-free or overall survival and is therefore not recommended.