Molecular alterations at chromosome 9p21 in melanocytic naevi and melanoma.

BACKGROUND: The chromosome 9p21 and its CDKN locus, with the p16 tumour suppressor gene (CDKN2A), are recognized as the genomic regions involved in the pathogenesis of melanoma. OBJECTIVES: To elucidate further the role of such regions during the different phases of melanocytic tumorigenesis. METHODS: Tissue sections from naevi, primary and metastatic melanomas were investigated by fluorescence in situ hybridization for allelic loss at the 9p21 chromosome and by immunochemistry for p16CDKN2A expression. RESULTS: Dysplastic naevi and primary or secondary melanomas were found to carry hemizygous deletions within the entire 9p21 region at similar frequencies (varying from 55% to 62%). Allelic deletion spanning the CDKN locus was observed at significantly increased rates moving from early (7%) to advanced (28%) primary melanomas and to secondary melanoma lesions (37%) (P=0.018). Also, inactivation of the p16 gene (CDKN2A) was absent in naevi and present at steadily increasing rates moving from primary melanomas (7% early lesions to 17% advanced lesions) to melanoma metastases (62%) (P=0.004). CONCLUSIONS: Our findings indicate that, in a model of sequential accumulation of genetic alterations, 9p21 deletions may play a role in melanocytic transformation and tumour initiation whereas rearrangements at the CDKN locus, and p16 gene (CDKN2A) inactivation may contribute to tumour progression.

Sequential treatment with interferon and chemotherapy of metastatic malignant melanoma. Total remission of cutaneous and visceral metastasis, but not of cerebral metastasis.

A woman 35 years of age suffering from cutaneous and visceral metastatic melanoma was treated with recombinant Interferon alpha 2b (rIFN alpha 2b) subcutaneously 3 X 10(6) U/m2 3 times a week for 3 months with no apparent effect on the course of the illness. Two months after IFN therapy the patient developed cerebral metastasis. A cycle of carmustine, 100 mg/day for 3 days, was given, and complete disappearance of the cutaneous and visceral, but not of the cerebral manifestations was observed. Two consolidation cycles based on vincristine, dacarbazine and lomustine were then administered. The patient died 26 months after beginning treatment with IFN and 18 months after chemotherapy for the cerebral metastasis. No trace of tumor at the cutaneous or visceral level was found at autopsy.

Ethinyl estradiol and medroxyprogesterone treatment in advanced breast cancer: a pilot study.

Twenty patients with disseminated breast cancer unresponsive to conventional chemotherapy and chemohormonotherapy were treated with an alternating sequential schedule of ethinyl estradiol and medroxyprogesterone on the basis of correlations between hormones and estrogen and progestin receptors. Of 19 evaluable patients, six underwent partial or complete remission, while five others showed minor responses.

PIP: A pilot study was conducted on 20 patients with disseminated breast cancer previously unresponsive to conventional chemotherapy and chemohormonotherapy. The 20 women were treated with ethinyl estradiol orally on days 1 and 2, medroxyprogesterone on days 3-9. After a 2-day interval, the sequential cycle was repeated. 10% of the women had complete remission and 20% more had partial remissions. More than 1/4 had minor remissions and 10% had their disease stabilized. Side effects with the therapy were practically absent. The rationale for the sequential therapy was suggested by interactions among hormones and receptors and the priming activity of estrogens on progesterone receptors. These preliminary results indicate that an alternated sequential therapy of ethinyl estradiol and medroxyprogesterone may be useful in managing advanced cancer.