Cerebral metastases of malignant melanoma: contemporary treatment modalities and survival outcome.

The aim of our study was to analyze prognostic factors, effect of treatment and survival outcome of a contemporary cohort of melanoma patients with cerebral metastases and eventually propose new recommendations regarding therapy. Sixty four patients with melanoma brain metastases were treated in our department within a 15-year period. We performed a retrospective analysis of their survival with respect to the type of treatment instituted. Four groups were formed according to treatment: Group A patients treated with surgery followed by radiotherapy; group B temozolomide as first-line treatment and radiotherapy after cerebral disease progression; group C radiotherapy alone; group D supportive care only. Patients* characteristics influenced the selection of treatment modality: Group A (7.8%) patients with a single brain metastasis (p=0.001) and controlled extra-cranial disease (p<0.0001), while Group D (21.8%) patients with ulcerated primary lesions (p=0.010) and uncontrolled extra-cranial disease (p<0.0001). Only group B (26.6%) and C (43.7%) patients with similar characteristics including more than one brain lesion. Median overall survival was 3 months. In univariate analysis, median survival for groups A, B, C and D was 12, 5, 3 and 2 months, respectively (p<0.0001). The survival difference between the surgery and non-surgery groups was statistically significant (p=0.0011). Patients treated with supportive care had the worse prognosis (p<0.0001). A survival benefit for patients receiving first-line treatment with temozolomide, as compared to those receiving radiotherapy alone was noted (p=0.0267). In multivariate survival analysis, the number of brain lesions (p=0.0138), the absence of uncontrolled extra-cranial disease (p=0.00221) and the type of treatment for the cerebral disease (p=0.0053) remained significant independent survival predictors. Patients' characteristics remain a critical factor for treatment selection. The number of brain metastases, the extent of disease and the type of treatment represent independent survival predictors. Melanoma patients with a single brain metastasis and controlled extra-cranial disease gain a survival benefit, if surgically treated. Including temozolomide in the first-line treatment of melanoma patients with brain metastases who would have been treated with radiotherapy alone, might present a promising future direction affecting the length of survival.

Identification of several human homologs of hamster DNA damage-inducible transcripts. Cloning and characterization of a novel UV-inducible cDNA that codes for a putative RNA-binding protein.

Low ratio hybridization subtraction technique was previously used in this laboratory to enrich and isolate a number of low abundance UV-inducible hamster transcripts (Fornace, A. J., Jr., Alamo, I. J., and Hollander, M. C. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 8800-8804) that led to the identification and cloning of five important hamster and human GADD genes (Fornace, A. J., Jr., Nebert, D. W., Hollander, M. C., Luethy, J. D., Papathanasiou, M., Fargnoli, J., and Holbrook, N. J. (1989) Mol. Cell. Biol. 9, 4196-4203). In this study we have characterized the remaining DNA damage-inducible (DDI) transcripts. Of the 24 DDI clones, 3 clones (A13, A20, and A113) representing different regions of the same hamster cDNA exhibited near perfect homology to human p21(WAF1/CIP1) cDNA. The DDI clones A26, A88, and A99 displayed very high sequence homologies with the human proliferating nuclear antigen, rat translation initiation factor-5 (eIF-5), and human thrombomodulin, respectively, whereas clones A29 and A121 matched with express sequence tagged sequences of unknown identity. The DDI clones A18, 106, and A107 were different isolates of the same hamster cDNA (hereafter referred to as A18) and displayed high sequence homology with the members in the heterogeneous ribonucleoprotein (hnRNP) family. Using the hamster A18 partial-length cDNA as a probe, we screened human fibroblast cDNA library and isolated the corresponding full-length human cDNA. The deduced amino acid sequence revealed that the putative protein contains all the canonical features of a novel glycine-rich hnRNP. The A18 mRNA levels were specifically increased in response to DNA damage induced by UV irradiation or UV mimetic agents. Thus the putative A18 hnRNP is the first hnRNP whose mRNA is specifically regulated in response to UV-induced DNA damage; accordingly, it may play some role in repair of UV-type DNA damage.

Precise placement of sphenoidal electrodes via fluoroscopic guidance.

Fluoroscopically guided placement of sphenoidal electrodes for the assessment of epileptiform activity in the mesial-basal-temporal lobes offers distinct advantages over standard techniques, such as more precision in placement, reduced likelihood of facial pain, and fewer complications (vessel perforation or nerve injury). We describe our instrumentation, technique, and results in over 40 patients.

Induction by ionizing radiation of the gadd45 gene in cultured human cells: lack of mediation by protein kinase C.

The effect of ionizing radiation on the expression of two DNA-damage-inducible genes, designated gadd45 and gadd153, was examined in cultured human cells. These genes have previously been shown to be strongly and coordinately induced by UV radiation and alkylating agents in human and hamster cells. We found that the gadd45 but not the gadd153 gene is strongly induced by X rays in human cells. The level of gadd45 mRNA increased rapidly after X rays at doses as low as 2 Gy. After 20 Gy of X rays, gadd45 induction, as measured by increased amounts of mRNA, was similar to that produced by the most effective dose of the alkylating agent methyl methanesulfonate. No induction was seen after treatment of either human or hamster cells with 12-O-tetradecanoylphorbol-13-acetate, a known activator of protein kinase C (PKC). Therefore, gadd45 represents the only known mammalian X-ray-responsive gene whose induction is not mediated by PKC. However, induction was blocked by the protein kinase inhibitor H7, indicating that induction is mediated by some other kinase(s). Sequence analysis of human and hamster cDNA clones demonstrated that this gene has been highly conserved and encodes a novel 165-amino-acid polypeptide which is 96% identical in the two species. This gene was localized to the short arm of human chromosome 1 between p12 and p34. When induction in lymphoblast lines from four normal individuals was compared with that in lines from four patients with ataxia telangiectasia, induction by X rays of gadd45 mRNA was less in the cell lines from this cancer-prone radiosensitive disorder. Our results provide evidence for the existence of an X-ray stress response in human cells which is independent of PKC and which is abnormal in taxia telangiectasia.

Expression of the O6-methylguanine-DNA methyltransferase gene MGMT in MER+ and MER- human tumor cells.

DNA probes prepared from human O6-methylguanine-DNA methyltransferase complementary DNA were hybridized to mRNA isolated from human liver and fifteen human tumor cell lines proficient (Mer+) or deficient (Mer-) in transferase activity. Liver and Mer+ cells contained levels of transferase-specific mRNA that correlated with their transferase activity levels, whereas Mer- cells contained undetectable amounts of transferase mRNA. The mRNA levels were not induced in human cells by treatments that induce other DNA damage-inducible genes. These results demonstrate that in human cells the transferase gene is constitutively expressed, that its expression is related to activity levels, and that in Mer- tumor cells the expression of the transferase gene is probably blocked at the level of mRNA production.