Activating mutations in exon 15 of BRAF have been detected in a high proportion of cutaneous melanomas. To determine whether such mutations are a feature of conjunctival or uveal melanomas, we screened DNA from these tumours. Twenty-one conjunctival and 88 uveal tumours were included in the study. Mutation analysis of BRAF exons 11 and 15 was undertaken using a combination of conformationally sensitive gel electrophoresis and direct sequencing. Mutations in exon 15 were detected in three of the conjunctival tumours (two V599E and one E585 K). None of the uveal tumours possessed a BRAF mutation in either exon 15 or 11. We conclude that uveal melanomas arise independently of oncogenic BRAF mutations, but the development of a proportion of conjunctival tumours involves mutation of this gene.

A total of 154 patients were recruited: 79 G17DT and 75 placebo. A final analysis of the intention-to-treat population, using a proportional hazards model, stratifying by disease stage and adjusting for interim analysis, gave a hazard ratio for mortality of 0.75 (95% confidence interval, 0.51-1.10, P = 0.138; G17DT/placebo). A conventional analysis without adjustment for disease stage or interim analysis, censoring for chemotherapy and excluding protocol violators, gave median survival periods of 151 (G17DT) and 82 days (placebo) (log-rank test, P = 0.03).Patients developing anti-G17DT responses (73.8%) survived longer than nonresponders or those on placebo (median survival, 176 vs 63 vs 83; log-rank test, P = 0.003). G17DT was well tolerated.

Defining regions of genomic imbalance can identify genes involved in tumour development. Conventional cytogenetics has identified several nonrandom copy number alterations (CNA) in uveal melanomas (UVM), which include monosomy 3, chromosome 6 abnormalities and gain of 8q. To gain further insight into the CNAs and define the regions involved more precisely we analysed 18 primary UVMs using 1 Mb BAC microarray comparative genomic hybridisation (CGH). Our analysis showed that the most common genomic imbalances were 8q gain (78%), 6p gain (67%) and monosomy 3 (56%). Two distinct CGH profiles could be delineated on the basis of the chromosome 3 status. The most common genetic changes in monosomy 3 tumours, in our study, were gain of 8q11.21 -q24.3, 6p25.1 -p21.2, 21q21.2 -q21.3 and 21q22.13 -q22.3 and loss of 1p36. 33 -p34.3, 1p31.1 -p21.2, 6q16.2 -q25.3 and 8p23.3 -p11.23. In contrast, disomy 3 tumours showed recurrent gains of only 6p25.3 -p22.3 and 8q23.2 -q24.3. Our approach allowed definition of the smallest overlapping regions of imbalance, which may be important in the development of UVM.

D17DT consists of the GnRH decapeptide linked to diphtheria toxoid. The aim of this pilot study was to assess the tolerance of D17DT and the production of anti-GnRH antibodies from two doses, 30 and 100 μg, in patients with locally advanced prostate cancer. Twelve patients with histologically proven prostate cancer in whom hormonal therapy was indicated were recruited. Patients received either 30 or 100 μg given intramuscularly on three separate occasions over six weeks. Patients were followed up and blood was taken for estimation of serum testosterone, PSA and anti-GnRH antibody titre. Overall the drug was well tolerated. In 5 patients a significant reduction in serum testosterone and PSA was seen. Castrate levels of testosterone were achieved in 4 and maintained for up to 9 months. Patients with the highest antibody titre had the best response in terms of testosterone suppression. This study shows that it is possible to immunize a patient with prostate cancer against GnRH to induce castrate levels of testosterone. This state appears to be reversible. This novel form of immunotherapy may have advantages over conventional forms of hormonal therapy and further studies are warranted in order to try and increase the proportion of responders. © 2000 Cancer Research Campaign

PURPOSE.Reports suggest that a subset of uveal melanoma is familial. The association of uveal melanoma with breast and ovarian cancer and the increased risk in BRCA2-linked families implicates germline BRCA2 mutations as the cause of a subset of uveal melanomas. Similarly, the association between cutaneous and uveal melanomas in some families, coupled with the high frequency of somatic deletions of the INK4A-ARF locus in uveal melanomas, strongly suggests that mutations in P16 INK4Aand P15 account for a proportion of uveal melanomas. METHODS. To examine this proposition, a systematically ascertained series of 385 patients with uveal melanoma were screened for germline mutations in BRCA2, P16INK4A , P14 ARF , and P15. RESULTS. One patient was found to harbor a Gly35Ala substitution in exon 1␣ of P16 INK4A , which has previously been reported to be pathogenic. No mutations were detected in P14 ARF or P15. None of the patients harbored germline nucleotide changes that lead to truncation or that create or disrupt consensus splice sites of BRCA2 or missense variants with clear pathogenic potential. CONCLUSIONS. These findings suggest that less than 2% of cases of uveal melanoma can be ascribed to germline mutations in BRCA2, P16INK4A , P14 ARF , or P15. It is likely that mutations in other genes contribute to an inherited predisposition to uveal melanoma. (Invest Ophthalmol Vis Sci. 2003;44:458 -462)