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We have previously shown that avirulent but replication-competent herpes simplex virus (HSV) 1716 causes cell death in human melanoma cell lines in vitro and selectively replicates in melanoma tissue in nude mice. We now present a pilot study of intratumoral injection of HSV1716 into subcutaneous nodules of metastatic melanoma in five patients with stage 4 melanoma. Two patients each received one injection, two received two injections, and one received four injections of 103 plaque-forming units HSV1716. In one patient, flattening of previously palpable tumour nodules was seen 21 days after two direct injections of HSV1716, and in injected nodules from all three patients who received two or more injections there was microscopic evidence of tumour necrosis. Immunohistochemical staining of injected nodules revealed evidence of virus replication confined to tumour cells. These findings suggest that HSV1716 is non-toxic and could be of therapeutic benefit in patients with metastatic melanoma.

To the Editor: We report a case of fatal melanoma that had been transferred in a donated kidney and that occurred 16 years after surgery for primary melanoma in the donor. A woman with polycystic disease received a renal transplant in May 1998. The graft functioned well. In November 1999, routine mammography showed a nodule in the left breast, and a biopsy specimen was obtained. Primary breast cancer was diagnosed. Pain and swelling then developed over the renal transplant, and two subcutaneous nodules were found. Biopsy confirmed the presence of secondary melanoma. No primary melanoma was identified. The pathological features . . .

Background: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer. Methods: These four features were examined in 385 families with ⩾3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents. Results: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, ⩾2 patients with MPM, median age at melanoma diagnosis ⩽40 years and ⩾6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only ⩾1 patient with MPM and age at diagnosis ⩽40 years simultaneously predicted the mutation risk. Conclusions: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer–CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.

DNA was extracted from 52 thick primary melanomas and mutations sought in exon 15 of the BRAF (v-raf murine sarcoma viral oncogene homolog B1) gene using denaturing high performance liquid chromatograph (dHPLC) fragment analysis, sequencing, and allele-specific PCR. Exon 15 BRAF mutations were found in 13 of 52 (25%) primary melanomas. These comprised five of 17 (29%) superficial spreading melanomas, three of 11 (27%) nodular melanomas, two of 13 (15%) acral lentiginous melanomas, one of one (100%) mucosal melanoma and two of 10 (20%) lentigo maligna melanomas. In common with other groups, our findings show a relative concentration of the exon 15 BRAF mutation in superficial spreading and nodular melanomas, but add further evidence that this mutation not necessary for malignant transformation of the melanocyte.

Less than half of patients with melanoma that has spread to local draining regional lymph nodes (stage III melanoma) live with no disease for 5 years or longer after surgery. We aimed to see whether interferon alpha-2a increased survival prospects in these patients. 444 patients from 23 centres in the WHO Melanoma Programme had complete lymphadenectomy for pathologically proven regional nodal spread of melanoma and were randomly assigned to receive either 3 MU subcutaneously of recombinant interferon alpha-2a three times a week for 3 years, or to observation alone after surgery. Patients were stratified by centre, nodes with macroscopic or microscopic melanoma, number of affected nodes, and nodal metastatic spread. Treatment was continued for 3 years or until first sign of relapse. 424 patients entered the study. 5-year disease-free survival of those who had surgery plus interferon alpha-2a was 27·5% (95% Cl 21·7–33·6); for those who received surgery alone, survival was 28·4% (22·5–34·6) (p=0·50). Neither Kaplan-Meier cumulative survival rates, nor multivariate anaysis of survival, showed a difference between those who had surgery and interferon alpha-2a (35%, 95% Cl 29–42) and those who had surgery alone (37%, 31–44). Patients with melanoma that has spread to the local draining regional lymph nodes tolerate well 3 MU of interferon alpha-2a given subcutaneously three times a week for 3 years, but this treatment does not improve either disease-free or overall survival.

We aimed to assess the incidence and survival for all patients with invasive primary cutaneous malignant melanoma diagnosed in Scotland, UK, during 1979–98. The Scottish Melanoma Group obtained data for 8830 patients (3301 male and 5529 female) first diagnosed with invasive cutaneous malignant melanoma. Age-standardised incidence rose from 3·5 in 1979 to 10·6 per 10 5 population in 1998 for men, and from 7·0 to 13·1 for women, a rise of 303% and 187%, respectively. After 1995, the rate of increase levelled in women younger than 65 years at diagnosis. Melanoma incidence increased most in men on the trunk, head, and neck and in women on the leg. 5-year survival rose from 58% to 80% for men diagnosed in 1979 and 1993, respectively, and from 74% to 85% for women; improvements of 38% (p<0·001) and 15% (p<0·001), respectively. Most improvement was attributable to a higher proportion of thinner tumours. Male mortality from melanoma was 1·9/10 5 population per year at the start and end of the study, whereas mortality for men younger than 65 years at diagnosis rose from 1·2 to 1·35 (p=0·24). For all women, mortality fell slightly from 1·9 to 1·85/10 5 population per year (p=0·61), whereas for women younger than 65 years at diagnosis, mortality fell from 1·3 to 1·15 (p=0·62). Interventions aimed at both primary and secondary prevention of melanoma are justified. Specialist tumour registers for entire countries can be used to plan and monitor public health interventions. Published online June 25, 2002. http://image.thelancet.com/extras/01art7335web.pdf

We compared trends in melanoma incidence by body site in two populations exposed to different levels of sunlight and different approaches to melanoma prevention. We analysed site-specific melanoma incidence during the period 1982-2001 in Queensland, Australia (n=28 862 invasive melanomas; 2536 lentigo maligna melanomas) and the west of Scotland (n=4278 invasive melanomas; 525 lentigo maligna melanomas). Analyses were stratified by sex and age group (< 40 years, 40-59 years, ≥ 60 years). We estimated annual percentage change (APC) in melanoma incidence by regressing the logarithms of the rates and exponentiating the coefficients. Among men, overall melanoma incidence increased log-linearly in both settings, but significantly more rapidly in the west of Scotland (APC 2.8%) than Queensland (APC 1.4%). Rates of increase among Scottish men were higher for every body site and all ages than among Queensland men. Among women, overall melanoma incidence increased more rapidly among Scottish (APC 1.8%) than Queensland women (APC 0.7%). Most discrepant were trends in upper limb melanomas, which underwent large annual increases among Scottish women, but declined among younger Queensland women. Melanoma incidence continues to rise rapidly in all age groups in Scotland and among older people in Queensland. Rates of melanoma in younger people in Queensland are stabilizing, as might be expected if primary prevention campaigns were effective in reducing solar exposure. Variations in rates of change at different body sites warrant further monitoring.

Abstract Objective: To determine the changing incidence of and mortality from cutaneous malignant melanoma in Scotland from 1979 to 1994. Design: Detailed registration of clinical and pathological features, surgical and other treatment, and follow up of all cases of cutaneous malignant melanoma diagnosed from 1979 to 1994 and registered with specialist database for Scotland. Setting: Scotland. Subjects: 6288 patients with invasive primary cutaneous malignant melanoma diagnosed between 1 January 1979 and 31 December 1994. Results: The annual age standardised incidence of cutaneous malignant melanoma rose significantly from 3.5 to 7.8 per 100 000 per year in men and from 6.8 to 12.3 per 100 000 per year in women (P<0.001 for both). World standardised rates increased from 2.7 to 6.0 per 100 000 per year in men and 4.6 to 8.50 per 100 000 in women. The incidence of melanoma continued to increase significantly in men of all ages during the study, but the rate stabilised in women after 1986. Mortality from cutaneous malignant melanoma was 1.3 per million per annum in men in 1979, rising to 2.3 per million per annum in 1994 (P<0.01); it was 2.4 per million per annum in women in 1979, falling to 1.9 per million per annum in 1994 (P=0.09). The underlying mortality trends showed a continuing rise for men but a downward trend for women that was not significant (P=0.09). In men, melanoma free survival was 69% at 5 years and 61% at 10 years; in women the corresponding rates were 82% and 75%. Younger patients had higher survival rates, which were not entirely explained by thinner tumours. Over the 15 year period, survival rates improved by 12% overall, only partly owing to thinner tumours. Conclusions: In Scotland the incidence of melanoma in women has stabilised, while mortality associated with melanoma in women shows a downward trend. Key messages Data from Scotland based on 6288 patients with primary invasive cutaneous malignant melanoma show a rise overall in the incidence of melanoma over 15 years but a stabilisation in the incidence of melanoma in women under 65 since 1986 Mortality associated with melanoma is now falling in women of all ages, especially in women under 65 Survival prospects remain strongly related to tumour thickness at the time of diagnosis: disease free survival at 5 years for patients with melanoma thinner than 1.5 mm was 96% in women and 91% in men, while for those with tumours thicker than 3.5 mm survival was 54% and 42% respectively

To explore whether the anatomic distribution of melanoma differs with ambient sunlight levels, we compared age- and site-specific melanoma incidence in two genetically similar populations from different geographic regions. We ascertained all new cases of invasive cutaneous melanoma in the west of Scotland and Queensland 1982-2001. Melanoma incidence was calculated for four anatomic regions (head and neck, trunk, upper and lower limbs), standardized to the European population and adjusted for relative surface area of each site. Highest rates among males aged <40 years and 40-59 years were observed on the trunk, but on the upper limbs among Queensland females and lower limbs among Scottish females. After age 60, melanoma rates were highest on the head and neck in both sexes. In both sexes and at all ages, lower limb melanomas were more common in Scotland than expected from the Queensland population. These analyses indicate that while the overall distribution of melanoma is similar in populations with different levels of ambient sunlight, important differences remain. Identifying the causes of these differences is likely to provide better understanding of how sunlight causes melanoma.