Lower 25-hydroxyvitamin D2/D3 levels at melanoma diagnosis are associated with thicker primaries and poorer survival. We postulated that this might relate to the deleterious effect of systemic inflammation as 25-hydroxyvitamin D2/D3 levels are inversely associated with levels of C-reactive protein. 2182 participants in the Leeds Melanoma Cohort (median follow up 7.98 years) provided data on drug exposure, co-morbidities and a serum 25-hydroxyvitamin D2/D3 level at recruitment. Factors reported to modify systemic inflammation (low vitamin D levels, high body mass index (BMI), use of aspirin or non-steroidal anti-inflammatory drugs or smoking were tested as predictors of microscopic ulceration (in which primary tumours are inflamed) and melanoma specific survival (MSS). Ulceration was independently associated with lower 25-hydroxyvitamin D2/D3 levels (OR=0.94 per 10nmol/L, 95% CI 0.88–1.00, p=0.05) and smoking at diagnosis (OR=1.47, 95% CI 1.00–2.15, p= 0.04). In analyses adjusted for age and sex, a protective effect was seen of 25-hydroxyvitamin D2/D3 levels at diagnosis on melanoma death (OR=0.89 per 10nmol/L, 95% CI 0.83–0.95, p<0.001) and smoking increased the risk of death (OR=1.13 per 10 years, 95% CI 1.05–1.22, p=0.001). In multivariable analyses (adjusted for tumour thickness) the associations with death from melanoma were low 25-hydroxyvitamin D2/D3 level at recruitment (<20 nmol/L vs. 20–60 nmol/L, HR=1.52, 95% CI 0.97–2.40, p=0.07) and smoking duration at diagnosis (HR=1.11, 95% CI 1.03–1.20, p=0.009). The study shows evidence that lower vitamin D levels and smoking are associated with ulceration of primary melanomas and poorer MSS. Further analyses are necessary to understand any biological mechanisms that underlie these findings.

A high number of naevi is the most significant phenotypic risk factor for melanoma and is in part genetically determined. The number of naevi decreases from middle age onwards but this senescence can be delayed in melanoma patients. We investigated the effects of naevus number count on sentinel node status and melanoma survival in a large cohort of melanoma cases. Out of 2184 melanoma cases, 684 (31.3%) had a high naevus count (>50). High naevus counts were associated with favourable prognostic factors such as lower Breslow thickness, less ulceration and lower mitotic rate, despite adjustment for age. Naevus count was not predictive of sentinel node status. The crude 5- and 10-year melanoma specific survival rate was higher in melanomas cases with a high naevus count compared to those with a low naevus count (91.2% vs 86.4% and 87.2% vs 79%, respectively). The difference in survival remained significant after adjusting for all known melanoma prognostic factors (HR= 0.43, CI 0.21-0.89). The favourable prognostic value of a high naevus count was also seen within the positive sentinel node subgroup of patients (HR=0.22, CI 0.08-0.60). High naevus count is associated with a better melanoma survival, even in the subgroup of patients with positive sentinel lymph node. This suggests a different biological behaviour of melanoma tumours in patients with an excess of naevi.

The relationship between risk of cutaneous malignant melanoma and total body and site-specific naevus counts and other host factors was investigated in a Caucasian population aged 15-84 years in New South Wales, Australia. The study sample comprised 244 cases with melanoma diagnosed in 1989-1 993, and 276 controls. The strongest relationship was with total body naevus count. Risk of melanoma was raised I 2 times in those with more than 100 naevi compared with those with less than 10. There were also strong risks, with odds ratios of 5 or more, associated with having multiple atypical naevi, multiple large naevi, high naevus counts in sun-exposed or sun-protected areas and being unable to tan on repeated sun exposure. The effect of inability to tan was stronger at younger than older ages. Lesser risks, with odds ratios of 2-3, were associated with being prone to burn on sun exposure, having many freckles as a child and having red hair. The site distribution of naevi in males compared with females resembled the distribution of melanoma by sex. Risk of melanoma of the back was significantly more closely related to back naevus count than naevus count for the remainder of the body. For other anatomical sites, naevus count was non-significantly more closely related to naevus counts at that site than counts over the remainder of the body. Naevus count declined with age in both cases and controls. In those aged under 40, having I00 or more naevi was associated with an aetiological fraction (AF) of 41%. In those aged 60 and over, however, the AF associated with this number of naevi was only 5%.o 1996 Wiley-Liss, Inc.

Summary Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To understand this problem more clearly we used a combination of natural killer (NK) cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment. In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem‐like cells, a source of post‐treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM‐infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of transforming growth factor (TGF)‐β‐mediated inhibition. This NK cell inhibition is accompanied by expression of multiple immune checkpoint molecules on T cells. Single‐cell transcriptomics demonstrated that both tumour and haematopoietic‐derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co‐expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognized by the immune system but that anti‐tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more probably benefit from combination immunotherapies directed against multiple immunosuppressive pathways.