Epidemiological evidence of carcinogenicity of sunbed use and of efficacy of preventive measures.

The International Agency for Research on Cancer classified, in July 2009, exposure to artificial tanning devices (sunbeds) as carcinogenic to humans. This classification was based on evidence from epidemiological and experimental animal studies. The present chapter will review these epidemiological evidences. The summary risk estimates from 27 epidemiological studies obtained through a meta-analysis showed an increased risk of melanoma: summary relative risk (SRR) = 1.20 [95% confidence interval (CI) 1.08-1.34]. The risk was higher when exposure took place at younger age (SRR = 1.59; 95% CI 1.36-1.85). The risk was independent of skin sensitivity or population and a dose response was evident. A meta-analysis of 12 studies was conducted for non-melanoma skin cancers and showed a significantly increased risk for basal cell carcinoma (SRR = 1.29; 95% CI 1.08-1.53) and for squamous cell carcinoma (SRR = 1.67; 95% CI 1.29-2.17). As for melanoma, the risk for other skin cancers increased for first exposures at young age. Epidemiological studies have gradually strengthened the evidence for a causal relationship between indoor tanning and skin cancer and they fit with prior knowledge on relationship between UV exposure and skin cancer. Additionally, several case-control studies provided consistent evidence of a positive association between use of sunbed and ocular melanoma, also with greater risk for first exposures at younger age. Preventive measures based on information on risk or by requiring parental authorization for young users proved to be inefficient in several studies. The significant impact of strong actions or total ban, such as performed in Iceland, or a total ban of sunbed use, as in Brazil or Australian states, needs to be further assessed.

Advanced breast cancer incidence following population-based mammographic screening.

BACKGROUND: Breast cancer mortality is declining in many Western countries. If mammography screening contributed to decreases in mortality, then decreases in advanced breast cancer incidence should also be noticeable. PATIENTS AND METHODS: We assessed incidence trends of advanced breast cancer in areas where mammography screening is practiced for at least 7 years with 60% minimum participation and where population-based registration of advanced breast cancer existed. Through a systematic Medline search, we identified relevant published data for Australia, Italy, Norway, Switzerland, The Netherlands, U.K. and the U.S.A. Data from cancer registries in Northern Ireland, Scotland, the U.S.A. (Surveillance, Epidemiology and End Results (SEER), and Connecticut), and Tasmania (Australia) were available for the study. Criterion for advanced cancer was the tumour size, and if not available, spread to regional/distant sites. RESULTS: Age-adjusted annual percent changes (APCs) were stable or increasing in ten areas (APCs of -0.5% to 1.7%). In four areas (Firenze, the Netherlands, SEER and Connecticut) there were transient downward trends followed by increases back to pre-screening rates. CONCLUSIONS: In areas with widespread sustained mammographic screening, trends in advanced breast cancer incidence do not support a substantial role for screening in the decrease in mortality.

Public awareness about risk factors could pose problems for case-control studies: the example of sunbed use and cutaneous melanoma.

In a large case-control study we found no association between sunbed use and melanoma risk, but indications for potential recall and recruitment biases made the interpretation of the results difficult. Associations with skin phototype (adj OR for skin type I vs. IV: (2.6, 95% CI 1.5-4.8)), hair colour (adj OR red/blond vs. brown/black 2.0 (95% CI 1.4-2.8)) and number of naevi on both arms (OR>10 vs. 10 3.13 (95% CI: 2.47; 3.97)) were comparable to previous studies, but negative associations were found between sun exposure and melanoma risk (adj. OR 0.87 (95% CI: 0.65-1.18)) and in cases between sun exposure and naevus count. These observations led us to speculate that cases may have underreported their sun exposure and, most likely, their sunbed exposure. High percentages of sunbed use among controls indicated possible recruitment bias: eligible controls who were sunbed users were probably more likely to accept the invitation to participate than non-users, possibly due to a feeling of 'guilt' or 'worry' about their habits. Such selective participation may have strongly influenced the risk estimates of sunbed use in our study.

Lower incidence rates but thicker melanomas in Eastern Europe before 1992: a comparison with Western Europe.

The objective of this study was to investigate the epidemiology of melanoma across Europe with regard to Breslow thickness and body-site distribution. Incidence data from Cancer Incidence in 5 Continents and the EUROCARE-melanoma database were used: 28?117 melanoma cases from 20 cancer registries in 12 European countries, diagnosed between 1978 and 1992. Regression analysis and general linear modelling were used to analyse the data. Melanomas in Eastern Europe were on average 1.4 mm thicker (P<0.05) than in Western Europe and appeared more often on the trunk. From 1978 to 1992, their Breslow thickness had decreased in Western but not Eastern Europe. There was a latitude gradient in incidence, with highest rates in southern regions in Eastern Europe and an inverse gradient in Western Europe, with highest rates in the North. Mortality:incidence ratios were less favourable in southern parts across Europe, especially in Eastern Europe. If Eastern European populations copy the sunbathing behaviour of the West it is likely that in the near future a higher melanoma incidence can be expected there.

Sun exposure and sun protection in young European children: an EORTC multicentric study.

Most European children experience exposure to the sun during the summer holidays. The aim of this study was to examine the behaviour of European children when in the sun during their holidays. In 1995-1997, a total of 631 young children were recruited during a multicentric study in Belgium, Germany, France and Italy. For each holiday period from birth, parents gave detailed information on sun exposure and child behaviour. Predictors and trends over time of sun protection were investigated. Forty percent of children were exposed to sunlight in the first and 86% in the sixth year of life. At the same time, the number of children who experienced sunburns rose from 1 to 23%. In the whole period of 6 years, only 8% of children always wore trousers and shirt when in the sun, while 25% children always used a sunscreen. The proportion of sun-exposed children who used sunscreen was stable with age (approximately 50%), while those who always wore trousers and shirts dropped from 46% (1st year) to 19% (6th year). Multinomial logistic regression showed that sunscreen use, but not the wearing of clothes was associated with sun-sensitivity. In summary, sun exposure increases steadily, while sun protection decreases in the first 6 years of life in our cohort of children. In this cohort, use of a sunscreen was much more frequent than the wearing of clothes and a reduction in sun exposure.

The specific activation of gadd45 following UVB radiation requires the POU family gene product N-oct3 in human melanoma cells.

Here we report the specific regulation of gadd45 expression in human melanoma cell lines following UVB radiation. This solar wavelength is likely to be involved in melanoma aetiology. We have previously shown that gadd45 expression is strongly enhanced in a p53-independent manner following UVB irradiation, unlike the other p53 target genes studied. Furthermore, gadd45 is specifically activated in melanocytes since its induction in response to UVB, is not observed in other skin cells such as keratinocytes or fibroblasts. To investigate this particular regulation of gadd45, we analysed the UVB-induced response of different gadd45 promoter regions. Thus, a minimal promoter region of 50 bp length, responsible for gadd45 activation in melanoma cell lines following UVB irradiation, was determined. In electrophoretic mobility shift assays (EMSAs), we showed that this region (-106/-56) of the gadd45 promoter which contains two identical octamers, binds the POU family gene products oct-1 and N-oct3. Given the specific expression pattern of N-oct3 in melanocyte, we invalidated the expression of this transcription factor in melanoma cells: such an abrogation of N-oct3 protein expression in melanoma cells impeded gadd45 UVB-response. Thus the response of melanocyte to UVB may use an original and previously undescribed pathway.

IL-6 gene amplification and expression in human glioblastomas.

The aggressiveness of human gliomas appears to be correlated with the upregulation of interleukin 6 (IL-6) gene. Using quantitative PCR methods, we detected amplification and expression of the IL-6 gene in 5 of 5 primary glioblastoma samples and in 4 of 5 glioblastoma cell lines. This finding suggests that the amplification of IL-6 gene may be a common feature in glioblastomas and may contribute to the IL-6 over-expression.

The body site distribution of melanocytic naevi in 6-7 year old European children.

The number and size of melanocytic naevi are the main predictors of cutaneous melanoma. Naevus development per unit of skin surface is greatest during childhood. We assessed the body distribution of naevi 2-4.9 mm and > or = 5 mm in 649 European children aged 6-7 years old from Brussels (Belgium), Bochum (Germany), Lyon (France) and Rome (Italy). The numbers of naevi 2-4.9 mm and naevi > or = 5 mm were strongly correlated, especially on the trunk. For naevi 2-4.9 mm, the highest relative densities were found on the face, back, shoulders and the external surface of the arms. The lowest relative densities were found on the hands, legs, feet and abdomen. The relative density of naevi > or = 5 mm was higher on the trunk than on any other body site. Similar body distributions were observed in both sexes and at each centre. The body site distribution of naevi 2-4.9 mm seemed to parallel the usual sun exposure patterns of young European children. It is suggested that the development of naevi > or = 5 mm might be a marker of the vulnerability of melanocytes to the harmful effects of solar radiation. Vulnerability would be maximal on the back, and would decrease from proximal to distal skin areas, with melanocytes of the hands and feet having the lowest vulnerability. The number of naevi acquired on a specific area of skin would result from the combined effects of local vulnerability to solar radiation and local sun exposure history. The origin of acquired body site differences in the susceptibility of melanocytes to ultraviolet radiation is unknown, although it seems to parallel the body site density of sensory innervation.

Quantity of sunscreen used by European students.

BACKGROUND: The ability of sunscreen products to delay sun-induced skin erythema is indicated by the sun protection factor (SPF), which is measured using an internationally agreed sunscreen thickness of 2 mg cm(-2). OBJECTIVES: To determine the thickness of sunscreen used under practical conditions. METHODS: In two double-blind randomized trials performed in five different places in Europe in 1997 and 1998, 148 18--24-year-old students received either an SPF 10 or an SPF 30 sunscreen to be used during their summer holidays. RESULTS: Complete, detailed data on quantities of sunscreen used and skin areas on to which sunscreen was applied were available for 124 students. The median thickness of sunscreen applied was 0.39 mg cm(-2). We found no variation in sunscreen thickness according to sex, skin phototype, study place or SPF. CONCLUSIONS: Our results indicate that most consumers do not benefit from the SPF indicated on sunscreen bottles, and do not support the idea that thickness of sunscreen applied would be greater if these products were cheaper. We suggest that information on ability of a sunscreen product to prevent sunburn should be adapted in order to reflect actual usage patterns.

Intermediate-effect biomarkers in prevention of skin cancer.

Skin cancers, both non-melanoma and melanoma, usually progress through sequential steps towards malignant transformation, leading to mutant clones and precancerous lesions. Prevention of skin cancers relies on reduction of exposure to solar radiation and may be evaluated by measuring induction of intermediate-effect biomarkers such as sunburn cells or p53 mutations in the epidermis, actinic (solar) keratoses, UV-induced immunosuppression or naevi. Sunburn cells (apoptotic keratinocytes) and p53 mutations are indicators of UV-induced DNA lesions as early steps of malignant transformation of epidermal keratinocytes. Actinic keratoses are premalignant sun-induced skin lesions, characterized as keratinized patches with aberrant cell differentiation and proliferation; they represent risk factors for basal-cell carcinoma and melanoma and are precursors of squamous-cell carcinoma. Studies in humans have investigated UV-induced immunosuppression and its modulation by topical sunscreen application, focusing on contact hypersensitivity as measured by immunization or response to haptens, or on modulation of stimulation of allogeneic lymphocytes by epidermal cells, or local release of immunomodulatory molecules such as cis-urocanic acid or interleukin-10. Naevi are focal collections of melanocytes, usually found at the junction of the epidermis and dermis or at various depths in the dermis. Common acquired naevi arise after birth both spontaneously and in response to sun exposure. Most acquired naevi are clonal, while most melanocytes in non-naeval areas are not. Although it is not yet certain whether naevi represent premalignant lesions or risk factors, many melanomas arise in acquired naevi, and the number of naevi constitutes the best predictor of individual risk of melanoma. The presence of large (i.e., >5 mm) or atypical naevi (i.e., large naevi with non-uniform colour and irregular borders) is associated with elevated melanoma risk, independently of the number of smaller naevi. Children seem particularly vulnerable to sun-induced biological events involved in the genesis of melanoma, and the greatest increase in naevus numbers per unit of skin surface occurs before adolescence. Therefore, the distribution of naevi and their development in children are relevant to understanding melanoma occurrence in adults.

Sunscreen use and intentional exposure to ultraviolet A and B radiation: a double blind randomized trial using personal dosimeters.

A previous randomized trial found that sunscreen use could extend intentional sun exposure, thereby possibly increasing the risk of cutaneous melanoma. In a similarly designed trial, we examined the effect of the use of sunscreens having different sun protection factor (SPF) on actual exposure to ultraviolet B (UVB) and ultraviolet A (UVA) radiation. In June 1998, 58 European participants 18-24 years old were randomized to receive a SPF 10 or 30 sunscreens and were asked to complete daily records of their sun exposure during their summer holidays of whom 44 utilized a personal UVA and UVB dosimeter in a standard way during their sunbathing sessions. The median daily sunbathing duration was 2.4 hours in the SPF 10 group and 3.0 hours in the SPF 30 group (P = 0.054). The increase in daily sunbathing duration was paralleled by an increase in daily UVB exposure, but not by changes in UVA or UVB accumulated over all sunbathing sessions, or in daily UVA exposure. Of all participants, those who used the SPF 30 sunscreen and had no sunburn spent the highest number of hours in sunbathing activities. Differences between the two SPF groups in total number of sunbathing hours, daily sunbathing duration, and daily UVB exposure were largest among participants without sunburn during holidays. Among those with sunburn, the differences between the two groups tended to reduce. In conclusion, sunscreens used during sunbathing tended to increase the duration of exposures to doses of ultraviolet radiation below the sunburn threshold.

Development of an intracerebral glioma model in whole body irradiated hairless rats.

AIMS: To study the in vivo radiosensitivity of malignant gliomas, an animal glioma model was developed using the implantation of glioma cell lines into the brain of the Hairless rat (a mutant from the Sprague-Dawley strain, characterised by its complete absence of hair). METHODS: 10(6) malignant cells were suspended in 10 microliters phosphate buffered saline (PBS) and injected at a 4 microns depth into the left frontal lobe of an anaesthetised animal through a small craniotomy hole without opening the dura mater. The glioma cell line C6 (obtained from a chemically-induced rat glioblastoma) was introduced into 11 animals, and the human glioblastoma line G5 into 12 animals. RESULTS: The tumour take was checked using histological criteria. It was poor: 0% for the G5 line and only 27.3% for the C6 line. To improve the tumour growth rate, rats were subjected to a single dose (3.5 Gray) total body irradiation, 24 hours prior to injection, causing a marked immunosuppression. 84.6% of the rats grafted with the C6 line then produced tumours. Similar results (75% tumour take) were obtained using a stereotactic inoculation of the tumour cells. CONCLUSIONS: Thanks to the contribution of whole body irradiation, an animal intracerebral glioma model was establish, which can be used for clinical and biological studies.

[Standards, Options and Recommendations (SOR): clinical practice guidelines for diagnosis, treatment and follow-up of cutaneous melanoma. Fédération Nationale des Centres de Lutte Contre le Cancer]. / Standards, Options et Recommandations (SOR) pour la prise en charge des patients atteints de mélanome cutané.

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature systematic review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines according to the definitions of Standards, Options and Recommendations for the management of patients with cutaneous melanoma. METHODS: Data have been identified by literature search using Medline - until December 1998 - and the personal reference lists of the expert group. Once the guidelines were defined, the document was submitted for review to national and international independent reviewers and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations for the management of cutaneous melanoma (CM) are: 1) The primary prevention of melanoma is based on a reduction in exposure to ultraviolet rays (solar or artificial). 2) The diagnosis of CM requires the surgical removal and histological examination of the lesion (standard). 3) The pathological report must include the diagnosis of primary malignant melanoma, the maximum thickness of the tumour in millimeters (Breslow), the clearance of surgical margins, the level of invasion (Clark), the presence and extension of regression and the presence of any ulceration (standard). 4) The standard treatment of a primary melanoma without lymph node involvement is based on surgery that must ensure adequate margins depending on the thickness of the tumour (standard, level of evidence B). 5) After surgery of a stage I melanoma, there is no indication for additional treatment outside a prospective therapeutic study (standard, level of evidence B, French Consensus Conference). 6) For a local recurrence without node involvement, in the absence of other metastases, surgical excision is the standard treatment. 7) In the case of metastatic regional lymph nodes, a complete regional lymphadenectomy is required. There is no indication for additional treatment outside a prospective therapeutic study (standard, level of evidence B). The inclusion of these patients in controlled studies of immunotherapy is recommended. 8) There is no standard therapeutic strategy for metastatic melanoma. Conventional palliative treatment is chemotherapy with dacarbazine (level of evidence B). 9) Follow-up is based on physical examination (standard). Patient information must encourage self-surveillance. Clinical surveillance and self-detection are indicated in all cases throughout life (standard).