Incidence and survival of cutaneous melanoma in Belgium and the Netherlands from 2004 to 2016: striking differences and similarities of two neighbouring countries.

BACKGROUND: Cutaneous melanoma (CM) is a multifactorial disease, with both environmental and genetic factors involved. The incidence of CM has risen rapidly during the last decades, making it a growing public health problem. OBJECTIVES: The purpose of this retrospective study was to compare incidence and survival data of CM between two neighbouring countries, Belgium (BE) and the Netherlands (NL). METHODS: Data were collected by the Belgian Cancer Registry (BCR) and the Netherlands Cancer Registry (NCR) from 1 January 2004 until 31 December 2016. Mucosal melanoma, in situ CM and melanoma in children from 0 to 14 years were excluded. Age-standardized incidence rates were calculated using the World Standard Population (WSR) per 100 000 persons. Five-year relative survival ratios were calculated using the Ederer II methodology. RESULTS: Total number of CM was higher in NL (63 789) compared with BE (27 679). The WSR was 1.5 times higher in NL compared with BE (27.7 vs. 18.6/100 000/year). The WSR of stage IV tumours was higher in BE than in NL (0.3 vs. 0.2/100 000/year). Five-year relative survival of stage IV tumours was higher in BE compared with NL (27.2% vs. 13.7%). CONCLUSIONS: Incidence of CM was higher in NL, indicating a higher risk of CM diagnosis. Stage IV tumours were relatively more frequent in BE for both sexes, while relative survival of stage IV tumours was higher in BE. As geographical location and latitude of both neighbouring countries are almost identical, other factors like differences in behaviour, follow-up and/or treatment may explain these differences.

Mechanisms of and variables affecting UVR photoadaptation in human skin.

Humans have been exposed to solar UV radiation since their appearance on Earth and evolution has enabled most individuals to adapt to this exposure, to some degree. UV radiation produces several deleterious effects in human skin and light-skinned individuals are at greatest risk for both acute and long-term negative effects such as DNA damage, sunburn, immune suppression and skin cancer. The benefits of photoadaptation, which leads to a decreased response after acclimatization, are that humans who have skin that is capable of photoadaptation can work and play in the sun with reduced fear of painful sunburn. However, the effects of photoadaptation on DNA damage and development of skin cancer are quite complex and less well-understood. In this article, we have reviewed the current state of knowledge of UVR photoadaptation in human skin. However, more studies are needed to explore the use of UVR photoadaptation to protect against critical endpoints, such as skin cancer.

Vitamin D supplementation in cutaneous malignant melanoma outcome (ViDMe): a randomized controlled trial.

BACKGROUND: Previous studies have investigated the protective effect of vitamin D serum levels, at diagnosis and during the follow-up period after treatment, on melanoma outcome. In the present study we assess whether vitamin D supplementation, in the follow-up period after diagnosis and surgical resection of the primary tumor, has a protective effect on relapse of cutaneous malignant melanoma and whether this protective effect correlates with vitamin D levels in serum and Vitamin D Receptor immunoreactivity in the primary tumor. METHODS/DESIGN: This study is a multicenter randomized double blind placebo- controlled phase III trial. Patients between the age of 18 and 80 years diagnosed and treated surgically for a melanoma stage IB-III are eligible for randomization in a 1:1 ratio to active treatment or placebo. The study drug is taken each month and consists of either 100,000 International Unit cholecalciferol or arachidis oleum raffinatum used as a placebo. The primary endpoint is relapse free survival. The secondary endpoints are 25 hydroxyvitamin D3 serum levels at diagnosis and at 6 month intervals, melanoma subtype, melanoma site and stage of melanoma at diagnosis according to the 2009 American Joint Committee on Cancer melanoma staging and classification. At randomization a bloodsample is taken for DNA analysis. The study is approved by the local Ethics Committees. DISCUSSION: If we can confirm our hypothesis that vitamin D supplementation after removal of the tumor has a protective effect on relapse of cutaneous malignant melanoma we may reduce the burden of CMM at several levels. Patients, diagnosed with melanoma may have a better clinical outcome and improved quality of life. There will be a decrease in health care costs related to treatment of metastatic disease and there will be a decrease in loss of professional years, which will markedly reduce the economic burden of the disease. TRIAL REGISTRATION: Clinical Trial.gov, NCT01748448 , 05/12/2012.

Epidemiology of basal and squamous cell carcinoma in Belgium: the need for a uniform and compulsory registration.

BACKGROUND: Non-melanoma skin cancer (NMSC) is the most common type of cancer among Caucasians, however, few data exist on its incidence. Because of a sheer volume of these tumours, NMSC is often not systematically registered. OBJECTIVE: To describe and analyse the incidence of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in Belgium. METHODS: Incidence data of BCC and SCC, including multiple primary skin tumours in the same patient, were extracted from the Belgian Cancer Registry from 2004 to 2012 (predominantly coming from pathology notifications). Belgian legislation makes cancer registration compulsory for oncological care programmes and for all pathological anatomy laboratories. RESULTS: Between 2004 and 2012, 113 254 BCC and 33 153 SCC cases were reported in Belgium. A total of 130 339 patients had 146 407 tumours. Approximately, 10% of the patients (12 759 patients) had multiple tumours. The world age-standardised incidence rate (WSR) for BCC increased from 36.9 in 2004 to 98.4 per 100 000 person years in 2012 for males and from 34.2 in 2004 to 102.0 in 2012 for females. For SCC, the WSR increased from 14.9 in 2004 to 24.7 in 2012 for males and from 6.8 in 2004 to 13.5 in 2012 for females. CONCLUSIONS: From 2004 to 2012, the incidence of BCC and SCC markedly rose in Belgium, as also seen worldwide. Known causes are increased sun exposure caused by changed sunlight-related behaviour (increased outdoor activities and holidays, use of tanning beds and changes in clothing style), ageing and improved registration. Because of their high and increasing incidence, these cancers will have major implications on healthcare planning and preventive measures. Therefore, we recommend compulsory registration, whenever is possible, of BCC and SCC, although it is an ambitious objective, especially in countries with a high burden of these tumours and in countries where registration is currently unavailable.

Cutaneous adverse effects of BRAF inhibitors in metastatic malignant melanoma, a prospective study in 20 patients.

BACKGROUND: BRAF inhibitors frequently cause significant cutaneous adverse reactions. OBJECTIVE: To study the timing, prevalence and response to treatment of skin lesions in patients receiving V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors. METHODS: We prospectively studied the cutaneous side-effects of patients with a BRAF mutant (V600E, V600K, V600R) metastatic malignant melanoma treated with a BRAF inhibitor. We systematically registered prevalence, timing of onset and response to treatment. RESULTS: Twenty patients were treated for 2-52 weeks with a BRAF inhibitor. Eleven patients on vemurafenib (58%) developed cutaneous side-effects and 10 patients (42%) had more than one cutaneous adverse event. Verrucous papillomas were observed in eight patients (42%), after 1-12 weeks. We diagnosed four keratoacanthomas in two patients (11%) after 6-10 weeks and two squamous cell carcinomas in two patients (11%) after 10-16 weeks. Seven patients (37%) developed a hyperkeratotic, folliculocentric eruption after 2-8 weeks, resolving quickly under topical steroids. Four patients (21%) presented a facial erythema, two patients (11%) a seborrhoeic dermatitis-like eczema on the scalp. Three patients (16%) developed cystic lesions after 2-11 weeks. Three patients (16%) presented a hand-foot skin reaction after 4-6 weeks, which was successfully treated with topical steroids and keratolytics. Hyperkeratosis of the nipples was seen in one patient (5%). We observed phototoxic reactions after UV exposure in five patients (26%) and alopecia in two patients (11%) after 8-10 weeks. One patient on dabrafenib developed curly hairs (24 weeks), keratotic papules (1 and 36 weeks), a keratoacanthoma (4 weeks) and a hand-foot skin reaction (31 weeks). CONCLUSION: Multiple cutaneous toxicities were observed in patients under BRAF inhibitors, mostly well controlled with adequate treatment. We recommend a multidisciplinary approach with regular assessments of the skin by a dermatologist. This allows early identification and adequate treatment to avoid premature discontinuation of a life-prolonging therapy.

Epithelial-mesenchymal transition during invasion of cutaneous squamous cell carcinoma is paralleled by AKT activation.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is required for tumour invasion and dissemination to occur. OBJECTIVES: To investigate EMT during invasion of cutaneous squamous cell carcinoma (cSCC) and the involvement of AKT. METHODS: Using a tissue microarray, we measured expression of EMT-markers and AKT activation in 140 samples from patients with skin cancer and matched samples of normal skin adjacent to cSCC in cSCC in situ (cSCCIS) and in invasive cSCC. We investigated EMT using functional assays and the expression of EMT markers in an isogenic skin cancer progression model using cell lines derived from dysplastic forehead skin (PM1), primary invasive cSCC (MET1) and its lymph node metastasis (MET4). This model was used to investigate AKT-specific inhibition of the EMT process. RESULTS: In comparison with normal skin, and normal skin plus cSCCIS, the invasive cSCCs show significantly increased vimentin expression, decreased E-cadherin expression and increased expression of the active form of AKT. In the cell culture model, the primary MET1 cells display the lowest adhesion potential, the highest migratory and invasive ability through a Matrigel-coated porous membrane, the highest expression of EMT markers vimentin and Slug and the lowest expression of the epithelial marker E-cadherin. Pharmacological AKT inhibition in this model suppressed EMT mechanisms. CONCLUSIONS: AKT may serve as a therapeutic target to avoid dissemination of cSCC cells.

[Lack of compliance to topical corticosteroid therapy: possible cause and solutions]. / Manque d'observance thérapeutique a la corticothérapie topique: causes et solutions possibles.

Adherence to therapy is low for topical therapy used in dermatological disorders. particularly in chronic diseases like atopic dermatitis and psoriasis. One of the reasons is that patients do not trust their therapy and fear side effects, particularly with topical corticosteroids. In order to make patients more confident, it is it important to provide correct and detailed information about the prescribed products and the amount to apply, to involve them in the implementation of therapy and to harmonize the information given by various care providers (physicians, nurses, pharmacists). The message needs to be clear and consistent between caregivers and not lead to unjustified worries. Poor adherence may result in the use of stronger preparations or switch to systemic treatment, which eventually will result in more severe side effects.

Sunlight exposure and sun sensitivity associated with disability progression in multiple sclerosis.

BACKGROUND: Sunlight and vitamin D have been inversely associated with the risk of multiple sclerosis (MS). OBJECTIVE: We investigated sunlight exposure and sun sensitivity in relation to disability progression in MS. METHODS: We conducted a survey among persons with MS, registered by the Flemish MS society, Belgium, and stratified data according to relapsing-onset and progressive-onset MS. We used Kaplan-Meier survival and Cox proportional hazard regression analyses with time to Expanded Disability Status Scale (EDSS) 6 as outcome measure. Hazard ratios for the time from onset and from birth were calculated for the potentially predictive variables, adjusting for age at onset, gender and immunomodulatory treatment. RESULTS: 704 (51.3%) of the 1372 respondents had reached EDSS 6. In relapsing-onset MS, respondents reporting equal or higher levels of sun exposure than persons of the same age in the last 10 years had a decreased risk of reaching EDSS 6. In progressive-onset MS, increased sun sensitivity was associated with an increased hazard of reaching EDSS 6. CONCLUSION: The association of higher sun exposure with a better outcome in relapsing-onset MS may be explained by either a protective effect or reverse causality. Mechanisms underlying sun sensitivity might influence progression in progressive-onset MS.

Deregulation of cell-death pathways as the cornerstone of skin diseases.

Deregulation of cell-death pathways plays a key role in the pathogenesis of various skin diseases. The different types of cell death are mainly defined by morphological criteria, and include apoptosis, autophagic cell death, and necrosis. The process of apoptosis is well characterized at the molecular level and involves the activation of two main pathways, the intrinsic and extrinsic pathways, converging into the execution of apoptosis by intracellular cysteine proteases, called caspases. The relevance and implication of these apoptotic pathways in the pathophysiology of skin diseases, such as toxic epidermal necrolysis, graft-versus-host disease and skin cancer, has been extensively studied. The role of autophagic cell death in progression of skin tumours and response to cytotoxic drugs is only beginning to be elucidated.

Adaptive response of the skin to UVB damage: role of the p53 protein.

Different adaptation mechanisms like heat shock response, cell cycle arrest and DNA repair, melanin pigmentation and thickening of the epidermis are present in the human skin to protect against the adverse effects of solar UV irradiation. When DNA damage is beyond repair, cells undergo apoptosis to prevent their replication. We discuss the current knowledge on these different adaptation mechanisms to UVB damage, the most energetic fraction of solar UV that reaches the skin. As p53 protein, the guardian of the genome, plays a key role in protective response to genotoxic damage, its role in this adaptive response of the skin to UV will be further discussed.

Epidermal differentiation does not involve the pro-apoptotic executioner caspases, but is associated with caspase-14 induction and processing.

The epidermis is a stratified squamous epithelium in which keratinocytes progressively undergo terminal differentiation towards the skin surface leading to programmed cell death. In this respect we studied the role of caspases. Here, we show that caspase-14 synthesis in the skin is restricted to differentiating keratinocytes and that caspase-14 processing is associated with terminal epidermal differentiation. The pro-apoptotic executioner caspases-3, -6, and -7 are not activated during epidermal differentiation. Caspase-14 does not participate in apoptotic pathways elicited by treatment of differentiated keratinocytes with various death-inducing stimuli, in contrast to caspase-3. In addition, we show that non-cornifying oral keratinocyte epithelium does not express caspase-14 and that the parakeratotic regions of psoriatic skin lesions contain very low levels of caspase-14 as compared to normal stratum corneum. These observations strongly suggest that caspase-14 is involved in the keratinocyte terminal differentiation program leading to normal skin cornification, while the executioner caspases are not implicated. Cell Death and Differentiation (2000) 7, 1218 - 1224

Evaluating the UVA photoprotection of sunscreens with murine skin edema.

The acute and chronic deleterious effects of UVA on skin have prompted a growing interest in developing effective UVA-photoprotective sunscreens. The quantification of their UVA photoprotection remains, however, a major problem. In the present study, murine skin edema induced by 8-methoxypsoralen plus UVA (PUVA) is evaluated as a screening method for quantifying the UVA photoprotection of commercially available sunscreens. The PUVA-induced murine skin edema is provoked on the dorsa of female hairless albino mice and measured with a hand-held micrometer. A clear time course and a well-defined dose-response relationship are demonstrated. Therefore, a UVA-photoprotection factor (UVA-PF) could be defined by dividing the minimal edema dose with sunscreen by the minimal edema dose without sunscreen. The UVA-PF values obtained with this method were quantitatively and qualitatively very similar to those obtained in 8-methoxypsoralen-photosensitized murine skin by using the number of sunburn cells as the biologic end point and were qualitatively similar to UVA-PF values obtained in human skin using phototoxic erythema and UVASUN-induced tanning as the parameter. It is concluded that PUVA-induced murine skin edema offers an objective, reproducible, and easily applicable screening method for quantifying the degree of UVA photoprotection of a sunscreen.

Modification of sunburn cell production in 8-MOP sensitized mouse epidermis: a method of assessing UVA sunscreen efficacy.

The UVA(320-400 nm) photoprotection of four commercially available sunscreens with different sun protection factors was evaluated in 8-methoxypsoralen (8-MOP) treated mouse epidermis with the number of sunburn cells (SBCs) as the end-point. SBC production in 8-MOP sensitized mouse epidermis with and without application of sunscreens is dose-related. The difference between the slopes of the dose-response curves of the control group and the four sunscreens was highly significant (p less than 0.001). It appears that the SBC production was modified both by the dose of the UVA irradiation administered and by the UVA photoprotection of the four sunscreens. It could be concluded that the number of SBCs in 8-MOP sensitized mouse epidermis is a useful parameter to quantify the degree of UVA photoprotection of sunscreens.

A first approach to an action spectrum for 8-MOP phototumorigenesis in mice.

Groups of hairless albino mice were treated with 8-MOP and exposed to a fixed daily dose of UVR obtained from one of four different emission spectra. Each spectrum was obtained by filtering a xenon arc source with a different WG filter. The resultant spectra showed differences in their proportions of shorter UVA wavelengths. A decreased proportion of the shorter wave bands systematically increased the time to first tumor. These data suggest that the action spectrum for 8-MOP sensitized phototumorigenesis is similar to that of acute 8-MOP action spectra in mammalian skin, which usually show maximal activity in the 320-335 nm region.

Retinoic acid modulates the anti-proliferative effect of 1,25-dihydroxyvitamin D3 in cultured human epidermal keratinocytes.

Both 1,25-dihydroxyvitamin D3 (VD) and retinoids have potent effects on keratinocyte proliferation. Parallelism in their action as steroid hormones, which involves interaction of their receptors, and in their therapeutic efficacy for hyper-proliferative skin diseases provides a rationale to investigate their combined action on proliferation in pre-confluent human epidermal keratinocyte cultures. As shown by [3H]thymidine incorporation, all-trans retinoic acid (atRA) at subpharmacologic concentrations and 9-cis retinoic acid (9cRA) diminished the anti-proliferative effect of VD. Pre-incubation of the cells with the retinoids clearly enhanced this effect. Cell-cycle analysis revealed G1 arrest upon VD treatment that was attenuated by retinoic acid (RA). Moreover, Northern and Western blot analysis demonstrated that retinoic acid opposed VD-induced accumulation of transforming growth factor-beta1, p21WAF1, and p27KIP1. Finally, retinoic acid reduced VD-elicited hypophosphorylation of the retinoblastoma protein. AtRA at micromolar concentrations conversely potentiated most of the aforementioned VD-dependent actions. In addition, atRA and 9cRA (but not VD) caused a rapid, sustained reduction of RXR alpha protein. VD receptor protein was induced by VD regardless of the presence of RA. In conclusion, RA modulates VD-dependent effects at different levels of keratinocyte proliferation. This could have implications for the use of combinations of both drugs for skin diseases.

Suppression of vitamin D receptor and induction of retinoid X receptor alpha expression during squamous differentiation of cultured keratinocytes.

To gain more insight in the role of the vitamin D system in epidermal differentiation, we studied the expression of the vitamin D receptor and its heterodimeric partner retinoid X receptor alpha in cultured normal human keratinocytes during squamous differentiation, as triggered by different approaches. Northern and western blot analysis allowed us to investigate mRNA and protein levels of these nuclear receptors and of markers for growth control (c-myc, cyclin D1, p21WAF1) and differentiation (keratinocyte transglutaminase, small proline rich proteins). Growing cells to postconfluence was a potent stimulus for growth arrest and differentiation with concomitant suppression of vitamin D receptor and induction of retinoid X receptor alpha, at both the mRNA and the protein level. These changes could be prevented by concomitant treatment with epidermal growth factor or keratinocyte growth factor. Subjecting the cells to a calcium switch leading to stratification and differentiation lowered vitamin D receptor protein levels without affecting vitamin D receptor mRNA and induced both retinoid X receptor alpha mRNA and protein. Interferon-gamma and the phorbolester 12-O-tetradecanoyl phorbol 13-acetate, two well-known inducers of keratinocyte differentiation, both inhibited vitamin D receptor expression but only interferon-gamma induced retinoid X receptor alpha. The decreased vitamin D receptor expression was accompanied by reduced vitamin D responsiveness (as assessed by 24-hydroxylase mRNA induction) in postconfluent, high calcium, and 12-O-tetradecanoyl phorbol 13-acetate treated keratinocytes but not with interferon-gamma treatment. Taken together, our results associate vitamin D receptor expression with undifferentiated, proliferating keratinocytes, whereas retinoid X receptor alpha expression appears to be related to the differentiated phenotype. Therefore, proliferating and differentiating keratinocytes may be differentially targeted by active vitamin D metabolites.

Anchorage-dependent expression of the vitamin D receptor in normal human keratinocytes.

Although the nuclear vitamin D receptor (VDR) is involved in the control of keratinocyte proliferation and differentiation by its ligand 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], its role in epidermal physiology remains poorly understood. Because VDR abundance reflects cellular responsiveness to 1,25(OH)2D3, we investigated VDR expression in cultured human keratinocytes and identified cell anchorage and cytoskeletal integrity as essential requirements for the maintenance of VDR levels. Suspension culture rapidly suppressed VDR expression and 1,25(OH)2D3 responsiveness (as estimated by induction of 24-hydroxylase mRNA), due to decreased transcription of the VDR gene. Concomitantly, overt growth arrest with p21WAF1 induction and cyclin D1 and c-myc suppression occurred, together with induction of differentiation markers and retinoid X receptor alpha, the heterodimeric partner for VDR. Reattachment of suspended keratinocytes to fibronectin led to a rapid restoration of VDR expression, which could be blocked by RGD peptides or a blocking anti-beta1 integrin antibody. VDR expression was also reduced by disruption of the actin cytoskeleton with cytochalasin D. Malignant keratinocytes (SCC12B2 and A431), characterized by, anchorage-independent growth, displayed a profound resistance to suspension-induced suppression of VDR, cyclin D1, and c-myc. Taken together, our results associate VDR expression [and 1,25(OH)2D3 responsiveness] with cell adhesion and an organized cytoskeleton, which are also required for cell growth of primary cells.