Regular sun exposure benefits health.

Since it was discovered that UV radiation was the main environmental cause of skin cancer, primary prevention programs have been started. These programs advise to avoid exposure to sunlight. However, the question arises whether sun-shunning behaviour might have an effect on general health. During the last decades new favourable associations between sunlight and disease have been discovered. There is growing observational and experimental evidence that regular exposure to sunlight contributes to the prevention of colon-, breast-, prostate cancer, non-Hodgkin lymphoma, multiple sclerosis, hypertension and diabetes. Initially, these beneficial effects were ascribed to vitamin D. Recently it became evident that immunomodulation, the formation of nitric oxide, melatonin, serotonin, and the effect of (sun)light on circadian clocks, are involved as well. In Europe (above 50 degrees north latitude), the risk of skin cancer (particularly melanoma) is mainly caused by an intermittent pattern of exposure, while regular exposure confers a relatively low risk. The available data on the negative and positive effects of sun exposure are discussed. Considering these data we hypothesize that regular sun exposure benefits health.

[Favourable and unfavourable effects of exposure to sunlight]. / Gunstige en ongunstige effecten van zonlichtexpositie.

The negative effects of sunlight include the more frequent or earlier development of skin cancer and degenerative changes in the skin, and the occurrence ofphotodermatoses. - However, sunlight also has a favourable effects; specifically, it may inhibit the development and progression of diseases of the bones, muscles and skin, ofvarious malignancies (carcinoma of the prostate, breast, colon and ovary, non-Hodgkin lymphoma), and may prevent certain autoimmune diseases, particularly multiple sclerosis. - This protective effect is ascribed to an increased synthesis of vitamin D, which is important for bone metabolism and is also able to regulate cell proliferation and differentiation, apoptosis, tumour invasion and angiogenesis. - The possible consequence of this new information is that public information regarding exposure to sunlight must continue to include a warning against excessive exposure to the sun, while at the same time stimulating regular although limited sunbathing.

Does sunlight prevent cancer? A systematic review.

Accumulating evidence for beneficial effects of sunlight on several types of cancer with a high mortality rate makes it necessary to reconsider the health recommendations on sun exposure, which are now mainly based on the increased risks for skin cancer. We reviewed all published studies concerning sun exposure and cancer, excluding skin cancer. All selected studies on prostate (3 ecologic, 3 case-control and 2 cohort), breast (4 ecologic, 1 case-control and 2 cohort) and ovary cancer (2 ecologic and 1 case-control) showed a significantly inverse correlation between sunlight and mortality or incidence. Two ecologic, 1 case-control and 2 prospective studies showed an inverse relation between sunlight and colon cancer mortality; 1 case-control study found no such association. Ecologic studies on non-Hodgkin lymphoma (NHL) mortality and sunlight gave conflicting results: early studies showing mostly positive and later studies showing mostly negative correlations. Three case-control studies and 1 cohort study found a significant inverse association between the incidence of NHL and sunlight. The question of how to apply these findings to (public) health recommendations is discussed.

[Guideline 'Melanoma' (3rd revision)]. / Richtlijn 'Melanoom' (3e herziening).

The guidelines 'Melanoma' (3rd revision) are evidence-based in nature. A number of outcomes are summarised in this article. Dermatoscopy deserves a standard role in the clinical diagnosis of pigmented skin abnormalities. Pathological findings from a diagnostic excision should be recorded meticulously to include anatomical localisation, type of intervention used, excision margin, diagnosis, Breslow thickness, and the completeness of the removal. The sentinel node procedure should be reserved for patients who want to be as informed as possible about their prognosis. The procedure is not considered a part of standard diagnosis. Sentinel node assessment should include stains for specific markers and should be conducted in multiple sections. The following margins of non-affected skin are recommended for therapeutic re-excision of melanoma: in situ melanoma, 0.5 cm; Breslow thickness < or = 2 mm, 1 cm; Breslow thickness > 2 mm, 2 cm. Pathological assessment of a re-excised specimen depends on the completeness of the first excision. Systematic adjuvant treatment of patients with melanoma is not recommended outside the context of a clinical study. Patients with metastatic melanoma are preferably treated within a clinical study. Outside of a clinical study, these patients should be treated with dacarbazine. There is no evidence to suggest that survival is improved by frequent follow-up. However, follow-up can be a useful way to meet the information needs of patients and care requirements for physicians.

[Interferon for adjuvant therapy in melanoma; although approved, not indicated]. / Interferon als adjuvante therapie bij het melanoom: wel geregistreerd, niet geïndiceerd.

The Dutch melanoma group reconsidered their 1997 consensus statement on treatment of melanoma because new studies on adjuvant treatment with interferon(IFN)-alpha have been published. These have resulted in its registration for stage IIa; for stage IIb/III IFN-alpha was already registered. Overall survival should be the main endpoint of adjuvant clinical studies, especially when treatment is associated with toxicity. Since a benefit has not been unequivocally demonstrated in melanoma with Breslow thickness > 1.5 mm and/or regional lymph node metastases, there is no need to change the Dutch consensus statement. Drug registration authorities and medical professionals should cooperate more closely.

[Prevention of cutaneous melanoma]. / Preventie van het melanoom van de huid.

Cutaneous melanoma exhibited a rapidly increasing incidence during the 70 s and 80 s. As a consequence primary and secondary prevention campaigns were developed, starting in Australia, where the incidence was by far the highest, but later also in the Netherlands. Mortality from melanoma in the Netherlands is stable at a rate of 2.4 per 100,000 person years since 1980. The melanoma incidence has stabilized since 1989 at a level of about 11 per 100,000. In the development of the melanoma it is not so much the accumulated exposure to sun that is of importance, as in squamous carcinoma, but rather incidental serious sunburn. It is especially exposure at an early age that increases the risk of melanoma as well as that of basal cell carcinoma. Primary prevention must be focussed on avoiding sunburn in young people. Secondary prevention can be realised by frequent controls of risk groups and a raised awareness for changing moles in the general population but also in physicians who see patients' skins for whatever reason.

Increase in and stabilization of incidence and mortality of primary cutaneous malignant melanoma in Western Netherlands, 1980-95.

In summer 1989, a skin cancer campaign was organized in the coastal area of western Netherlands. In order to assess the impact of this and future campaigns on detection rates for melanomas of various thicknesses, a frame of reference for the epidemiology of cutaneous melanoma was established. We performed a retrospective investigation of all melanomas diagnosed in this region in the period 1980-95. A total of 3705 (2967 invasive and 738 in situ melanomas) cases was analysed. During the 1980s the age-adjusted incidence of invasive melanoma steadily increased (from five in 100,000 to 11 in 100,000 for men and from nine in 100,000 to 14 in 100,000 for women). Since 1988/89 the rate has remained stable for men and has increased only slightly among women. Detection rates for in situ melanomas followed the same pattern. Mortality rates remained largely unchanged for both sexes (European standard rates are about 2.6 in 100,000 for men and 2.2 in 100,000 for women). The median Breslow thickness decreased from 1.2 to 1.1 mm for men and from 1.1 to 0.8 mm for women. A marked increase occurred in the proportion of thin melanomas in comparison with intermediate and thick tumours, particularly among women. The female/male ratio declined in the period studied from 2.0 to 1.5. Directly after the campaign in 1989 a temporary increase occurred in the total number of melanomas diagnosed, largely due to more thin melanomas (

Site, histological type, and thickness of primary cutaneous malignant melanoma in western Netherlands since 1980.

An increasing incidence of cutaneous malignant melanoma had been observed in the Netherlands. Therefore, between 1989 and 1992 a preventive skin cancer campaign was organized in part of western Netherlands. The effect of this screening campaign has yet to be evaluated by investigating the distribution of all in situ and invasive primary cutaneous melanoma according to anatomical subsite, tumour thickness, and histological type in a population-based study during 1980-92. A total number of 2236 (1361 female; 875 male) invasive and 580 (395 female; 185 male) in situ melanomas were diagnosed. The median age of patients with thin lesions was 46 years, intermediate lesions 54 years, and thick lesions 65 years, which may be indicative of slow tumour progression. The median thickness of the invasive lesions was 0.9 mm for women and 1.1 mm for men and the invasive to in situ ratio was 3.4 for female and 4.7 for male subjects, suggesting a reasonable awareness of melanoma in this population. The relative tumour density (RTD) was remarkably high for melanomas in the head/neck area for both sexes and invasive melanoma on the male trunk and the lower legs of females. The low RTD of invasive melanomas on the lower limbs of men and the high density in the head/neck area for both sexes are remarkable and support the aetiological role of ultraviolet exposure. It is concluded that our findings are in many ways similar to those of other descriptive studies.

The long-term safety and efficacy of cyclosporin in severe refractory atopic dermatitis: a comparison of two dosage regimens.

An open, randomized trial was performed to determine the optimal dosage schedule with regard to the efficacy and safety of cyclosporin in severe atopic dermatitis. The study also provided clinical experience with regard to the efficacy and safety of long-term cyclosporin treatment. During a 2-month dose-finding period, 78 patients with severe, long-standing atopic dermatitis received cyclosporin at a dose of either 5 mg/kg per day, decreasing to 3 mg/kg per day (Group A), or 3 mg/kg per day, increasing to 5 mg/kg per day (Group B), Patients were maintained on their optimal dose for a further 10 months. Patients in Group A showed a significantly greater improvement in efficacy parameters over the first 2 weeks than with patients in Group B, but as the dose was decreased in Group A and increased in Group B, these differences were minimized. After 1 year, cyclosporin showed an efficacy of 59.8% in Group A and 51.7% in Group B, assessed by a severity score. Assessed in terms of an area score, these figures were 48.7% and 40%, respectively. Cyclosporin demonstrated a good safety profile during long-term treatment and was generally well tolerated. The lower starting dosage was not associated with higher dropout rates. This study showed no differences in efficacy or adverse events between the two dosage schedules in long-term treatment.

Invasive cutaneous melanoma in The Netherlands, 1989-1990.

The Breslow or tumour thickness is the most important prognostic factor for survival from cutaneous melanoma. We studied the occurrence of melanoma in relation to tumour thickness and subsite in The Netherlands. Data on all newly diagnosed invasive cutaneous melanomas in the Netherlands Cancer Registry in 1989 and 1990 were used to estimate age and sex-specific incidence rates according to site and depth of tumour invasion. The incidence among women (9.5 per 100,000 person-years) was relatively high compared with other European countries. The predominant site was the trunk among men and the leg among women. After age 70, one-third of the melanomas were observed in the head and neck region. According to data from PALGA, the national computerized archive of Dutch pathology laboratories, 37% of the men and 29% of the women had a melanoma > 1.5 mm thick. Among persons younger than age 60, 26% had a melanoma > 1.5 mm thick, compared with 44% among those 60 years and over. In both registries the absolute and relative risks for a thicker melanoma increased with age, particularly for men. In The Netherlands, preventive measures for population groups with thicker melanomas should be targeted towards men and elderly persons.

Screening for skin cancer in The Netherlands.

In the summer of 1989 a screening campaign for skin cancer was organized along part of the beach in the western region of The Netherlands, using a mobile trailer. On 4 consecutive Saturdays, 3,069 individuals were examined. A total of 65 individuals with a suspected lesion were found and referred to their general practitioner. The compliance with referral was 80%. Histological reports, obtained from 46 suspected lesions, showed: 6 melanomas (all with a thickness less than 1 mm), 2 squamous cell carcinomas, 23 basal cell carcinomas, 5 dysplastic naevi and 10 benign skin lesions. The positive predictive value of the visual examination appeared to be 83%. The campaign attracted much publicity. The effects of this publicity were measured by a questionnaire sent to all general practitioners and dermatologists in the region. It appeared that during the campaign and in the ensuing 2 months there had been an increase in the number of diagnoses of benign skin lesions and a moderate increase in the diagnoses of malignant lesions.

[The 'freckle bus' campaign; an unhealthy phenomenon or a sensible experiment?]. / De 'sproetenbus'; een ongezond verschijnsel of een bezonnen experiment?

In the summer of 1989 a screening campaign for skin cancer was organized in four seaside resorts of The Netherlands using a mobile examination room. On 4 consecutive Saturdays 3069 individuals were examined. A total of 65 individuals with a suspected lesion were found. Histological reports were obtained on 46 suspected lesions and showed: 6 melanomas (all with a thickness less than 1 mm), 2 squamous cell carcinomas, 23 basal cell carcinomas, 5 dysplastic naevi and 10 benign skin lesions. The positive predictive value of the clinical examination appeared to be 83%. Much publicity was given to the campaign by the (inter)national media. The effects of this publicity were measured by a questionnaire sent to the general practitioners (856) and dermatologists (25) in the region, of whom 44% and 84%, respectively, responded. It appeared that during and after the campaign there had been an increase in the number of consultations for skin lesions, and an increase in the diagnoses of malignant lesions.

[The treatment of chronic skin ulcers with cryo-preserved cultured allogeneic epidermis transplants]. / De behandeling van chronische ulcera van de huid met cryo-gepreserveerde gekweekte allogene epidermistransplantaten.

In 18 patients with 25 chronic stasis ulcers and in 15 patients with 22 chronic leg ulcers of different aetiology, and in 7 patients with a variety of skin defects the effect of cryopreserved cultured allografts (CPA) on wound healing was investigated. The ulcers were grafted weekly or every other week on an outpatient basis until healing occurred. In 78% of the patients with stasis ulcers (84% of the ulcers) there was complete healing with a mean healing time of 31 days and a mean healing rate of 4.9 cm2 per week. The mean healing time of arterial and rheumatoid ulcers was 68 days and 56 days, respectively, while donor sites and erosive skin lesions all healed within 5 days. Five ulcers (9%), including one stasis ulcer, in 5 patients showed no change. We conclude that CPA is an easily applicable and effective biological product that profoundly stimulates the host epithelialisation, reduces the pain and is specifically effective in accelerating the healing of chronic stasis ulcers and donor sites.

Efficacy and transdermal absorption of permethrin in scabies patients.

The clinical efficacy and transdermal absorption of permethrin, a new synthetic insecticide was investigated in ten scabies patients. All patients were successfully treated with one application of a cream, containing 5% permethrin. Apart from mild postscabies dermatitis no side-effects were observed. The mean weight of cream used per patient was 25 g (range 21-32; mean content of permethrin 1250 mg). The degree of permethrin absorption was assessed indirectly by determination of conjugated and unconjugated cis- and trans-CVA (a metabolite of permethrin) excretion in urine using two dimensional gas chromatography mass spectrometry. It was found that during the first 48 hours the mean estimated absorption was 6 mg (range 3-11), which is approximately 0.5% of the total dose.

A three-year follow-up study of psoriasis patients treated with low dosages of etretinate orally and corticosteroids topically.

Etretinate 0.5 mg/kg body weight combined with 0.1% triamcinolone acetonide and 5% salicylic acid in an O/W cream gave more than 70% improvement in 62% of 75 patients. Of this satisfactorily improved group, at least 41% were still in the same condition after 3 years on a maintenance dose of, on average, 0.3 mg/kg body weight etretinate daily and 20 g weekly of a relatively strong corticosteroid cream. The side effects were acceptable and the convenience for the patients is great as compared with other treatment.

Combined treatment of psoriasis with a new aromatic retinoid (Tigason) in low dosage orally and triamcinolone acetonide cream topically: a double-blind trial.

In a multicentre double-blind trial the effect of three therapy regimens was studied for 6 weeks in ninety psoriasis patients: (1) aromatic retinoid (Ro 10-9359) orally (0.50-0.66 mg/kg body weight) and placebo cream topically; (2) aromatic retinoid (Ro 10-9359) (same dosage) with 0.1% triamcinolone acetonide and 5% salicylic acid in lanette wax cream; (3) placebo capsules with 0.1% triamcinolone acetonide and 5% salicylic acid in lanette wax cream. Regimen 1 had virtually no effect and regimen 2 gave better results than regimen 3 for almost all parameters, although statistical significance was reached for only some of them. The 6 week double-blind period was followed by an open study in which all patients were treated according to regimen 2. The clinical result could be maintained up to the end of the study (18 weeks), when more than 60% of the patients showed good to excellant (80-100%) improvement. Most of the side-effects of retinoid were mild and relatively rare. It is concluded that the combination of the aromatic retinoid (Ro 10-9359) given in low dosage orally with corticosteroids topically is as effective as therapy with the retinoid in high dosage alone, but with markedly less side-effects.

Is the use of Ro 10-9359 (Tigason) in children justified?

In 5 children ranging in age from 8 to 12 years, treatment with Ro 10-9359 for either psoriasis or erythrokeratodermia variabilis for periods of between 11 and 17 months did not cause marked growth retardation and gave excellent therapeutic results.

The differentiation of monocytes into macrophages, epithelioid cells, and multinucleated giant cells in subcutaneous granulomas. I. Fine structure.

The morphological changes occurring in monocytes during their differentiation into macrophages, epithelioid cells, Langhans-type giant cells, and foreign-body-type giant cells were investigated in foreign-body granulomas induced by subcutaneous implantation of pieces of Melinex plastic. Analysis based on Adams's (1974) criteria for discrimination between the several types of cell of the monocyte line, showed that each type has a characteristic type of granule. Primary and secondary granules, numerous in the Golgi area of monocytes were generally found close to the cell membrane and decreased in number in maturing macrophages. This was accompanied by an increase in the number of microtubules. Mature macrophages show numerous characteristic macrophage granules, which are round (average diameter: 280 nm) and have a halo between the limiting membrane and granular matrix. Mature epithelioid cells have characteristic epithelioid cell granules, and multinucleated giant cells a heterogenous population of granules. Fusing macrophages generally have their Golgi areas facing each other, and also show a reduced thickness of the cell coat. The morphology of the multinucleated giant cell is closely related to the number of nuclei present. In Langhans-type giant cells, which generally have two to ten nuclei, a giant centrosphere with numerous aggregated centrioles is found. In transition forms between Langhans-type and foreign-body-type giant cells, which generally contain 10--30 nuclei, the centrioles show less aggregation. In the foreign-body-type giant cells, which generally have more than 30 nuclei, centrioles are virtually absent and never aggregated. These differences between the Langhans-type giant cells, the foreign-body-type giant cells, and the transition forms, support our previous finding that Langhans-type giant cells are the precursors of foreign-body-type giant cells.