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We have investigated the formation of strand-breaks following UVC irradiation in lymphocytes from psoriasis patients with or without basal cell carcinoma (BCC). Isolated lymphocytes were irradiated with UVC light at a dose of 3.6 J/m 2 , and the level of DNA strand-breaks were measured 25 min after the irradiation by the alkaline comet assay. The generation of strand-breaks following UVC irradiation indicates DNA-repair-mediated incisions, as UVC light does not generate strand-breaks per se. We found that psoriasis patients with BCC had more DNA-repair incisions than non-cancer patients. The incision level correlated to two polymorphisms of the XPD gene. At present, it is not clear if the association is a primary effect that is related to differences of the XPD protein. Genes encoding for other repair proteins, namely XRCC1 , ERCC1 , and LIG1 are located close to the XPD gene, and it is possible that the association is due to a cosegregation with a polymorphism in one of these genes.

We have studied DNA repair in patients with psoriasis aiming at investigating the importance of repair in chemically induced cancer. An increased risk of non-melanoma skin cancer has been observed in psoriasis patients extensively treated with tar, methotrexate and photochemotherapy (psoralen + UVA). We measured the DNA repair capacity (DRC) by a host cell reactivation (HCR) assay in lymphocytes from psoriasis patients with and without basal cell cancer and non-psoriatic persons with and without basal cell cancer (4 x 20 study persons). Among psoriasis patients we observed a significant lower DRC in patients with skin cancer compared to patients without skin cancer (P = 0.015; Mann-Whitney, one-sided). Using the median of the healthy control group (group 4) as a cutoff value to divide the psoriasis patients into groups of high and low repair, we found that individuals who had a low repair capacity had a 6.4-fold increased skin cancer risk compared to individuals with high repair (95% confidence interval (CI), 1.44-28.5). The level of DNA repair was correlated with the age at which the psoriasis patients got their first skin cancer. The lower the level of DNA repair, the earlier the psoriasis patients had their first skin tumor (P = 0.070 Spearman; one-sided). Psoriasis patients without BCC had marginally higher repair than healthy controls (P = 0.11, Mann-Whitney, two-sided). We found no difference between BCC patients without psoriasis and healthy controls. In conclusion, these findings suggest a protective role of DNA repair in a predominantly chemically induced cancer.

Quadruples of skin cancer patients with and without psoriasis and referents with and without psoriasis (4×20 study persons) were identified and examined for DNA damage by single cell gel electrophoresis (comet-assay) and DNA-repair by UV-induced unscheduled DNA synthesis (UDS) in mononuclear blood cells (lymphocytes and monocytes). DNA damage (strand breaks and alkaline labile sites) as assessed by the comet assay and DNA repair as assessed by UDS were significantly associated with the season in which blood sampling took place. This variation might be explained by an increased exposure to solar radiation. When the comet tail moment data were stratified by sampling period, an interaction between psoriasis and skin cancer was detected, with patients with psoriasis and skin cancer exhibiting more DNA damage. Patients with psoriasis and skin cancer also had lower UDS compared to healthy study persons, suggesting that the more DNA damage may be caused by a lower rate of DNA repair. In all study persons, the extent of UDS correlated positively with the amount of DNA damage determined by the comet assay.

The European Academy of Dermatology and Venereology (EADV) prioritises the provision of high quality continuing medical education (CME) to its members. The European Union of Medical Specialists (UEMS) is currently establishing European Boards of the individual medical specialities to monitor and ensure high professional standards of European medical specialists and harmonisation among member nations. Within the next few years, national and supra-national authorities in Europe are expected to request documentation of participation in continuing medical education from physicians in order to maintain their full specialist competence, analogous to the conditions now pertaining in the US. In Belgium, participation in CME is mandatory for standard appointments with the health insurance. The EADV has developed procedures for quality assurance of the CME activities for the 3rd EADV congress in Copenhagen 1993, and the Skin Therapy Update Symposium in Crete 1994, using participant evaluation of the scientific programme. Following these meetings the EADV has issued individual certificates to the participants, documenting their CME activities. The results of the programme evaluation indicate a high standard of CME at the above meetings. The EADV wishes to develop as a competent sponsor of CME activities, to offer extensive membership service in this field, and to administer recognition of EADV-CME accreditation to other bodies.

Non-melanoma skin cancer is historically known to be associated with certain professions. Reporting is mandatory in Denmark when occupational exposure is suspected. In a retrospective register-based study of all cases of suspected occupational non-melanoma skin cancer reported to the Directorate of National Labour Inspection and the National Board of Industrial Injuries in Denmark in the period January 1, 1984 to December 31, 1994, we assessed the extent to which occupational exposures today are of importance in the occurrence of non-melanoma skin cancer. A total of 74 individuals (11 women and 63 men) aged 32-82 years (median 58 years) had been reported. Of these, 15 cases (20%) were approved as being occupational, 37 (50%) were rejected and 22 (30%) were either shelved or could not be further clarified. Most commonly approved were exposures such as asphalt, tar, and the like, and ionizing radiation, and localization on the arms or multiple tumours. Unexpected occupational exposure could not be identified but continued reporting is recommended in order to follow this in the future.

Background: There is strong epidemiologic evidence that psoriasis treatments may cause nonmelanoma skin cancer and possibly other types of cancer. Objective: This study from Denmark reports the cancer incidence in 6910 patients with psoriasis discharged from the hospital from 1977 through 1987. Methods: Patients were identified in the National Hospital Discharge Register and information on cases of cancer was obtained through the files of the Danish Cancer Registry; observed figures were compared with those expected on the basis of cancer incidence rates for the national population. Results: A 2.5-fold increased risk was observed for nonmelanoma skin cancer in men and women, with no preponderance of any specific histologic subtype of cancer. In addition, excesses were seen of lung cancer in men (relative risk [RR] = 1.4) and women (RR = 1.6), of cancer of the larynx and pharynx in men (RR = 2.8 and 3.9), and of colon and kidney cancer in women (RR =1.6 and 2.3). Conclusion: The effect of cigarette smoking on the risk for noncutaneous cancer could not be assessed in this study; however, antipsoriatic treatment such as ionizing radiation and oral arsenicals must be considered as a possible cause of colon cancer, which has been observed in excess in two other studies of psoriatic patients.

We have previously shown that high DNA repair capacity protects psoriasis patients against chemically induced basal cell carcinoma [Dybdahl et al. Mutat. Res. 433 (1999) 15-22]. We have used the same study persons to investigate the correlation between expression of eight genes involved in nucleotide excision repair and DNA repair capacity. mRNA levels of XPA, XPB, XPC, XPD, XPF, XPG, CSB and ERCC1 in primary lymphocytes from 33 individuals were quantified by dot-blots and normalized to beta-actin. ERCC1 and XPD mRNA quantities were highly correlated (r=0.89; P

Denmark has a well-established nation-wide registration system for cancer incidence and mortality. In 1984, 2984 new cases of non-melanoma skin cancer were notified to the Danish Cancer Registry and 40 deaths were attributed to this cause. An evaluation and validation of the death certificates indicate that the true number of deaths caused by non-melanoma skin cancer was 18. Basal cell and squamous cell carcinoma accounted for three and 15 of the deaths, respectively. The estimated lethality is 4.3% for squamous cell carcinoma and 0.12% for basal cell carcinoma.

This paper focuses on photocarcinogenesis and non-melanoma skin cancer in man and discusses facts and theories on the role of the immune system for this process. Since photocarcinogenesis in man is closely connected with sun-exposure no details on the role of the specific wavelengths of UV radiation will be discussed.

Two groups of patients with subtotal to universal areate type alopecia were serially treated, 6 with intralesional triamcinolone acetonide suspension and 6 with contact irradiation by ultraviolet light from a high-pressure mercury-arc source with a quartz envelope (Kromayer lamp®). The treatment was limited to one half of the scalp while the untreated half served as a control. Triamcinolone acetonide suspension gave in 2 of the 6 treated patients a temporary stimulating effect on hair growth; later, however, hair growth inhibition was noted in 3 patients. Contact irradiation with ultraviolet light from a Kromayer lamp gave in 4 of the 6 treated patients a stimulatory effect upon hair growth, but did not seem to initiate it.

Summary Flow cytometrical measurements of individual nuclear DNA content in single nuclei suspensions prepared from normal skin of twenty leg ulcer patients aged 36–87 were used to study the variability in the fractions of cells with 2–4c DNA-content (S-fraction) and 40 DNA-content (G2+ M-fraction). No significant changes were found in these cell kinetic parameters in tower abdominal skin, as assessed by age and sex. However, the females, all being postmenopausal, exhibited wider variability in values than males, particularly in the G2+ M fraction. Significant regional differences were found in the S-fraction, with higher values for the extensor surface of the forearm than for the thigh and lower abdominal skin.

Summary We used DNA flow cytometry to determine whether the uninvolved skin of twenty-four patients with multiple epidermal cancers differed from normal skin with regard to its epidermal cell kinetics. We also studied the relationship between the cell kinetics and the type of cancer, previous exposure to ionizing or UV radiation, previous arsenic intake, skin type and coexisting psoriasis. Both exposed and unexposed skin was studied. In thirteen patients the S and G2M fractions of a monoclonal tumour were compared with the values in unexposed and exposed skin. The S and G2M fractions increased progressively from unexposed skin to exposed skin to tumor tissue. Patients who had developed both squamous and basal cell carcinoma differed from those who had developed only basal cell carcinoma by having a significantly higher G2M fractions in the exposed skin, and significantly higher S and G2M fractions in the unexposed skin. Patients exposed to ionizing radiation tended to show higher G2M fractions in exposed skin compared with the remaining individuals (P=0·06). The presence of psoriasis, exposure to UVR or sunlight and previous arsenic ingestion did not appear to affect the results.

Biopsies of involved and uninvolved skin from psoriatic patients and of normal skin were stained immunocytochemically with monoclonal antibodies against urokinase-type (u-PA) and tissue-type (t-PA) plasminogen activator using a multilayer peroxidase technique. Epidermis from psoriatic lesions showed focal staining for u-PA in and between the basal keratinocytes in the suprapapillary epidermal areas, while t-PA was found in the superficial keratinizing cells, including both stratum spinosum and the parakeratotic layer. No staining of keratinocytes was observed in uninvolved and normal skin. The specificity of the staining was supported by the finding that 3 different monoclonal antibodies and polyclonal antibodies against each of the plasminogen activators gave identical staining, while monoclonal antibodies of irrelevant specificity gave no staining. The present findings suggest abnormalities in the regulation of both types of plasminogen activators in psoriatic epidermis.

A basal cell carcinoma, a Bowenoid carcinoma and clinically normal nonexposed skin from a 76-yr-old male with numerous epidermal tumors on sun-damaged skin were investigated by DNA flow cytometry and the results were compared with data obtained from normal skin of a control group. From each type of skin lesion 3 different biopsies were examined. Each of the DNA frequency distribution histograrns showed bimodal configuration revealing no more than one DNA stem line, which was diploid in the unaffected skin and the Bowen carcinoma and hyperdiploid in the basal cell carcinoma. The 3 different types of skin could be clearly separated by means of at least 1 of 3 parameters: S-fraction, G 2 + M fraction or S/G 2 + M index. The S/G 2 + M index came out as the most sensitive discriminator for the tumors. The S-fraction level was higher in the clinically normal skin of the investigated male than in the control group and further high in the tumors.

A method for single cell DNA measurements by flow cytometry based on a technique successfully used for the hamster cheek pouch epithelium was extended for studies on human epidermis. A least squares estimation procedure was used for the statistical analysis of the initially obtained DNA frequency distribution. In 14 specimens of abdominal skin from a young healthy female the precentages of epidermal cells with an S-phase DNA content were 3.0 +/- 0.6 (SD), and the percentages of epidermal cells with a G2+M phase DNA content 1.1 +/- 0.1 (SD). No significant differences in values were found for specimens investigated in different experiments. No influence of tissue storage time for a maximum of 32 days in liquid nitrogen was discernible. Values from the corresponding dermal tissue were significantly more variable then the epidermal values, but the levels were of the same magnitude. It is concluded that this technique used for human epidermis yields sufficient stable and accurate estimates of S and G2+M fractions that it should be a valuable tool useful as an alternative or a supplement to conventional cell kinetic methods.

SUMMARY The effect of serial biopsy sampling on S- and G2+M-fractions in lower abdominal skin from leg ulcer patients was studied by single-nuclei DNA flow cytometry. Significant differences in both measurements were found in four biopsies taken at equal intervals within 24 h, but not in four biopsies taken at noon on four consecutive days. The variation in S-fractions was closely related to the injury from previous biopsy sampling(s) while the G2+M-fraction variation tended to follow the time of the day. The study indicated local as well as systemic effects from previous biopsy sampling.

Direct and indirect immunofluorescence investigations performed for 11 patients with scabies. All patients had punch biopsies taken from (1) a lesion containing Sarcoptes scabiei, (2) an inflammatory papule which did not contain a mite, and (3) normal skin. In four patients IgE deposits were found in the vessel walls of the upper dermis both in biopsies containing mits and biopsies of inflammatory papules with no mites. No IgE deposits were found in biopsies of normal skin from the same patients. Two patients had IgM and/or C3 deposits along the basal membrane in biopsies containing mites and one of them also had C3 in this area in the biopsy from a papule with no mite, as well as normal skin.

SUMMARY Two cases of eosinophilic pustular dermatosis are reported and both were associated with infection by human immunodeficiency virus (HIV-1). We suggest that eosinophilic pustular dermatosis may occur as an early sign of infection with HIV.

Tumour ploidy and proliferative characteristics can be estimated by flow cytometric measurements of the nuclear DNA content. This study considers the question whether human epidermal tumours are intrinsically homogeneous with regard to these properties, i.e. whether a single biopsy analysed by flow cytometry is representative of the entire tumour. Analyses of multiple biopsies from ten human epidermal tumours--two kerato-acanthomas (KA), two basal cell carcinomas (BCC), two basosquamous carcinomas (BSC), one Bowen's disease (BO) and three squamous cell carcinomas (SCC)--indicated that both ploidy and proliferation characteristics were reproducible and specific for the peripheries of the different tumours regardless of the histopathologic diagnosis. The tumour centres, however, may deviate considerably from the corresponding periphery. None of the ten tumour peripheries contained more than one cell clone, but six of the ten clones were aneuploid. Both the BO and the KA's were hypodiploid, while one SCC, one BSC and one BCC were hyperdiploid as assessed in their peripheries. The remaining BSC was diploid in its periphery, while both a hypodiploid and a hypotetraploid cell clone were found in the corresponding centre.

The distribution of peripheral lymphocyte subsets was studied in fifteen patients with multiple nonmelanoma skin cancers, selected according to history of ultraviolet (UV) or X-ray exposure. The skin cancer was associated with previous heavy exposure to UV light in seven patients, and past exposure to x-rays in eight patients. In the UV group, the helper T-lymphocytes/suppressor T-lymphocytes (Th/Ts) ratio was abnormally low (P less than 0.01) compared with the ratios of the x-ray and control groups. The low Th/Ts ratio was associated with an absolute increase in the number of Ts. This suggests that heavy sun exposure may cause a permanent increase in the number of Ts in certain persons. These extra T-lymphocytes may in turn prevent immune rejection of transformed keratinocytes.

The lymphocyte response to u.v. radiation (254 nm) was investigated by two different methods in 29 unselected patients with multiple epidermal cancer. The u.v.-induced DNA synthesis was determined as the increase in incorporation of [3H]thymidine in irradiated cells compared with nonirradiated cells after incubation for 2 h. The u.v. tolerance was measured as the u.v. dose necessary for 50% reduction in phytohemagglutinin-stimulated lymphocyte proliferation. Patients with both squamous cell differentiated tumors and basal cell carcinomas had very high u.v.-induced DNA synthesis values (p less than 0.01, when compared with patients with basal cell carcinoma only and p less than 0.005, when compared with controls). The u.v. tolerance in patient lymphocytes was considerably lower than in control lymphocytes (p less than 0.001), with the lowest values occurring in patients with clinical sun intolerance (p = 0.05, when compared with the remaining patients). These investigations may be of predictive value in skin carcinogenesis.

A new method is described for flow cytometric cell cycle analysis of normal and psoriatic human epidermis, based on non-enzymatic tissue disaggregation. The epidermis was isolated by treatment with acetic acid and stored by freezing. After thawing, the epidermis was disintegrated into a nuclear suspension by 3 steps: incubation with dithiotreitol, whirling in a buffer (pH 7.4) with the non-ionic detergent Nonidet P40, EGTA, RNase and spermine, and whirling after addition of citric acid to a final concentration of 1% (pH 2.4). The suspension was stained with propidium iodide and filtered before flow cytometry. The yield of suspended nuclei was approximately 70% of the original number of cells in the tissue. The detergent/citric acid method was found to be preferable to an ultrasonication method previously used on human epidermis. All cell cycle and cell maturation stages were represented in the detergent/citric acid suspension, in contrast to the selection of immature G1, S and G2 stages with enzymatic methods. In the analysis of psoriatic epidermis inadequately matured (parakeratotic) cells were present in the suspension and had to be discriminated by gating on light scattering intensity, as they were not susceptible to lysis and did not stain properly. The fraction of S phase nuclei was on average 1.9% in normal and 7.7% in psoriatic epidermis, thus confirming the results of other investigators using enzymes. The presence of mitotic figures in the suspension was demonstrated by flow sorting. In this way the mitotic fraction was estimated to 0.06% in normal and 0.22% in psoriatic epidermis, confirming histological data of other investigators.

In 28 patients, nonmelanoma skin cancers developed in areas previously exposed to grenz rays. In 17 patients who did not have psoriasis, no other relevant carcinogenic exposure could be incriminated. Women were more often affected than men. Most of the tumors were basal cell cancers, and most of the patients had multiple tumors. No threshold dose could be established. The distribution of the latency time among patients without psoriasis was strictly normal (median 18 years). These observations suggest that usual therapeutic doses of grenz rays, as a single agent, are capable of causing skin cancer, but only in those persons who are abnormally sensitive to x-rays.

SUMMARY DNA frequency distributions analysed by single nuclei flow cytometry were studied in sixty-five curetted human epidermal tumours, i.e. five actinic keratoses (AK), seven Bowen's diseases (BO), nine squamous cell carcinomas (SCC), forty-three basal cell carcinomas (BCC) and one baso-squamous carcinoma (BSC). Seventy-five per cent (16/21) of the samples with squamous cell differentiation (AK, BO and SCC) showed features suggestive of more than one stem cell population, against 24% of the pure BCC samples (11/43). The DNA indices for the tumours, i.e. the ratio between the DNA content of the tumour stem cell line G1 cells and normal epidermis G, cells were calculated. For BCC and SCC a preponderance was found for near-diploid and near-tetraploid cell clones. The precancerous lesions contained clones with more broadly scattered DNA indices. The fractions of cells in S and G2M and S + G2M phases were calculated for the samples with only one detectable stem cell population. For the squamous cell tumours and the nodular (but not the superficial) BCC, these fractions were significantly different from the unaffected skin of patients with multiple epidermal cancers. The usefulness of cell cycle fraction determinations for curetted tumours is discussed.

Demographic studies in patients with skin cancer have demonstrated the importance of exposure to ultraviolet and x-ray irradiation. This paper describes in vitro studies in peripheral lymphocytes from three patients with the nevoid basal cell carcinoma syndrome. Particular stress was placed on the following factors: (1) the distribution of the lymphocyte subsets, (2) the frequency of spontaneous sister chromatid exchange, (3) the effect of ultraviolet C (UVC) (254 nm) on deoxyribonucleic acid (DNA) synthesis, (4) the effect of UVC on the phytohemagglutinin-stimulated lymphocyte proliferation, and (5) the capacity to repair x-ray-induced DNA damage. Our data indicate that the distribution of the peripheral lymphocytes was normal, while the frequency of spontaneous sister chromatid exchange was high. The capacity of the lymphocytes to repair x-ray-induced DNA damage was low in all three patients. In two patients the UVC-induced DNA synthesis was reduced, while an increased UVC-induced inhibition of lymphocyte proliferation was observed. These cellular responses in vitro to ultraviolet and x-ray irradiation correspond to the clinical features of the nevoid basal cell carcinoma syndrome. A clearly defective in vitro cellular response to x-ray irradiation, reflecting the clinically evident x-ray sensitivity in the nevoid basal cell carcinoma syndrome, has not been reported previously.

Several studies have investigated medical intervention in common aspects of lifestyle, and the subject has been discussed from a legal, ethical, and practical point of view.1 Fluoridation of water supplies, legal enforcement of safety measures such as compulsory wearing of seat belts or helmets, and restriction of unhealthy habits such as drinking alcohol or smoking are typical examples of paternalistic programmes—actions that aim to prevent harm or promote the good of others, irrespective of the individual's own wishes. 2 3 What is the position, however, when a doctor's action is neither solicited nor part of his or her contractual duties? In such a situation—which we define as unsolicited medical intervention—the doctor can only speculate about whether his or her action will be welcomed and hence understood as an act of beneficence or whether it will be regarded as an unjustified paternalistic intrusion into privacy.4 According to the 1949international code of medical ethics of the World Medical Association5 and to legislation in many different countries, doctors are obliged to offer first aid in an emergency. However, apart from this relatively clear situation, dilemmas in relation to unsolicited medical intervention have rarely been discussed. The European Code of Medical Ethics, issued in Paris in January 1987by representatives of the medical associations of the European Community, emphasises the principle that “doctors can only use professional knowledge to improve and maintain the health of those who put themselves in their care.”5 We aimed to assess the attitudes of doctors and the expectations of the lay public to unsolicited medical intervention by asking them to consider the ethics of unsolicited medical intervention in three scenarios. We believed that a comparison of the responses of doctors, subgroups of doctors, and lay people would help us to identify gaps between expectations and reality. …

MUNCH-PETERSEN, B., AND FRENTZ, G. X-Ray and UV-Radiation Sensitivity of Circulating Lymphocytes in Multiple Epidermal Cancer in Relation to Previous Radiation Exposure. Radiat. Res. 103, 432-440 (1985). The cellular sensitivity to X rays (200 kV, 16 mA) and UV radiation (254 nm) was examined in lymphocytes from three groups of patients with multiple epidermal malignant tumors, selected by their clinical history of carcinogenesis. Eight patients previously exposed to low energy ionizing radiation (