Trends in incidence and predictions of cutaneous melanoma across Europe up to 2015.

BACKGROUND: Melanoma is a significant health problem in Caucasian populations. The most recently available data from cancer registries often have a delay of several months up to a few years and they are generally not easily accessible. OBJECTIVES: To assess recent age- and sex-specific trends in melanoma incidence and make predictions for 2010 and 2015. METHODS: A retrospective registry-based analysis was performed with data from 29 European cancer registries. Most of them had data available from 1990 up to 2006/7. World-standardized incidence rates (WSR) and the estimated annual percentage change (EAPC) were computed. Predictions were based on linear projection models. RESULTS: Overall the incidence of melanoma is rapidly rising and will continue to do so. The incidence among women in Europe was generally higher than in men. The highest incidence rates were seen for Northern and north-western countries like the UK, Ireland and the Netherlands. The lowest incidence rates were observed in Portugal and Spain. The incidence overall remained stable in Norway, where, amongst young (25-49 years) Norwegian males rates significantly decreased (EAPC -2.8, 95% CI -3.6; -2.0). Despite a low melanoma incidence among persons above the age of 70, this age group experienced the greatest increase in risk during the study period. CONCLUSIONS: Incidence rates of melanoma are expected to continue rising. These trends are worrying in terms of disease burden, particularly in eastern European countries.

Basal cell carcinomas without histological confirmation and their treatment: an audit in four European regions.

BACKGROUND: Limited data are available on how often basal cell carcinomas (BCCs) are clinically diagnosed without histological confirmation and how they are treated. OBJECTIVES: Within the framework of the EPIDERM project, an audit was conducted in four European countries to study the occurrence of clinically diagnosed BCCs without histological confirmation and to investigate how these are treated. METHODS: In the Netherlands, Scotland, Finland and Malta studies were performed within different timeframes. Patients with one or more BCC(s) were selected and the number of clinically diagnosed BCCs without histological confirmation and their treatment was investigated by (manually) reviewing the (electronic) patient records and checking the (hospital) pathology databases to find evidence of histological confirmation. RESULTS: In the Netherlands, 1089 patients with a first histologically confirmed BCC developed 1974 BCCs of which 1833 (92·9%) were histologically confirmed and 141 (7·1%) were not. A 4-month retrospective study conducted in Scotland selected 294 patients with 344 BCCs; 306 (89·0%) were histologically confirmed and 38 (11·0%) were not. A 3-month prospective study performed at the same centre in Scotland identified 44 patients who developed 58 BCCs; 44 (75·9%) of these were histologically confirmed and 14 (24·1%) were not. In Finland, there were 701 patients who developed 977 BCCs, of which 807 (82·6%) were histologically and 170 (17·4%) nonhistologically confirmed. In Malta, there were 420 patients with 477 BCCs. Only three (0·7%) of them were clinically diagnosed without histological confirmation. In the Netherlands and Finland, clinically diagnosed BCCs without histological confirmation were most often treated with cryotherapy, whereas in Scotland 5% imiquimod cream was the preferred treatment modality. CONCLUSIONS: Although the frequency of clinically diagnosed BCCs without histological confirmation differed between the four European regions (range 0·7-24·1%), this confirms that the burden of BCC in Europe is underestimated when based on data from pathology and/or cancer registries.

Known and potential new risk factors for skin cancer in European populations: a multicentre case-control study.

BACKGROUND: During recent years numerous studies have suggested that personal and environmental factors might influence cancer development. OBJECTIVES: To investigate environmental and personal characteristics associated with skin cancer risk. METHODS: A multicentre hospital-based case-control study was performed in Finland, Germany, Greece, Italy, Malta, Poland, Scotland and Spain, including 409 patients with squamous cell carcinoma (SCC), 602 with basal cell carcinoma (BCC) and 360 with cutaneous malignant melanoma (CMM) and 1550 control persons. Exposures were assessed by questionnaires that were partly self-administered, partly completed by dermatologists. Unconditional logistic regression modelling was used to assess associations including the influence of certain drugs and food items on skin cancer risk. RESULTS: The usual associations were observed for sun exposure and pigmentation characteristics, with chronic sun exposure being most strongly associated with SCC risk, and naevi and atypical naevi with CMM risk. Use of ciprofloxacin was associated with a decreased risk of BCC [odds ratio (OR) 0·33] and use of thiazide diuretics was associated with an increased risk of SCC (OR 1·66). Ciprofloxacin was also associated with SCC (OR 0·34) and thiazines with BCC (OR 2·04), but these associations lost significance after correction for multiple testing. Consumption of pomegranate, rich in antioxidants, was associated with decreased BCC and SCC risk, also after correcting for multiple testing. Recent experience of stressful events was associated with increased risk, particularly of CMM. CONCLUSIONS: In this large case-control study from across Europe the expected associations were observed for known risk factors. Some new potential protective factors and potential risk factors were identified for consumption of certain food items, medication use and stress, which deserve further investigation in future studies.

Risk factors for actinic keratosis in eight European centres: a case-control study.

BACKGROUND: There are limited data regarding the association of actinic keratosis (AK) and other types of nonmelanoma skin cancer (NMSC); studies investigating possible correlation of AK with melanocytic naevi are even scarcer. To our knowledge, there are no data examining the risk of AK in people using specific medications. OBJECTIVE: To investigate constitutional and exposure risk factors leading to AK and the coexistence of AK with NMSC and melanoma. METHODS: A multicentre hospital-based case-control study was performed in Finland, Germany, Greece, Italy, Malta, Poland, Scotland and Spain, including 343 patients with actinic keratosis (AK), 409 with squamous cell carcinoma (SCC), 602 with basal cell carcinoma (BCC), 360 with invasive melanoma and 119 with in situ melanoma, and 686 control subjects. Exposures were assessed by questionnaires that were partly self-administered and partly filled out by dermatologists. Unconditional logistic regression modelling was used to assess associations including the influence of phenotypic characteristics, presence of naevi, sun-exposure habits and certain drugs on AK risk. RESULTS: Differences in hair and eye coloration variably influenced the risk for AK, with red hair signifying a seven times higher risk [odds ratio (OR) 6·9, 95% confidence interval (CI) 4·34-11·00), and brown - compared with blue - eyes, about a 40% reduced risk (OR 0·61, 95% CI 0·13-0·92). The darker the skin phototype, the lower the risk for AK, with phototype IV exhibiting nine times less risk of developing AK. Some and many freckles on the arms were associated with an OR of 1·8 (95% CI 1·08-2·81) and 3·0 (95% CI 1·10-3·54), respectively, while overall number of naevi and high educational level were inversely associated with AK. Sun exposure, thiazide diuretics and cardiac drugs had a higher risk for AK. SCC was the most frequent (58%) skin neoplasm coexisting with AKs, followed by BCC (30%), melanoma in situ (12%) and invasive melanoma (6%). CONCLUSION: In this large case-control study from across Europe the expected associations were confirmed for known risk factors. Some possible new risk factors, including cardiac and diuretic drugs, were identified, creating a new field for further investigation in future studies.

Mutation screening of the muscarinic M(2) and M(3) receptor genes in normal and asthmatic subjects.

1. Muscarinic receptors are important in the development of airway hyperresponsiveness, and dysfunction of these receptors has been suggested to be present in asthma. 2. The human muscarinic M(2) and M(3) receptor genes were screened for polymorphic variation using single-stranded conformation polymorphism (SSCP) analysis, complemented by direct fluorescent sequencing. Forty-six random DNA samples and 46 respiratory physician diagnosed asthmatic samples were used as a template for analysis. 3. Within the muscarinic M(2) receptor gene, we identified two degenerate single base substitutions (1197T-->C, Thr-->Thr and 976A-->C, Arg-->Arg) in one random and one asthmatic sample respectively. Analysis of the 3' UTR region revealed an additional 'A' at bp 1793 (c.f. ATG). This was present in all of 49 samples analysed by sequencing or BsmI digest, suggesting that the published sequence (GenBank Accession NO: M16404) is incorrect. A common 3' UTR polymorphism (T-->A) was found at bp 1696 (c.f. ATG) (allelic frequency=65%, n=60), but this does not alter transcription factor recognition sites. 4. We were unable to identify any polymorphic variation within the muscarinic M(3) coding region or the flanking regions investigated, using the methods described. 5. The coding regions for the human muscarinic M(2) and M(3) receptor genes are both highly conserved. These data suggest that polymorphic variation within these coding sequences is unlikely to account for inter-individual variability in response to methacholine or anticholinergic therapy. The potential functional significance of the muscarinic M(2) receptor 3' UTR polymorphism (bp 1696) remains to be determined.

Interferon gamma induction in human melanoma cell/allogeneic leukocyte co-cultures is enhanced by interleukin 18 but drug resistant melanoma cells are poorer inducers of IFN-gamma.

Human melanoma Colo 679 cells were made resistant to doxorubicin (adriamycin, ADM) by continuous exposure to ascending concentrations of the drug and Colo/ADM80; a variant which grew continuously in the presence of 80 ng/ml of ADM was thus established. Human peripheral blood mononuclear cells (PBMC) produced interferon gamma (IFN-gamma) when cultured with mitomycin C (MMC)-treated parental Colo 679 cells. The synthesis of IFN-gamma was synergistically enhanced by adding interleukin-18 (IL-18) and this was IL-12-dependent because a neutralizing antibody against IL-12 almost completely inhibited IFN-gamma production while control antibodies (Abs) were inactive. The cellular sources of IFN-gamma were found to be B cells, CD8+ T cells and CD4+ T cells as revealed by flow cytometry after double staining for surface antigens and staining for intracellular IFN-gamma. Interestingly, the resistant cell line induced much less IFN-gamma production than the parental cell line under the same co-culture conditions; however, IL-18 could still enhance the production of IFN-gamma. In conclusion, our study shows that acquired resistance to anti-cancer agents can also reduce immune responses to cancer cells. However, the immunostimulatory cytokine IL-18 could still enhance IFN-gamma production in drug resistant tumor cell-PBMC cultures indicating that such immunostimulatory agents could still be beneficial in immunotherapy for patients with recurrent drug resistant tumors.

The age and symptomatology of natural menopause among United Arab Emirates women.

OBJECTIVES: To determine the median age of natural menopause in United Arab Emirates women, the factors affecting that age and the prevalence of climacteric symptoms amongst those women. METHODS: A population-based survey was conducted on a community sample of United Arab Emirates women who had had natural menopause defined as cessation of menstruation for at least 6 months at the end of reproductive years. A total of 742 women aged 40 years and above were recruited from both urban and rural areas of the country using the multi-stage stratified cluster sampling technique. Data were collected using a structured questionnaire and face to face interviews and included a number of familial, reproductive and life-style variables. RESULTS: The median age of the menopause in the United Arab Emirates is 48 years (mean = 47.3 +/- 3.29, range 40-59). This is significantly lower than the median age reported from the West (50.3 years). The subject median age of the menopause was significantly related to that of the mother (P < 0.001), older sister (P < 0.001), parity (P < 0.0001) and the previous use of oral contraceptive pills for more than 1 year (P < 0.001). Hot flushes were the commonest feature of the menopause occurring in 45% of women. CONCLUSION: The age of natural menopause in United Arab Emirates women, as in other developing countries, is less than in Western women and may be influenced by genetic factors, parity and previous use of oral contraceptives. Climacteric symptomatology, however, is similar in the different patient groups.

PIP: A population-based survey of 742 United Arab Emirates women aged 40 years and over who had attained natural menopause (amenorrhea of at least 6 months' duration) investigated age at onset and the prevalence of climacteric symptoms. Women from both urban and rural areas of Al-Ain City and Abu Dhabi, Dubai, and Sharjah Emirates were recruited through use of the multi-stage stratified cluster sampling technique. The median age at menopause in this sample was 48 years (mean, 47.3 +or- 3.29 years; range, 40-59 years)--significantly lower than the 50.3 year mean recorded among Western women. Median age at menopause was significantly associated with that of the mother (p 0.001) and older sister (p 0.001), parity (p 0.0001), and a history of use of oral contraceptives for more than 1 year (p 0.001). 394 women (53%) reported at least one climacteric symptom. Most common were hot flushes, reported by 47% of women. 145 women (19.5%) were currently taking hormone replacement therapy. The relatively low age at menopause in this population could reflect additional social, economic, environmental, or genetic factors that were not explored in this study.

Consanguinity and the age of menopause in the United Arab Emirates.

OBJECTIVE: The study examined the association between some biosocial factors, consanguinity and age at natural menopause in the United Arab Emirates (UAE). METHOD: A cross-sectional population-based study using a multi-stage sampling design and face-to-face interview. RESULTS: In a sample of 800 UAE females aged 40 years and above, there were 742 (85.8%) respondents. The median age of natural menopause was 48 years. The bodyweight, parity number, occupation, smoking habits and consanguinity in marriage were the significant variables associated with the age at natural menopause. There were statistically significant differences between women in consanguineous and non-consanguineous marriages with regard to BMI (P < 0.002), occupation (P < 0.008), weight (P < 0.0001), age (P < 0.03), age of menopause (P < 0.005), parity (P < 0.0001), mother's age at menopause (P < 0.007) and sister's age at menopause (P < 0.002). CONCLUSION: The study showed that among UAE women, consanguinity of marriage, maternal and sister's age at menopause, BMI, parity number and smoking habits significantly influence the natural age of menopause.

Effect of oral sodium cromoglycate and ketotifen in fish-induced bronchial asthma.

The effects of sodium cromoglycate and ketotifen were studied in a group of 20 patients in whom fish repeatedly provoked an attack of wheezing and dyspnoea within one hour of its being eaten. Fish ingestion resulted in a fall in forced expiratory volume in one second (FEV1) of at least 15%. All patients had a weal greater than 4 mm in response to fish antigen in the skinprick test and most had blood eosinophilia and raised serum IgE levels. Administration of drugs and placebos was carried out under double-blind conditions, in a randomised fashion, on different days. Cromoglycate blocked the fall in FEV1 either completely or significantly in 16 patients. Ketotifen did not appear to have any significant effect in the group as a whole.

The acute effects of corticosteroids in bronchial asthma.

Corticosteroids have now been used in the treatment of bronchial asthma for about 30 years but objective physiological evidence of their effects in this condition has only become available over the past 8 years. Studies with oral prednisolone, intravenous prednisolone and hydrocortisone, as well as with inhaled budesonide, in patients with chronic bronchial asthma, have shown that there is a time lag between the administration of these drugs and the onset of improvement in the patients' conditions. This time lag is even longer when corticosteroids are given to patients with severe asthma. It appears that these drugs exert an effect on both the central and the peripheral airways. Unlike bronchodilators corticosteroids do not appear to increase the degree of ventilation perfusion mismatching present in asthma. They have been shown to decrease the alveolar-arterial oxygen tension gradient and the venous admixture effect with a consequent rise in arterial oxygen tension. It is still uncertain how corticosteroids work in asthma; it seems, however, that one of the ways may be through their effects on the beta adrenergic receptors.

Effect of terbutaline sulphate in chronic "allergic" cough.

The effects of terbutaline sulphate were studied in 30 patients who presented with chronic cough at an allergy clinic. After a three week baseline period terbutaline and its placebo were given for two periods of three weeks each in a randomised, double blind, crossover manner. Patients kept a daily record of day and night cough scores and peak expiratory flow readings. Twenty one patients responded to terbutaline; placebo produced no significant effect. Both day and night cough scores (p less than 0.001) and peak expiratory flow rates were significantly improved (p less than 0.05) by the end of the first week of treatment with terbutaline. This improvement was achieved with only a fairly small change in airway calibre.

The spectrum of bronchial asthma in Kuwait.

Kuwait, situated in the north-west corner of the Arabian Gulf, has an arid climate with very hot dry summers and mild winters. Sandstorms are a regular climatic feature, occurring most frequently in summer. Before the mid-1950s allergy was not considered to be a problem. Since then it has become a major cause of morbidity; 18% of the population are reported to suffer from its manifestations. Over the past 3 years 1000 asthmatic patients attending a central clinic have been carefully studied. The present paper analyses various aspects of the asthmatic condition in this desert country.

Selenium, glutathione peroxidase and superoxide dismutase in maltese asthmatic patients: effect of glucocorticoid administration.

Oxidative processes, mediated by free radical chemistry, are recognized to contribute significantly to the inflammatory pathology of bronchial asthma. This study analysed the degree of defence against reactive oxygen species in Maltese, asthmatic patients and in normal individuals, by measuring plasma selenium concentration, erythrocyte glutathione peroxidase (GSH-Px) activity and erythrocyte superoxide dismutase (SOD) activity, in order to determine their antioxidant status. The effect of glucocorticoids on the status of these antioxidants in patients was also investigated. The measurement of antioxidant status was carried out both in mild (n = 22) and severe (n = 37) asthmatics, as well as in healthy controls (n = 49). The same antioxidant profile was then investigated in a group of 16 severe asthmatics following treatment for 4 weeks with inhaled beclomethasone dipropionate (750 micrograms twice daily), and in a second group of 16 patients suffering from severe asthma, following 2-weeks treatment with oral prednisolone (15 mg daily during the first week and 10 mg daily during the second). No statistically significant difference was found in the plasma selenium concentrations and erythrocyte glutathione peroxidase activities between patients and controls. Both mild and severe asthmatics, however, exhibited a statistically significant lower erythrocyte superoxide dismutase activity than normal subjects (mild asthmatics: 62.9 (2.9) SOD 525 U/ml, severe asthmatics: 60.6 (1.9) SOD 525 U/ml, normal: 68.5 (1.1) SOD 525 U/ml, P < 0.01). Inhaled beclomethasone dipropionate exerted no effect on this antioxidant profile, while prednisolone caused a significant increase in plasma selenium concentration over pretreatment values (pretreatment: 118.3 (4.4) ng/ml, post-treatment: 138.1 (4.6 ng/ml, P < 0.01). It is thus suggested that asthmatic patients in Malta might be more susceptible to superoxide-induced damage than normal individuals. The reason for the prednisolone-induced augmentation of plasma selenium could not be determined from this study. It is postulated that the drug may decrease the excretion rate of the element, and may thus exert a positive antioxidant effect in individuals of established low selenium status.

Effect of intravenous prednisolone in asthmatics with diminished adrenergic responsiveness.

The beta effects of adrenergic stimulation are often diminished in asthmatics in whom the condition is active. Corticosteroids are thought to lower the threshold of beta-adrenergic receptors to the response of catecholamines. A single intravenous injection of 40 mg prednisolone appeared to restore responsiveness to inhaled isoprenaline in eight out of ten chronic asthmatics who were previously non-responsive to catecholamines.

Acute dose-response studies in bronchial asthma with a new corticosteroid, budesonide.

1 Budesonide is an epimeric mixture of a new synthetic non-halogenated glucocorticoid (16 alpha, 17 alpha,-(22R,S)-prophylmethylenedioxypregna-1,4-diene-11/3,21-diol-3, 20-dione). 2 Acute dose response studies with three different inhaled doses of budesonide, have been carried out in a group of 12 chronic asthmatic patients. 3 The lowest dose (100 micrograms) of inhaled budesonide produced a more marked effect in relieving airflow obstruction, than a much larger (1600 micrograms) oral dose of the drug. 4 When the area under the curve for peak expiratory flow rate values was calculated, a dose-response relationship could be seen between the different inhaled doses. 5 It appears that budesonide has a predominantly local anti-asthmatic action in the lung.

Intravenous prednisolone in chronic bronchial asthma.

A single injection of 40 mg prednisolone phosphate was given to 10 patients with chronic bronchial asthma. Changes in pulmonary function were followed over a 30-hour period. Statistically significant changes occurred in the tests employed one hour after the injection of prednisolone. The maximum change for the group as a whole was seen to occur after eight hours. This time course of response is very similar to that obtained in previous studies on similar groups of patients with oral prednisolone where the peak effect occurred nine hours after the drug had been given. Intravenous hydrocortisone produces a much earlier peak effect, at five hours, when it is administered to chronic asthmatic patients.

Melanoma-like pigmented cutaneous metastases from breast carcinoma.

We report a case of breast carcinoma that presented with pigmented cutaneous metastases clinically mimicking malignant melanoma. The pigmented nature of the tumour was probably caused by melanin release from the damaged epidermis (following invasion and destruction by tumour cells) and subsequent phagocytosis by melanophages. Clinically visible pigmentation in cutaneous metastases from breast carcinoma has been described previously but is very uncommon. This report is followed by a review of the few such cases published in the literature.

Measurement-specific quality-of-life satisfaction during the menopause in an Arabian Gulf country.

OBJECTIVE: The aim of this study was to use an instrument, the menopause-specific quality-of-life satisfaction questionnaire for the postmenopausal period, in the United Arab Emirates (UAE). DESIGN: A cross-sectional descriptive study was used to generate menopause symptoms experienced by Arabian Gulf women. Measurement-specific quality-of-life satisfaction questionnaires were used and face-to-face interviews were performed. SETTING: The study was based in primary health-care clinics in Al Ain City, Sharjah and Dubai Emirates, UAE. SUBJECTS: A multistage sampling design was used, and a representative sample of 450 UAE females aged 45 years and above were included during January-April 1999. RESULTS: Of the 450 women living in both urban and rural areas, 390 women agreed to participate (86.7%) and responded to the study. The mean age and standard deviation (SD) of the subjects was 56.5 +/- 6.6 years, and the median age of natural menopause in the present study was 48 years (mean +/- SD 48.4 +/- 3.8). The rate of consanguinous marriages in the sample was found to be 47.2%. The most common disease was found to be diabetes mellitus (10.3%), followed by osteoarthritis (7.7%), hypertension (7.2%) and asthma (6.2%), but the majority of subjects (68.7%) had no specific disease. Out of 29 possible symptoms, the mean number of symptoms was 7.57 (range 0-24). The most frequent symptom was 'aches in the back of the neck or head' at 46.4% followed by 'aches in the muscles/joints' at 34.6%. The least reported symptom was 'facial hair' at 15.9%. Increasing education resulted in more symptoms reported, and increasing parity resulted in fewer symptoms reported. In the present study, it was found that employed women experienced more symptoms and disorders. Of the total sample, 28.5% of the subjects reported no symptoms. In the four domains, 69% reported physical symptoms, 58.7% reported psychosocial symptoms, 40% reported vasomotor symptoms and 37.9% reported sexual symptoms. Spearman's rank correlation coefficient indicated that there is highly statistically significant concordance between the four domains (p < 0.01). CONCLUSION: The present study showed that menopause-related symptoms in UAE women are fewer and of less severity than in Western women. The postmenopausal women, despite a continued decline in estrogen levels, reported few symptoms as part of a normal life stage, suggesting that they were able to cope with stress.