Genetic susceptibility to cutaneous melanoma in southern Switzerland: role of CDKN2A, MC1R and MITF.

BACKGROUND: Nearly 10% of all cases of cutaneous melanoma (CM) occur in patients with a personal or family history of the disease. OBJECTIVES: To obtain information about genetic predisposition to CM in Ticino, the southern region of Switzerland, a zone with moderate-to-high CM incidence. METHODS: We identified germline mutations in highly CM-associated genes (CDKN2A and CDK4) and low/medium-penetrance variants (MC1R and MITF) in patients with multiple primary CMs or individuals with one or more CM and a positive family history for CM or pancreatic cancer among first- or second-degree relatives. Healthy blood donors (n = 146) were included as a control group. RESULTS: From July 2010 to July 2012, 57 patients (41 pedigrees) were included. Twenty-six were melanoma-prone families (with at least two cases) and 15 had multiple CMs. Pancreatic cancer was found in six families. The CDKN2A mutation p.V126D was identified in seven patients (four families) with a founder effect, whereas CDKN2A A148T was detected in seven cases (five families) and seven healthy donors (odds ratio 2·76, 95% confidence interval 0·83-9·20). At least one MC1R melanoma-associated polymorphism was detected in 32 patients (78%) and 97 healthy donors (66%), with more than one polymorphism in 12 patients (29%) and 25 healthy donors (17%). The MITF variant p.E318K was identified in four patients from three additional pedigrees (7%) and one healthy control (0·7%). CONCLUSIONS: Inclusion criteria for the Ticino population for genetic assessment should follow the rule of two (two affected individuals in a family or a patient with multiple CMs), as we detected a CDKN2A mutation in almost 10% of our pedigrees (four of 41), MITF p.E318K in 7% (three of 41) and a higher number of MC1R variants than in the control population.

[Swiss clinical practice guidelines for skin cancer in organ transplant recipients]. / Recommandations suisses pour la prise en charge des cancers cutanés chez les patients transplantés d'organe.

Swiss clinical practice guidelines for skin cancer in organ transplant recipients Transplant patients have increased over the last decades. As a consequence of long-term immunosuppression, skin cancer, in particular squamous cell carcinoma (SCC), has become an important problem. Screening and education of potential organ transplant recipients (OTRs) regarding prevention of sun damage and early recognition of skin cancer are important before transplantation. Once transplanted, OTRs should be seen yearly by a dermatologist to ensure compliance with sun avoidance as well as for treatment of precancerosis and SCC. Early removal is the best treatment for SCC. Reduction of immunosuppression, switch to mTOR inhibitors and chemoprevention with acitretin may reduce the incidence of SCC. The dermatological follow-up of OTRs should be integrated into a comprehensive post-transplant management strategy.

Swiss clinical practice guidelines for skin cancer in organ transplant recipients.

Patients with a solid organ transplant have increased in numbers and in individual survival in Switzerland over the last decades. As a consequence of long-term immunosuppression, skin cancer in solid organ recipients (SOTRs) has been recognized as an important problem. Screening and education of potential SOTRs about prevention of sun damage and early recognition of skin cancer are important before transplantation. Once transplanted, SOTRs should be seen by a dermatologist yearly for repeat education as well as early diagnosis, prevention and treatment of skin cancer. Squamous cell carcinoma of the skin (SCC) is the most frequent cancer in the setting of long-term immunosuppression. Sun protection by behaviour, clothing and daily sun screen application is the most effective prevention. Cumulative sun damage results in field cancerisation with numerous in-situ SCC such as actinic keratosis and Bowen's disease which should be treated proactively. Invasive SCC is cured by complete surgical excision. Early removal is the best precaution against potential metastases of SCC. Reduction of immunosuppression and switch to mTOR inhibitors and potentially, mycophenolate, may reduce the incidence of further SCC. Chemoprevention with the retinoid acitretin reduces the recurrence rate of SCC. The dermatological follow-up of SOTRs should be integrated into the comprehensive post-transplant care.

Teledermatoscopy in Switzerland: a preliminary evaluation.

BACKGROUND: Since devices for digital epiluminescence microscopy and for telemedicine have become affordable, a critical evaluation of this new method has been needed. OBJECTIVE: Our aim was a critical evaluation of teledermatoscopy under routine conditions in private practice. METHODS: Pigmented skin lesions (PSLs) scheduled for excision were documented with a digital epiluminescence microscopy (DELM) system. Images were sent to the PSL consultation at the Department of Dermatology of the University Hospital Geneva, where a diagnosis was established. The histopathologic report including the initial diagnosis was sent afterward. Both approaches were compared concerning diagnostic accuracy. RESULTS: Over a period of 6 months, 55 lesions on 51 patients have been included in this study. Picture quality was good or very good in more than 90%. Diagnostic accuracy of the teledermatoscopy approach was superior to that of the conventional approach for malignant melanocytic lesions. CONCLUSION: We have shown the feasibility of a teledermatoscopic consultation. The gain of diagnostic accuracy in this teledermatoscopic approach, especially for malignant melanocytic lesions, suggests that patients might benefit directly from such a consultation at distance.

Delayed hypersensitivity reactions to corticosteroids applied to mucous membranes.

Despite the widespread use of corticosteroids on the mucous membranes of the nose, eye and bronchial tree, mucosal contact sensitivity has apparently been uncommon. However, since the introduction of new corticosteroids such as tixocortol pivalate and budesonide, mucosal contact sensitivity, particularly that affecting the nasal mucosa, has increasingly been reported. Contact allergy on other mucosal surfaces and in the bronchial tree is very rare. We report three women who had contact allergy to tixocortol pivalate or budesonide in nasal sprays, and one woman who had an allergic contact stomatitis from tixocortol pivalate in oral lozenges.

Behavioural profile in the chicken of CQ 32-084 and CQP 201-403, two dopamine agonists.

CQ 32-084 and CQP 201-403, two ergot derivatives that previous behavioural studies in rats had suggested to be differently active on dopamine (DA) receptors, were IP injected into male chickens. Both compounds strongly modified the animals' behaviour. CQ 32-084 led to sedation, increased yawning, and decreased preening, while CQP 201-403 exerted a biphasic activity: At a low dose, it elicited sedation and yawning; at high doses, however, it induced a state of excitation manifested by diminished sedation and yawning, enhanced preening, and pecking. The sedation, increased yawning, and decreased preening induced by the two DA agonists were reversed by the D2-selective antagonist, sulpiride. The present studies indicate that, from a behavioural point of view, chickens respond similarly to rats to the DA agonists CQ 32-084 and CQP 201-403, which differ in their selectivity of action on the various DA receptor subtypes.

Behavioural evidence that different neurochemical mechanisms underly stretching-yawning and penile erection induced in male rats by SND 919, a new selective D2 dopamine receptor agonist.

The behavioural effects induced in male Wistar rats by SND 919, a new drug reputed to have selective agonistic activity at D2 dopamine (DA) receptors, were studied. The following aspects of behaviour were considered: motor activity, stretching-yawning (SY), penile erection (PE) and stereotyped behaviour (SB). Intraperitoneal injection (IP) of the drug (0.01-20 mg/kg) induced an SY syndrome in the form of a bell-shaped dose-response curve, the effect being maximal at the dose of 0.1 mg/kg and disappearing completely at 10 mg/kg. SND 919 also potently elicited PE; this latter effect, however, was not coincident with SY induction, being maximal at 1 mg/kg and persisting at 10 and 20 mg/kg. SND 919-induced SY was potently antagonized by pretreatment not only with the D2 antagonist, L-sulpiride (20 mg/kg), but also with the alpha 2 antagonist, yohimbine (1, 3 mg/kg), and the more selective alpha 2 antagonist, idazoxan (1, 2 and 5 mg/kg). While sulpiride also decreased SND 919-induced PE, idazoxan at all doses and yohimbine at 1 mg/kg did not affect this behaviour. Inhibition of motor activity was induced by the D2 agonist at low doses (0.05, 0.1 mg/kg), while at high doses (1, 10 and 20 mg/kg), it was actually replaced by a form of SB characterized by downward sniffing and licking. When, for comparison, the D2 agonist, RU 24213 (0.1-20 mg/kg IP), was tested for PE, SY, motor activity and SB, it displayed a behavioural pattern very similar to that obtained with SND 919. Idazoxan (2 mg/kg), administered before RU 24213 (10 mg/kg), significantly antagonized the drug-induced SY, but not PE.(ABSTRACT TRUNCATED AT 250 WORDS)

B-HT 920-induced effects on rat feeding behaviour.

Wistar rats, deprived of food for 15 h, were injected with B-HT 920 and 20 min later presented with their normal diet in their individual home cages. The parameters considered were latency to feeding and food intake which was determined 0.5, 1, 2, 3, 6 and 24 h later. B-HT 920 significantly reduced latency to feeding at 0.1, 0.5 and 1 mg/kg; food intake was increased by doses of 0.05 and 0.1 mg/kg 3 and 6 h after treatment and decreased by a dose of 1 mg/kg at 3 h. The amount of food eaten over a 24 h period by the various groups did not differ. At this time rats received a second injection of the drug at the same dosages, and preweighed food was presented again 20 min later. We confirmed that latency to feeding is lowered by B-HT 920 at 0.1, 0.5 and 1 mg/kg, doses which also induced feeding in sated rats within the first half-hour and even after 1 h in the case of the highest dose. Since penile erection and stretching and yawning, signs typically induced by all DA D2 agonists, were observed after B-HT 920 at 0.05, 0.1 and 0.5 mg/kg, discussion centres on the possible mechanisms involved in the B-HT 920-induced effects.

Suppressive effect of the dopamine D2 receptor agonist B-HT 920 on rat grooming.

The effect of the D2 agonist B-HT 920 was examined on three behavioural models of induced grooming in the rat. B-HT 920 potently inhibited the grooming elicited by a novel environment, whereas it stimulated the stretching-yawning syndrome. Pretreatment with the selective dopamine D2 receptor antagonist, sulpiride, reversed the phenomenon. When B-HT 920 was administered to rats before water immersion, it similarly antagonized total grooming; wet-dog shakes, detected in these same animals, were potently inhibited. Finally, B-HT 920 displayed inhibitory activity towards adrenocorticotropin hormone-induced excessive grooming. On the basis of these effects, the role of D2 receptor subtypes in the modulation of grooming is discussed.

Effects of the dopamine D2 agonists lisuride and CQ 32-084 on rat feeding behaviour.

The influence on rat-feeding behaviour of lisuride and CQ 32-084, agonists at dopamine D2 receptors, was examined using two procedures. In a first series of experiments, the apparatus was an X-maze baited with food pellets where individual fasted rats were observed for 5 min. A number of parameters were recorded: latency to tasting and feeding, interval between tasting and feeding, total feeding time, and total grooming time. Lisuride (0.05 and 0.1 mg/kg) and CQ 32-084 (0.05 and 0.5 mg/kg) behaved as stimulants of eating; lisuride (0.4 mg/kg) inhibited the phenomenon. Both drugs always antagonized grooming. Subsequently, when food intake was determined in the home cages of fasted animals lisuride reduced feeding at all doses during the first hour after treatment, while CQ 32-084 had no effect. The data show that the two compounds display different activity on ingestive behaviour according to the dose and experimental model used. Discussion centres on the possible dependence of feeding enhancement in the X-maze on the anxiolytic activity exerted by low D2 autoreceptorial doses.

B-HT 920 stimulates feeding and antagonizes anorexia induced by ACTH and immobilisation.

The influence of immobilisation and i.c.v. injection of ACTH on feeding in rats was examined using a new experimental model. An X-maze with alternate open and covered arms, each baited with standard laboratory chow was used, where individual rats were placed and observed for 5 min. Two essential aspects of the behaviour towards food were considered, namely, tasting and feeding. A number of parameters were applied to demonstrate the anorectic activity of ACTH and immobilisation, in accordance with data obtained using classical procedures for feeding analysis. ACTH at the dose used did not modify rat exploratory activity and grooming in the X-maze without food pellets. In the same X-maze feeding test, B-HT 920, a selective agonist of dopamine D2 receptors and alpha 2-adrenoceptors, shown earlier to have anxiolytic- and antidepressive-like properties in rats, enhanced appetite and exerted anxiolytic activity when injected i.p. Pretreatment with B-HT 920 counteracted the restraint- and ACTH-induced effects. The results are discussed in the light of the relation between control of feeding and affective disorders. B-HT 920 activity seems to be of particular interest in view of its antagonism towards the anorexia elicited by two different agents reputed to have in common a key role in the stress-related disturbances of food intake.

A prospective study of skeletal changes during short-term acitretin therapy.

We prospectively analyzed skeletal changes of 16 patients who were treated with acitretin for various disorders of keratinization at doses of 10-50 mg/day (overall mean 0.4 mg/kg/day) for 7-12 months (mean 11.4 months). Skeletal changes from pretherapy findings were observed in 5 patients. In 4 of 5 patients they appeared to be linked to a preexisting degenerative pathology and could not be attributed to acitretin therapy. However, in 1 patient a spinal osseous side effect could not be excluded. No retinoid-induced extraspinal tendon or ligament calcifications were observed.

Effect of the D2-autoreceptor agonist B-HT 958 on both spontaneous and ACTH-induced stretching, yawning and grooming in the rat.

The D2 autoreceptor agonist B-HT 958, intraperitoneally injected into Wistar male rats in a novel environment, significantly increased stretching and yawning (SY) while inhibiting grooming. Pretreatment with the D2 antagonist sulpiride reversed these effects, antagonizing SY and restoring grooming. Similarly, when B-HT 958 was administered to rats in their home cages, it elicited SY and abolished grooming; moreover, when administered before the i.c.v. injection of adrenocorticotropin hormone, dose-dependently enhanced SY and strongly antagonized the typical syndrome of intensified grooming induced by the peptide. The possible relationship between SY and grooming and the involvement of D2 autoreceptors are discussed.

Hyperphagic effect of B-HT 920 in a modified X-maze test.

The influence on rat-feeding behavior of B-HT 920 (a selective agonist of D2DA receptors at low doses, but also a potent stimulant of alpha 2-adrenoceptors at high doses) was examined using a new experimental model. The apparatus adopted was an X-maze with alternate open and covered arms, each baited with two food-pellets. Individual rats were placed in the apparatus and observed for 5 min. Two essential aspects of rat behavior in the presence of food were considered: tasting and feeding. A number of parameters were recorded: latency to tasting and feeding; interval between tasting and feeding; total feeding time. We also took into account the type of arm in which the rats indulged in their first bout of tasting and feeding. In the first series of experiments, B-HT 920 was injected intraperitoneally (0.1, 1, 2 and 3 mg/kg) into fed and fasted rats; in the second series, the drug was injected intracerebroventricularly (10, 20 and 80 micrograms/rat) into fasted rats. In both experimental conditions, the drug significantly modified the animals' feeding behavior and affected their natural preference for the closed arms as places of choice in which to feed. Comparison of the results with those obtained using norepinephrine (20 micrograms/rat, intracerebroventricularly), a well-known hyperphagic agent, shows that B-HT 920 strongly stimulates feeding. Also, the results of the intracerebroventricular experiments confirm that the effect on feeding appears at doses that are active both on alpha 2-adrenoceptors and on D2DA receptors, as can be deduced from penile erection and stretching and yawning elicited in rats by the same D2DA stimulant doses. The involvement of the latter receptors in feeding has been investigated by means of a new series of experiments with rats treated with the D2DA antagonist sulpiride, before B-HT 920 at 100 micrograms/kg. The possible mechanisms underlying B-HT 920-hyperphagic effects and the value of the X-maze feeding test as a simple procedure indicative of changes in rat feeding and emotionality are discussed in the light of these latest findings.

Frequency of congenital nevi, nevi spili and café-au-lait spots and their relation to nevus count and skin complexion in 939 children.

To determine the prevalence of congenital melanoevocytic nevi (CMN), of so-called congenital nevus-like nevi (CNLN), nevi spili (NS) and café-au-lait spots (CLS) in childhood, a series of 939 children aged 8-16 years had total skin examination. CMN/CNLN were observed in a frequency of 5.9%, NS in 2.1% and CLS even in 32.7%. Except CLS (which occurred more frequently in boys), all of these lesions were equally represented in both sexes. According to the classification of Kopf and coworkers, 44/55 CNM/CNLN were small and 11/55 medium-sized. CMN/CNLN affected preferentially trunk and upper limbs while head and neck were spared. Such nevi occurred more frequently in dark types of skin complexion and showed a tendency to be more frequent in groups of patients with increased average number of acquired melanonevocytic nevi. Remarkably, CLS were also found in 23/55 (41.7%) children with CMN/CNLN and in 12/20 (60%) children with NS (in a higher frequency than such combinations have to be expected). Compared with the data from other studies, both CMN/CNLN and CLS in our patients were observed in highest prevalence in the literature. Since the frequency of CLS in adults is much lower, it cannot be ruled out that some of the CLS disappear in adolescence.

[Focal melanocytic atypia in dysplastic nevus cell nevi. Results of a serial section study]. / Fokale melanozytäre Atypien in dysplastischen Nävuszellnävi. Resultate einer Serienschnittuntersuchung.

Dysplastic nevi were diagnosed according to the ABCDE rule for recognition of early melanomas in 11 patients with familial dysplastic nevus syndrome (DNS) and in 39 patients with the sporadic variant of DNS. All these 50 patients exhibited multiple dysplastic nevi. On routine histological examination melanocytic atypia confirming the histological diagnosis of dysplastic nevus was found only in 12/50 cases. However, when cut consecutively dysplastic nevi with melanocytic atypia were diagnosed in 17 further cases (34%). In most cases (72.4%) only a mild degree of atypia (grade I) was found. Dysplastic nevi with severe melanocytic atypia (grades II-III) were found in all groups of sporadic and familial variants of DNS (with and without melanoma). To improve the prognostic value of the histological examination in dysplastic nevi significantly it must be of interest to add the degree of melanocytic atypia. With increasing degree of melanocytic atypia also the typical histological feature of dysplastic nevi become more significant. Since such atypia in dysplastic nevi is not necessarily sited in the centre of the lesion and since in most cases melanocytic atypia occurs focally, we believe that histological examination of dysplastic nevi must be undertaken by step section. Lesions suspected of being dysplastic nevi must be excised with margins of at least 2-5 mm for a correct histological diagnosis.

[Increased incidence of multiple melanoma in sporadic and familial dysplastic nevus cell syndrome]. / Gehäufte Mehrfachmelanome bei sporadischem und familiärem dysplastichen Nävuszellnävus-Syndrom.

In 280 melanoma patients all data concerning familial and personal history, histology, and therapy were verified. All patients underwent total-body skin examination to check for the presence of dysplastic nevus syndrome (DNS). In 257/280 patients (91.8%) solitary melanomas were found, while in 23/280 patients (8.2%) multiple melanomas occurring simultaneously or consecutively were ascertained. Surprisingly, among the 12/280 patients (4.2%) with familial variants of melanoma, multiple melanomas were not found in a increased frequency. In patients with DNS (regardless of whether sporadic or familial) the frequency of multiple melanomas is higher: in patients with solitary melanomas DNS was found in 27/257 (10.5%), while in patients with multiple melanomas DNS was diagnosed in 11/23 (47.8%) (P less than 0.0005). In both groups (solitary and multiple melanomas) the mean age of patients with DNS was around 10 years lower. The frequency of additional primary malignancies in patients with cutaneous melanomas was 8.6%, and did not vary according as whether patients had solitary or multiple melanomas with or without DNS.