Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia.

PURPOSE: Ataxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. METHODS: From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. RESULTS: LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6-5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case-control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018). CONCLUSION: This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.

MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project.

BACKGROUND: The melanocortin-1-receptor (MC1R) gene regulates human pigmentation and is highly polymorphic in populations of European origins. The aims of this study were to evaluate the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC), and to investigate whether risk estimates differed by phenotypic characteristics. METHODS: Data on 3527 NMSC cases and 9391 controls were gathered through the M-SKIP Project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. We calculated summary odds ratios (SOR) with random-effect models, and performed stratified analyses. RESULTS: Subjects carrying at least one MC1R variant had an increased risk of NMSC overall, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC): SOR (95%CI) were 1.48 (1.24-1.76), 1.39 (1.15-1.69) and 1.61 (1.35-1.91), respectively. All of the investigated variants showed positive associations with NMSC, with consistent significant results obtained for V60L, D84E, V92M, R151C, R160W, R163Q and D294H: SOR (95%CI) ranged from 1.42 (1.19-1.70) for V60L to 2.66 (1.06-6.65) for D84E variant. In stratified analysis, there was no consistent pattern of association between MC1R and NMSC by skin type, but we consistently observed higher SORs for subjects without red hair. CONCLUSIONS: Our pooled-analysis highlighted a role of MC1R variants in NMSC development and suggested an effect modification by red hair colour phenotype.

Intensified fractional CO2 laser-assisted photodynamic therapy vs. laser alone for organ transplant recipients with multiple actinic keratoses and wart-like lesions: a randomized half-side comparative trial on dorsal hands.

BACKGROUND: Photodynamic therapy (PDT) is a well-documented treatment for actinic keratosis (AK), but achieves inferior efficacy in organ transplant recipients (OTRs), particularly in acral regions. Ablative fractional laser (AFXL) intensifies the PDT response and may improve the efficacy of AK clearance when used as monotherapy. OBJECTIVES: To compare the efficacy of a single treatment with AFXL-assisted PDT vs. AFXL alone for difficult-to-treat AKs and wart-like lesions (WLLs) in OTRs. METHODS: Ten OTRs were included with a total of 680 AKs (severity grade I-III) and 409 WLLs on the dorsal hands. Both hands were initially treated with targeted fractional ablation of thick keratotic lesions followed by AFXL field treatment. Treatment regions were then randomized to (i) PDT (AFXL-PDT) or (ii) no further treatment (AFXL). The primary end point was complete response (CR) at 4 months after treatment; secondary end points were improvement of AK severity grade, overall patient assessment of efficacy and tolerability of treatments. RESULTS: CR of AKs was significantly higher for AFXL-PDT (73%) compared with AFXL alone (31%) (P = 0·002). AFXL-PDT improved 82% of AKs to lower lesion grades compared with 52% after AFXL alone (P = 0.008). For WLLs, the rate of CR was 37% for AFXL-PDT compared with 14% for AFXL (P = 0·02). Overall assessment showed a preference for AFXL-PDT compared with AFXL (AFXL-PDT, n = 8; AFXL, n = 0; equal, n = 2). Mild pigment changes were observed in four patients (AFXL-PDT, n = 3; AFXL, n = 1). No scarring was observed. CONCLUSIONS: AFXL-PDT is more effective than AFXL in the treatment of acral AKs and WLLs in OTRs.

Photodynamic therapy for basal cell carcinomas in organ-transplant recipients.

The incidence of nonmelanoma skin cancer is significantly increased in recipients of solid-organ transplants. Photodynamic therapy (PDT) is a well-documented treatment option for superficial and selected nodular basal cell carcinomas (BCCs) in immunocompetent patients, but there are few reports describing PDT of BCCs in organ-transplant recipients (OTRs). We report a study of 18 OTRs with BCC on the head and trunk, who were treated with PDT, using methyl aminolevulinate as photosensitizer. There was only one recurrence during a total follow-up period of 407 months. PDT seems to be an effective treatment option for BCC in immunosuppressed OTRs.

Guidelines for practical use of MAL-PDT in non-melanoma skin cancer.

Methyl aminolaevulinate photodynamic therapy is increasingly practiced in the treatment of actinic keratoses, Bowen's disease and basal cell carcinomas. This method is particularly suitable for treating multiple lesions, field cancerization and lesions in areas where a good cosmetic outcome is of importance. Good treatment routines will contribute to a favourable result. The Norwegian photodynamic therapy (PDT) group consists of medical specialists with long and extensive PDT experience. With support in the literature, this group presents guidelines for the practical use of topical PDT in non-melanoma skin cancer.

Small diameter melanoma: a follow-up of the Norwegian Melanoma Project.

BACKGROUND: Melanoma prognosis is dependent upon early recognition and treatment. There is a need for good clinical guidelines that focus on the early signs of melanoma. The ABCD (asymmetry, border, colour and diameter) rule states that most melanomas are more than 6 mm in diameter. Critics crave a modification, arguing that small diameter melanomas are not infrequent. OBJECTIVES: The aim of the present study was to describe the frequency and prognosis of melanomas less than 7 mm in a clinical setting. METHODS: The Norwegian Melanoma Project was conducted as a multicentre, prospective study with inclusion criteria. Patients were recruited from five dermatological departments in Norway from 1990 to 1993. RESULTS: The frequency of small melanomas was 11.4% (18/158). One-third was in situ melanoma, the rest invasive with a median thickness of 0.8 mm. Four small melanomas were T2 lesions, with a Breslow thickness of more than 1 mm. One nodular T2 melanoma recurred locally 2 years after diagnosis and the patient died of distant metastasis only months later. CONCLUSIONS: The ABCD rule remains a practical guide for early recognition of melanoma. Clinicians must be aware of its limitations.

[Pathological findings in the eye of children with facial nevus]. / Patologiske funn i øyet hos barn med fødselsmerke i ansiktet.

BACKGROUND: Port-wine stains distributed to the trigeminal area may be associated with eye and/or central nervous system complications. Visual loss may be prevented with screening for eye pathology at an early age with adequate intervention. MATERIAL AND METHODS: 45 children with port-wine stains in the trigeminal area were examined by an ophthalmologist under general anaesthesia. RESULTS: Seven of 30 patients with one or both eyelids affected had a choroidal vascular anomaly. Four patients had glaucoma. These four patients had both eyelids affected. Two children with a vascular anomaly had only upper eyelid involvement. INTERPRETATION: Patients with facial port-wine stains affecting the eyelids should be screened for eye pathology at an early age.

Comparison of cyclosporin and UVAB phototherapy for intermittent one-year treatment of atopic dermatitis.

Although cyclosporin is effective for the treatment of severe atopic dermatitis, phototherapy is the standard second-line treatment for this disease. An open, randomized, controlled, parallel-group study was conducted to compare the efficacy, influence on quality of life and safety of cyclosporin and UVAB phototherapy during 1 year of intermittent treatment of atopic dermatitis in adult patients. The main endpoints of the study were the number of days in remission and the influence on quality of life. Seventy-two patients were treated, 36 in each group. Cyclosporin produced significantly more days in remission than UVAB phototherapy during the 1-year study period. At the end of the study no difference between the 2 groups was noted in terms of quality of life. A significant increase in serum creatinine occurred in 2 patients and 7 patients developed mild or moderate hypertension during cyclosporin treatment. It can be concluded that intermittent cyclosporin seems to be more effective than UVAB and is reasonably safe for the treatment of atopic dermatitis over a 1-year treatment period.

[Diagnostic delay in malignant melanoma]. / Diagnostisk forsinkelse ved malignt melanom.

BACKGROUND: Malignant melanoma accounts for 1 to 3% of all cancers and has been the most rapidly increasing type of cancer during the last decades. Early diagnosis and treatment favours a good prognosis. We wanted to investigate delays in the diagnostic process and patients' knowledge concerning malignant melanoma. MATERIAL AND METHODS: 457 patients with primary cutaneous malignant melanoma received a questionnaire through their physician; 352 (77%) returned the questionnaire. RESULTS: Median patient delay, defined as time between the patient's first observation of changes in a naevus and the first medical consultation, was eight weeks. Younger men had the longest patient delays. Median professional delay, defined as time from the first medical consultation to the time of diagnosis, was one week. 60% of the patients observing changes in a naevus did not initially seek medical advice, as they did not believe the changes were significant. In 65% of the cases, the patients themselves initiated the consultation. Television and other media were principal sources of information. INTERPRETATION: Public campaigns should be designed to reach younger men in particular and focus on self-examination of naevi and immediate contact with a physician when a suspicious lesion is discovered.

[Etiology of malignant melanoma--what do we know?]. / Etiologi ved malignt melanom--hva vet vi?

Cutaneous malignant melanoma is the cancer showing the highest rate of increase in Europe. Attempts to reduce this trend are based on epidemiological studies which show that the development of melanoma is influenced by both constitutional and behavioural factors. The author summarizes the current knowledge on etiologically important factors in cutaneous malignant melanoma. Constitutional factors such as inheritance, congenital nevi, atypical moles and hormones are discussed, as well as behavioural factors, with the emphasis on exposure to sun.

[Malignant melanoma. Diagnosis, treatment and follow-up]. / Malignt melanom. Diagnostikk, behandling og oppfølging.

The incidence and mortality of cutaneous malignant melanoma are increasing at a rate of between 3 and 7% in European countries. Although the prognosis for individual cases is improving, the rising mortality rate is attributed to a rapidly growing incidence that is not offset by improved diagnosis and treatment. The Norwegian Melanoma Group intends to publish and distribute national guidelines for the management of patients with cutaneous melanoma. National guidelines will ensure that the treatment and follow-up of melanoma patients are based on scientific data, contributing to a uniform practice, and thereby improving the quality of melanoma management. This article focuses on diagnosis, treatment and follow-up of stage I and II melanoma, i.e. melanoma without metastasis.

[Nevus flammeus in small children treated pulsed dye laser]. / Nevus flammeus hos små barn behandlet med pulset fargelaser.

We report the results of treating 30 children less than 7.5 years old for port wine stains of the face and neck using pulsed dye laser with a wave length of 585 nm. The children were given a general anaesthetic. In five children the stains disappeared completely and in 21 there was marked improvement (> 75% lighter). The younger age group, 7 months to 4 years, required fewer treatment sessions (mean 3.7) than the older age group, 4 to 7 years (mean 5.1 sessions), indicating the benefit of early treatment. No side effects were seen except for transient hyperpigmentation.

Bullous impetigo caused by group A streptococci. A case report.

Bullous impetigo is considered to be a staphylococcal disease. Staphylococcus aureus, phage type 71, produces an epidermolytic toxin, assumed to be the cause of bullous formation in the skin. We present a case of bullous impetigo. Microbiological tests suggested beta-hemolytic streptococci, group A, M-type 3, as the etiological agent. Group A streptococci were isolated from the throat of the patient's mother and brother. The strains were shown to be identical, by means of DNA-'fingerprinting' and M-typing.