High- and intermediate-risk susceptibility variants in melanoma families from the Mediterranean area: A multicentre cohort from the MelaNostrum Consortium.

BACKGROUND: Most of large epidemiological studies on melanoma susceptibility have been conducted on fair skinned individuals (US, Australia and Northern Europe), while Southern European populations, characterized by high UV exposure and dark-skinned individuals, are underrepresented. OBJECTIVES: We report a comprehensive pooled analysis of established high- and intermediate-penetrance genetic variants and clinical characteristics of Mediterranean melanoma families from the MelaNostrum Consortium. METHODS: Pooled epidemiological, clinical and genetic (CDKN2A, CDK4, ACD, BAP1, POT1, TERT, and TERF2IP and MC1R genes) retrospective data of melanoma families, collected within the MelaNostrum Consortium in Greece, Italy and Spain, were analysed. Univariate methods and multivariate logistic regression models were used to evaluate the association of variants with characteristics of families and of affected and unaffected family members. Subgroup analysis was performed for each country. RESULTS: We included 839 families (1365 affected members and 2123 unaffected individuals). Pathogenic/likely pathogenic CDKN2A variants were identified in 13.8% of families. The strongest predictors of melanoma were ≥2 multiple primary melanoma cases (OR 8.1; 95% CI 3.3-19.7), >3 affected members (OR 2.6; 95% CI 1.3-5.2) and occurrence of pancreatic cancer (OR 4.8; 95% CI 2.4-9.4) in the family (AUC 0.76, 95% CI 0.71-0.82). We observed low frequency variants in POT1 (3.8%), TERF2IP (2.5%), ACD (0.8%) and BAP1 (0.3%). MC1R common variants (≥2 variants and ≥2 RHC variants) were associated with melanoma risk (OR 1.4; 95% CI 1.0-2.0 and OR 4.3; 95% CI 1.2-14.6, respectively). CONCLUSIONS: Variants in known high-penetrance genes explain nearly 20% of melanoma familial aggregation in Mediterranean areas. CDKN2A melanoma predictors were identified with potential clinical relevance for cancer risk assessment.

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.

Sentinel lymph node biopsy or nodal observation in melanoma: study of an Italian series.

AIM: The purpose of this study was to investigate the disease-free time (DFT) and overall survival (OS) of patients with intermediate or high-risk cutaneous melanoma who were treated with conventional surgery alone, and to compare them with that of a second group of patients who were treated with surgery and SLN biopsy. METHODS: A retrospective, single-centre study was performed at the Department of Dermatology of the "M. Bufalini" Hospital, Cesena, Italy based on data collected between January 1990 and December 2007. A total of 757 consecutive patients with stage I-II melanoma were identified: the former group (control group), treated with conventional surgery, was composed of 224 patients; the latter, treated with surgery and SLN biopsy (SLN biopsy group), was formed of 529 patients. RESULTS: The 5-year disease free time (DFT) rate, estimated with Kaplan-Meyer, was 73.9% (95% CI: 67.5-79.2) in the control group, and 82.2% (95% CI: 78.6-85.3) in the SLN biopsy group. Although the DFT rate was significantly higher in the SLN group than in the control group in univariate analyses (P=0.004), this gain was lost in multivariate analysis (P=0.2). The 5-year overall survival (OS) rate was 88.4% (95% CI: 83.2-92.1) for the control group, and 87.9% (95% CI: 84.6-90.4) for the SLN biopsy group. Statistical comparison of specific OS was not statistically significant (P=0.93). CONCLUSION: On the basis of our follow-up data, we found that patients who underwent SLN biopsy technique experienced a reduction in the proportion of lymph nodal relapse, but DFT and OS were statistically equivalent between the two groups.

Five cases of melanoma in HIV positive patients.

BACKGROUND: Kaposi's sarcoma, high grade B-cell non-Hodgkin lymphoma and invasive carcinoma of the cervix are all AIDS-defining illnesses according to the CDC staging criteria classification. A number of other malignancies, not traditionally associated with HIV infection, such as Hodgkin's disease, cancers of the rectum, anus, and germ-cell tumours, appear to occur more often than would be expected in these patients. Malignant cutaneous lesions, including basal cell, squamous-cell carcinomas, Bowen's disease, and cutaneous melanoma (CM) have been less often reported. PATIENTS AND METHODS: We retrospectively evaluated the clinical data of 5 HIV+ seropositive patients and CM observed at the "M. Bufalini" Hospital, Cesena, Italy from 1994 to 2000. RESULTS: All the 5 subjects had a history of intense sun exposure and sunburns. Four patients reported homosexuality as their risk factor for HIV disease. Reviewing the international literature on the subject HIV infected homosexuals appear the group at higher risk of developing CMM, accounting for 80% of cases. CONCLUSION: As patients' life expectancy appears to be prolonged after the advent of the HAART therapy, skin cancers will probably become more frequent in the near future. Clinicians should keep close medical surveillance to promptly diagnose new cases of melanoma and non-melanoma skin cancers and advise their HIV-infected patients on the risk of prolonged sun exposure and severe sun burns for the development of skin cancers.

Cutaneous side effects induced by indinavir.

HIV-protease inhibitors demonstrated such high efficacy in short-term studies that they have been approved by the FDA, even though possible toxicity still needs further investigation. In the period between January 1997 and August 1998, 101 patients, staying at San Patrignano Medical Centre (Italy), received an HIV protease inhibitor (indinavir) plus two nucleoside reverse transcriptase inhibitors (NRTI's) selected from the following: AZT, didanosine, zalcitabine, lamivudine or stavudine. Seventy-three patients were male, 28 female and their ages ranged from 25 to 60 years, with an average of 34. At the end of the study, 84 patients were suitable for evaluation, as the other 17 dropped out for various reasons. Forty-eight patients (57.1%) developed cheilitis, 34 (40.5%) experienced diffuse cutaneous dryness and pruritus, 10 (11.9%) developed asteatotic dermatitis on the trunk, arms and thighs and another 10 (11.9%) complained of scalp defluvium. A severe alopecia was observed in only 1 patient (1.2%), while 6 reported that their body hair had become fairer, thinner and shed considerably. Multiple pyogenic granulomas were observed in the toenails of 5 patients (5. 9%). Softening of the nail plate was noted in 5 subjects as well. A peripheral lipodystrophy syndrome was noted in 12 patients (14.3%). Among these, one patient only developed a "buffalo hump" and another had diffused lipomatosis. The temporal relationship between the taking of indinavir and the onset of such cutaneous effects was striking. This was confirmed by the regression of symptoms in those patients who later discontinued indinavir. The emerging side effects of protease inhibitors require a multidisciplinary team for adequate diagnosis and treatment. Cutaneous toxicity involving the patient's own body image has a peculiar influence on compliance to the treatment and the patient's quality of life.

Resolution of disseminated molluscum contagiosum with Highly Active Anti-Retroviral Therapy (HAART) in patients with AIDS.

Molluscum contagiosum (MC), a cutaneous infection caused by a DNA virus belonging to the poxvirus group, affects about 5-10% of patients with HIV disease, often showing extensive, severe lesions, unresponsive to therapy [1]. During the follow-up of three patients with AIDS for MC recalcitrant to therapy, we noted their cutaneous lesions cleared 5-6 months after they had begun Highly Active Anti-Retroviral Therapy (HAART). This therapy includes an HIV protease inhibitor (indinavir) and two reverse transcriptase inhibitors [2, 3].

Analysis of Breslow tumor thickness distribution of skin melanoma in the Italian region of Romagna, 1986-1991.

AIMS AND BACKGROUND: In southern European countries, the availability of epidemiologic data on cutaneous malignant melanoma is limited. A descriptive analysis was performed on melanoma cases diagnosed in the Italian region of Romagna (population 600,000), 1986-91. METHODS: The main end point was the proportion of cases less than 1.5 mm thick by sex, age, and site. RESULTS: A total of 297 incident cases was evaluated. The average annual age-standardized (World) incidence rates were 6.2 (95% CI 5.2-7.2) per 100,000 females and 4.5 (95% CI 3.6-5.3) per 100,000 males. Females presented with significantly thinner melanomas than males. The proportion of cases less than 1.5 mm thick decreased significantly with increasing age in both sexes, with the most pronounced decrease (approximately from 2/3 to 1/3) being observed above 60 years for females and above 40 for males. Comparing sexes by 10-year age groups, a significant F:M advantage in thickness distribution was found only at age 40-49 and 50-59 years. Among females under 60, melanomas of the legs and those of the trunk showed no difference in thickness distribution. In both sexes, incidence appeared to increase progressively with age. No apparent elevation in incidence rates was observed in the age groups with the highest frequency of thin melanomas. CONCLUSIONS: The major implication of these data is that in public education programs specific messages should be aimed at those subgroups that show the poorest levels of self-surveillance.

Resolution of recalcitrant human papillomavirus gingival infection with topical cidofovir.

Cidofovir, a purine nucleotide analogue of cytosine, is a promising new drug that acts against a wide number of DNA viruses. In 1997, the Food and Drug Administration approved intravenous cidofovir for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome. Recent studies have shown cidofovir (1% gel or cream) to be effective for the treatment of recalcitrant and unmanageable viral cutaneous lesions induced by herpes, pox, and papillomavirus families. We report the case of a 45-year-old man who had been diagnosed as having acquired immunodeficiency syndrome in 1995. Recalcitrant to conventional therapies, the human papillomavirus lesions on his gingival mucosa were successfully treated with cidofovir 1% cream. To the best of our knowledge, this is the first case in which topical cidofovir has been used for the treatment of a human papillomavirus infection of the oral mucosa.

Disseminated granuloma annulare in acquired immunodeficiency syndrome: case report and review of the literature.

The authors report the case of a 27-year-old woman who presented with disseminated granuloma annulare in association with acquired immunodeficiency syndrome. The lesions were asymptomatic, tiny, erythematous or flesh-colored umbilicated papules on the neck, trunk, and flexor surface of the arms and knees that regressed without any treatment in two months. The case reported is the nineteenth description of the association of granuloma annulare and acquired immunodeficiency syndrome but the first in a female patient. The causes and pathogenesis of granuloma annulare are unknown, but after reviewing the previous case reports we hypothesize that circulating human immunodeficiency virus particles may be a precipitating factor in granuloma annulare and that the CD4+ and CD8+ cell dysfunction may be responsible for the atypically short course of the disease.

Lichen planus, erythema nodosum, and erythema multiforme in a patient with chronic hepatitis C.

After identification of the hepatitis C virus (HCV) in 1989, evidence was established supporting its role in the pathogenesis of a number of cutaneous diseases. This evidence ranges from mere epidemiologic associations, such as lichen planus, to molecular biological investigations that have identified the virus in the pathologic tissues of cutaneous vasculitis, vasculitis with mixed cryoglobulinemia, and porphyria cutanea tarda. We describe a 52-year-old man who was diagnosed with chronic hepatitis C, preceding the appearance of lichen planus, erythema nodosum, and erythema multiforme that coincided with the reactivation of viral replication.

Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study.

BACKGROUND: Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited. METHODS: We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided. RESULTS: Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10(-6) ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; P(trend) = 1.86 × 10(-8)). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10(-6) ≤ P ≤ .02). CONCLUSION: Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.