Simona Osella-Abate

microRNA-214 contributes to melanoma tumour progression through suppression of TFAP2C

Malignant melanoma is fatal in its metastatic stage. It is therefore essential to unravel the molecular mechanisms that govern disease progression to metastasis. MicroRNAs (miRs) are endogenous non‐coding RNAs involved in tumourigenesis. Using a melanoma progression model, we identified a novel pathway controlled by miR‐214 that coordinates metastatic capability. Pathway components include TFAP2C, homologue of a well‐established melanoma tumour suppressor, the adhesion receptor ITGA3 and multiple surface molecules. Modulation of miR‐214 influences in vitro tumour cell movement and survival to anoikis as well as extravasation from blood vessels and lung metastasis formation in vivo. Considering that miR‐214 is known to be highly expressed in human melanomas, our data suggest a critical role for this miRNA in disease progression and the establishment of distant metastases.

Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study

BACKGROUND The clinical features and the prognostic relevance of vitiligo lesions in melanoma patients are still controversial. This prospective observational study was designed to characterise the clinical features of melanoma-associated vitiligo, to analyse the association with other autoimmune manifestations and to ascertain whether the development of vitiligo lesions carries a prognostic relevance on the clinical course of melanoma. MATERIALS AND METHODS A total of 2954 consecutive patients have been included; multivariate analyses of distant metastasis-free survival (DMFS) and overall survival (OS) were carried out to ascertain the independent prognostic role of vitiligo as a time-dependent covariate. RESULTS Vitiligo was demonstrated in 83 of 2954 melanoma patients (2.8%). A significantly higher percentage of autoimmune diseases was demonstrated in vitiligo patients (7 of 83) with respect to patients without vitiligo (80 of 2871) (P = 0.004). Multivariate analyses selected the time-dependent covariate vitiligo as the favourable independent prognostic variable associated to a longer DMFS in stage III and a higher OS in both stage III and stage IV. CONCLUSION Melanoma-associated vitiligo should be considered as a distinct clinical entity, separate from vitiligo vulgaris, and identifies a subgroup of patients characterised by a high prevalence of immune-mediated diseases and by a favourable prognosis.

Regulatory T cells in the skin lesions and blood of patients with systemic sclerosis and morphoea

Background  Systemic sclerosis (SSc) and morphoea are connective tissue diseases characterized by fibrosis of the skin. Although to date their pathogenesis has not been clearly defined, it is thought that autoimmunity may play a role in the development of the skin lesions observed in both these diseases. As regulatory T cells (Tregs) play a key role in the modulation of immune responses, it has recently been suggested that Treg impairment may lead to the development of autoimmune diseases.

VEGF-165 serum levels and tyrosinase expression in melanoma patients: correlation with the clinical course.

Vascular endothelial growth factor (VEGF) is known to play a crucial role in the growth and metastatization of solid tumours. In cancer patients, high VEGF serum levels correlate with tumour status and prognosis, but to date few data have been reported concerning VEGF in melanoma patients. In the present study, immunoenzymatic and reverse transcription-polymerase chain reaction (RT-PCR) techniques were used to detect VEGF-165 serum levels and the presence of tyrosinase mRNA, respectively, in the peripheral blood of a cohort of 155 melanoma patients at different clinical stages (30 stage I, 40 stage II, 40 stage III and 45 stage IV; AJCC classification). Data were compared with both the extent of the disease and the clinical course. The aim was to assess the relationship between VEGF serum levels, the presence of detectable circulating melanoma cells and melanoma progression. A significant increase in VEGF serum levels was found in melanoma patients, in particular in those with metastatic disease; a higher incidence of relapses was found in stage I–III disease-free patients who showed an increase in VEGF during follow-up. VEGF serum levels were significantly higher in patients with detectable circulating melanoma cells than in those with negative tyrosinase mRNA expression. The finding of both an increase in VEGF and the presence of detectable melanoma cells during follow-up was associated with a relapse rate of 81%. The relapse rate was significantly lower when either of the two parameters were present separately. Multivariate analysis of both overall survival and time-to-progression selected baseline tyrosinase expression in peripheral blood but not VEGF serum levels as an independent prognostic factor.

Tyrosinase expression in the peripheral blood of stage III melanoma patients is associated with a poor prognosis: a clinical follow-up study of 110 patients

The aim of this study is to define the relationship between the tyrosinase expression in the peripheral blood and the clinical course of the disease in stage III disease-free melanoma patients after radical lymph node dissection. RT–PCR techniques were used to identify tyrosinase mRNA in 110 patients; a total of 542 blood samples were investigated. In all, 54 patients (49%) showed at least one positive result; 13 patients (11.8%) showed baseline positive results: six became negative thereafter, whereas seven showed follow-up positive results until disease progression occurred. One or more positive determinations were found during follow-up in 41 patients with negative baseline tyrosinase. No correlation was found between baseline results and the relapse rate or disease-free survival (DFS), whereas a significant correlation was found between positive tyrosinase results and disease recurrence during follow-up. In fact, 72.9% of positive patients relapsed, but only 19.3% of negative cases did so. The median interval between the positive results and the clinical demonstration of the relapse was 1.9 months (range 1–6.6). Disease-free survival multivariate analysis selected, as independent variables, Breslow thickness (P=0.05), lymph node involvement according to the AJCC classification (P=0.05) and tyrosinase expression (P=0.0001). In conclusion, RT–PCR tyrosinase mRNA expression is a reliable and reproducible marker associated with a high risk of melanoma progression and we encourage its clinical use in routine follow-up.

Skin metastases of malignant melanoma: a clinical and prognostic survey.

Skin metastases are a frequent event in the natural history of malignant melanoma, both in the early and late phases of disease progression. In this study, we reviewed our database of 4865 melanoma patients, who were diagnosed and followed up prospectively over a 30-year period at our institution. Statistical analyses were focused on patients with secondary involvement of the skin. Seven hundred and thirty-three of the 4030 patients that met the inclusion criteria (18.2%) developed cutaneous metastases; the skin was involved as first site in 413 patients (56.3%) and after regional lymph node spreading in 208 (28.4%) patients. In a lower number of patients, cutaneous metastases developed only in advanced stages of the disease. Skin metastases were mainly locoregional, when arising as the first site of relapse (89.3%) and/or in patients with a primary melanoma of the lower limbs; in contrast, disseminated metastases are more often observed after a visceral involvement and for primary melanomas of the trunk. Moreover, despite a lower disease-free survival rate (1.3 vs. 2.9 years), we showed a significantly longer time to progression to visceral involvement for the group of patients with cutaneous locoregional metastases (62.5 vs. 17.8 months). The site of primary melanoma is strictly related to the pattern of cutaneous recurrence. The disparity in clinical outcome between patients with locoregional or disseminated skin metastases should therefore be taken into consideration in their management.

The Risk of Melanoma in Airline Pilots and Cabin Crew: A Meta-analysis

IMPORTANCE Airline pilots and cabin crew are occupationally exposed to higher levels of cosmic and UV radiation than the general population, but their risk of developing melanoma is not yet established. OBJECTIVE To assess the risk of melanoma in pilots and airline crew. DATA SOURCES PubMed (1966 to October 30, 2013), Web of Science (1898 to January 27, 2014), and Scopus (1823 to January 27, 2014). STUDY SELECTION All studies were included that reported a standardized incidence ratio (SIR), standardized mortality ratio (SMR), or data on expected and observed cases of melanoma or death caused by melanoma that could be used to calculate an SIR or SMR in any flight-based occupation. DATA EXTRACTION AND SYNTHESIS Primary random-effect meta-analyses were used to summarize SIR and SMR for melanoma in any flight-based occupation. Heterogeneity was assessed using the χ2 test and I2 statistic. To assess the potential bias of small studies, we used funnel plots, the Begg rank correlation test, and the Egger weighted linear regression test. MAIN OUTCOMES AND MEASURES Summary SIR and SMR of melanoma in pilots and cabin crew. RESULTS Of the 3527 citations retrieved, 19 studies were included, with more than 266 431 participants. The overall summary SIR of participants in any flight-based occupation was 2.21 (95% CI, 1.76-2.77; P < .001; 14 records). The summary SIR for pilots was 2.22 (95% CI, 1.67-2.93; P = .001; 12 records). The summary SIR for cabin crew was 2.09 (95% CI, 1.67-2.62; P = .45; 2 records). The overall summary SMR of participants in any flight-based occupation was 1.42 (95% CI, 0.89-2.26; P = .002; 6 records). The summary SMR for pilots was 1.83 (95% CI, 1.27-2.63, P = .33; 4 records). The summary SMR for cabin crew was 0.90 (95% CI, 0.80-1.01; P = .97; 2 records). CONCLUSIONS AND RELEVANCE Pilots and cabin crew have approximately twice the incidence of melanoma compared with the general population. Further research on mechanisms and optimal occupational protection is needed.

Favourable prognostic role of regression of primary melanoma in AJCC stage I-II patients.

The prognostic significance of regression in primary melanoma has been debated over the past few years. Once it was considered to be a negative prognostic factor, as it may have prevented proper melanoma thickness measurement, therefore affecting the staging of the tumours. For this reason, it was considered to be an indication for sentinel lymph node biopsy (SLNB) in melanoma < 1 mm.

CD45RA+ immunophenotype in mycosis fungoides: clinical, histological and immunophenotypical features in 22 patients

Background: Mycosis fungoides (MF) is a cutaneous T‐cell lymphoma (CTCL) usually characterized by a T‐helper memory phenotype (CD3+, CD4+, CD8−, CD45R0+). Aberrant phenotypes are more commonly seen in the tumor stages. CD45RA expression has so far been documented in only a few cases of CD8+ or TCRγδ+ CTCL and in some pagetoid reticulosis cases.

Comparative profile of cutaneous adverse events: BRAF/MEK inhibitor combination therapy versus BRAF monotherapy in melanoma

BACKGROUND BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) frequently cause cutaneous adverse events. OBJECTIVE We sought to investigate the cutaneous safety profile of BRAFi versus BRAFi and MEKi combination regimens. METHODS We performed a retrospective cohort study, collecting data from 44 patients with melanoma treated either with BRAFi (vemurafenib or dabrafenib) or BRAFi and MEKi combination regimens (vemurafenib + cobimetinib or dabrafenib + trametinib). Patient characteristics, and the occurrence and severity of cutaneous adverse events, are described. RESULTS The development of cutaneous adverse events was significantly less frequent (P = .012) and occurred after longer treatment time (P = .025) in patients treated with BRAFi and MEKi combination regimen compared with patients treated with BRAFi monotherapy. Among patients who received both BRAFi and the combination of BRAFi and MEKi at different time points during their treatment course, the development of squamous cell carcinoma or keratoacanthoma was significantly less frequent when they received the combination regimen (P = .008). Patients receiving vemurafenib developed more cutaneous adverse events (P = .001) and in particular more photosensitivity (P = .010) than patients who did not. LIMITATIONS There were a limited number of patients. CONCLUSION Combination regimen with BRAFi and MEKi shows fewer cutaneous adverse events and longer cutaneous adverse event-free interval compared with BRAFi monotherapy.