The discovery of the role of the RAS/RAF/MEK/ERK pathway in melanomagenesis and its progression have opened a new era in the treatment of this tumor. Vemurafenib was the first specific kinase inhibitor approved for therapy of advanced melanomas harboring BRAF-activating mutations, followed by dabrafenib and encorafenib. However, despite the excellent results of first-generation kinase inhibitors in terms of response rate, the average duration of the response was short, due to the onset of genetic and epigenetic resistance mechanisms. The combination therapy with MEK inhibitors is an excellent strategy to circumvent drug resistance, with the additional advantage of reducing side effects due to the paradoxical reactivation of the MAPK pathway. The recent development of RAS and extracellular signal-related kinases (ERK) inhibitors promises to add new players for the ultimate suppression of this signaling pathway and the control of pathway-related drug resistance. In this review, we analyze the pharmacological, preclinical, and clinical trial data of the various MAPK pathway inhibitors, with a keen interest for their clinical applicability in the management of advanced melanoma.

In the last years the onset of new therapies changed the management of malignant melanoma. Anti CTLA-4 antibody ipilimumab was the first drug to achieve a significant improvement in survival of advanced stage melanoma. This new therapeutic agent is characterized by a number of side effects that are totally different from those of traditional chemotherapy, mainly caused by the immune system activation. The purpose of this paper is to underline the central role of ipilimumab in the treatment of metastatic melanoma and to characterize related adverse events in terms of incidence, duration and severity of presentation. The early recognition of these side effects is crucial in order to ensure an appropriate management of the toxicities, thus reducing the long term clinical sequelae and the inappropriate treatment discontinuation.

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.

Background: Moderate‐to‐severe atopic dermatitis (AD) in the adolescence is a high burden disease, and its treatment can be very challenging due to paucity of approved systemic drugs for this age and their side‐effects. Dupilumab was recently approved for treatment of adolescent AD.Objectives: A multicentre, prospective, real‐world study on the effectiveness and safety of dupilumab in adolescents (aged from ≥12 to <18 years) with moderate‐to‐severe AD was conducted. The main AD clinical phenotypes were also examined.Methods: Data of adolescents with moderate‐to‐severe AD treated with dupilumab at label dosage for 16 weeks were collected. Treatment outcome was assessed by EASI, NRS itch, NRS sleep loss and CDLQI scores at baseline and after 16 weeks of treatment. The clinical scores were also evaluated according to clinical phenotypes.Results: One hundred and thirty‐nine adolescents were enrolled in the study. Flexural eczema and head and neck eczema were the most frequent clinical phenotypes, followed by hand eczema and portrait‐like dermatitis. Coexistence of more than 1 phenotype was documented in 126/139 (88.5%) adolescents. Three patients (2.1%) contracted asymptomatic SARS‐CoV‐2 infection and 1 of the discontinued dupilumab treatment before the target treatment period. A significant improvement in EASI, NRS itch, NRS sleep loss and CDLQI was observed after 16 weeks of treatment with dupilumab. This outcome was better than that observed in clinical trials. Dupilumab resulted effective in all AD phenotypes, especially in diffuse eczema. Twenty‐eight (20.1%) patients reported adverse events, conjunctivitis and flushing being the most frequent. None of patients discontinued dupilumab due to adverse event.Conclusions: Dupilumab in adolescent AD showed excellent effectiveness at week 16 with consistent improvement of all clinical scores. Moreover, dupilumab showed a good safety profile also in this COVID‐19 pandemic era.

Despite frequent skin involvement with solid tumors, zosteriform metastases are a rare, not well-defined entity, with only few cases published in literature. The unifying characteristic is merely topographic: cutaneous lesions were distributed along dermatomes, despite the variety of clinical features, including vesicobullous, papular, and nodular lesions. Several theories have been proposed to explain the pathogenetic mechanism of zosteriform dissemination, even if none was adequately proved. In this article, we report three new cases of patients with melanoma with skin zosteriform metastases and present a meta-analysis of literature data. We collected all Entrez-PubMed articles about zosteriform skin metastasis since 1970 and reviewed 56 cases, including our own taken from a 4,774-patient series. The histotypes mainly implicated were melanoma (18%); lymphoma (14%); breast cancer (12%); squamous cell carcinoma (12%); and digestive (10.7%), respiratory (10.7%), and urinary tumors (7%), with other histotypes accounting for 14%. In only one case in our series did we describe a typical herpetiform pattern, whereas in the others we found papulonodular lesions with a dermatomeric distribution. Cutaneous metastases with zosteriform pattern are rare and show a wide clinicopathologic spectrum that could affect the disease course. The authors have indicated no significant interest with commercial supporters.

Unknown melanoma occurs as metastasis to skin, nodes or viscera, without a detectable cutaneous primary tumour. We reviewed our database of 4881 melanoma patients, diagnosed and followed up prospectively for a 33-year period. We identified 93 cases of metastatic melanoma without evidence of primary; however, five of these patients had a history of a previous excision of a presumed benign lesion without histological examination and were excluded from analyses. At diagnosis, metastases were cutaneous in 35.3% of cases, nodal in 43.2% and visceral in 17% of cases; in 4.5% of patients, both skin and nodes were involved. In all cases, clinical inspection and staging procedures performed at diagnosis of metastatic disease failed to identify a primary melanoma. In 11 cases (11.8%), extensively regressed pigmented lesions (without evidence of melanoma cells at the histological examination) were documented; moreover, we identified in our series five patients with unknown primary affected by vitiligo. The 5-year and 10-year overall survival rates were 49.6 and 41.4%, respectively, with a median of 4.9 years. The 5-year and 10-year time to progression rates were 39.4 and 32.3%, respectively, with a median of 2.3 years. Survival was longer in females and showed significant differences among patients with skin, lymph node or visceral involvement at diagnosis. In melanoma patients, unknown primary represents a not so rare event, with an uncertain origin. We confirmed the relatively good prognosis of unknown primary melanoma patients, a fact that has to be taken into consideration for their management.