Maria Francesca Morelli

The Transient Receptor Potential Ankyrin 1 (TRPA1) channel is a non-selective cation channel activated by a range of physical and chemical stimuli. While primarily studied in neuronal tissues, TRPA1 is also expressed in human keratinocytes, where its role remains poorly understood. Here, we investigated TRPA1 expression and function in keratinocytes and examined the effects of its activation on cellular proliferation, immune activation, and neuropeptide release under both basal and inflammatory stimuli. TRPA1 expression was detected in basal keratinocytes and was upregulated by pro-inflammatory cytokines. Stimulation with the TRPA1 agonist allyl isothiocyanate (AITC) induced a rapid calcium influx, confirming functional channel activity. AITC at 5 µM did not induce cytotoxicity but significantly reduced keratinocyte proliferation and caused cell cycle arrest. Under stimulation with TNF-α and IFN-γ, TRPA1 activation decreased the surface expression of HLA-DR and ICAM-1, and downregulated mRNA levels of CXCL10, CXCL8, CCL5, and CCL20, while IL-6 expression remained unchanged. Furthermore, AITC treatment reduced the secretion of Substance P, but not CGRP. These findings indicate that TRPA1 functions as a cytokine-inducible, immunomodulatory receptor in human keratinocytes, capable of attenuating proliferation and inflammatory activation without compromising cell viability, thereby suggesting a potential role in maintaining skin homeostasis and modulating cutaneous inflammation.

Background/Objectives: Radiomics is a powerful and emerging tool in oncology, with many potential applications in predicting therapy response and prognosis. To assess the current state of radiomics in melanoma, we conducted a systematic review of its various clinical uses. Methods: We searched three databases: PubMed, Web of Science and Scopus. Each study was classified based on multiple variables, including patient number, metastasis number, therapy, imaging modality, clinical endpoints and analysis methods. The risk of bias in the systematic review was assessed with QUADAS-2, and the certainty of evidence in the meta-analysis with GRADE. Results: Forty studies involving 4673 patients and 24,561 lesions were included in the analysis. Metastatic disease was the most frequently studied clinical setting (85%). Immunotherapy was the most commonly investigated treatment, featured in half of the studies. Computed tomography (CT) was the preferred imaging modality, appearing in 17 studies (42.5%). Radiomic features were most often extracted using three-dimensional (3D) analysis (72.5%). Across 24 studies investigating the prediction of treatment response and survival, only 9 provided sufficient data (Area Under the Curve, AUC, and standard error, SE) for inclusion. A random-effects model estimated a pooled AUC of 0.83 (95% CI: 0.74 to 0.92), indicating strong discriminative performance of the radiomic models included. Low to moderate heterogeneity was observed (I² = 28.6%, p = 0.4741). No evidence of publication bias was detected (p = 0.470). Conclusions: Radiomics is increasingly being explored in the context of melanoma, particularly in advanced disease settings and in relation to immunotherapy. Most studies rely on CT imaging and 3D feature extraction, while molecular integration remains limited. Despite promising findings with strong discriminative performance in predicting therapy response, further prospective, standardized studies with higher methodological rigor are needed to validate radiomic biomarkers and integrate them into clinical decision-making.

Background/Objective: Dabrafenib and trametinib (D + T) have been approved for the treatment of stage III melanoma with BRAF V600E V600K mutations in an adjuvant setting, based on the results from the COMBI-AD trial. To provide early access to this combination therapy prior to its commercial availability in Italy, a Managed Access Program (MAP) was run in Italy from June 2018 to December 2019. Methods: The MADAM (Maximing ADjuvAnt MAP) study is an Italian retrospective–prospective observational study that included patients who received at least one dose of D + T through the MAP. The primary endpoints were relapse-free survival (RFS) and overall survival (OS). Results: This interim analysis presents findings after the first 24 months of follow-up. A total of 310 patients were included in the study; 240 completed the 12-month treatment with D + T, while 70 discontinued the combination. RFS rates were 93.2% at 12 months and 80.2% at 24 months. The median RFS was not reached for the overall population or any subgroups. Similarly, the median OS was not reached, with OS rates of 96.4% at 12 months and 92.5% at 24 months. Conclusions: D + T achieved an RFS benefit, with effects sustained beyond the treatment period, indicating positive outcomes in this patient population.

Background: When monotherapy with PD-1 inhibitors in metastatic melanoma fails, there are currently no standard second-line choices. In case of the unavailability of clinical trials, ipilimumab represents a possible alternative treatment. Methods: We collected data of 44 patients who received ipilimumab after the failure of PD-1 inhibitors from July 2017 to May 2023 at our Institute. Overall survival (OS), progression-free survival (PFS), and post-progression survival (PPS) based on BRAF or NRAS mutation status, sex, and the presence of brain metastases were estimated using the Kaplan–Meier method. Cox regression was used to evaluate independence in multivariate analysis. The objective response rate (ORR) was estimated based on RECIST 1.1. Results: Among the 44 patients enrolled in this study, 28 BRAF-wildtype, 9 BRAF-mutated, and 7 NRAS-mutated patients were identified. OS analysis showed a significant difference between wildtype and BRAF- or NRAS-mutated patients: 23.2 months vs 5.3 and 4.59, respectively, p = 0.017. The presence of brain metastases and BRAF or NRAS mutation were independent factors for mortality in multivariate analysis. Conclusions: In case of failure to enroll patients in innovative clinical trials, second-line ipilimumab still represents an effective therapy in patients with metastatic wildtype melanoma and in the absence of brain metastases.

(1) Background: Mucosal melanoma (MM) is a rare tumor, accounting for about 1% of all diagnosed melanomas. The etiology and pathogenesis of this tumor are unknown. It is characterized by an aggressive phenotype with poor prognosis and a low response rate to approved treatments. (2) Methods: We retrospectively analyzed the clinical features, treatments and outcomes of patients diagnosed with MM from different sub-sites (head and neck, gynecological and gastro-intestinal region) between 2013 and 2023 at our Institute. Survival times were estimated with the Kaplan–Meier method. Multivariate Cox regression was used to test the independence of significant factors in univariate analysis. (3) Results: Twenty-five patients were included in this study; the disease was equally distributed among females and males. The median age at diagnosis was 74 years old. The majority had MM originating from the head and neck (56%), particularly from the nasal cavity. BRAF V600 mutations were detected in 16% of the study population, limited to gastro-intestinal and gynecological MM. At diagnosis, at least half the patients (52%) had the disease located also at distant sites. The median overall survival (OS) in the whole study population was 22 months, with a longer OS for patients diagnosed at an early stage (38 months, p < 0.001). Longer OSs were reported for head and neck MM compared to other anatomic regions (0.06). Surgery of the primary tumor and radiotherapy were performed in 64% and 36% of the study population, respectively. Radiotherapy was performed only in head and neck MM. At multivariate analysis, the single factor that showed a reduced hazard ratio for death was radiotherapy. (4) Conclusions: The overall survival of MM from different sub-sites treated at our Italian Institution was 22 months, with better outcomes for early-stage disease and head and neck MM. Performing radiotherapy may have a protective effect on OS for head and neck MM. New treatment strategies are urgently needed to improve the outcome in this disease.

In patients with B-RAF-mutated cutaneous melanoma, targeted therapies are the treatment of choice to achieve a rapid response. In this multicentric, prospective, observational study, patients with B-RAF-mutated cutaneous melanoma who were treated with dabrafenib and trametinib were categorized in two cohorts (cohort A: limited disease (n = 104) and cohort B: bulky disease (n = 97)) according to lactate dehydrogenase levels. The primary endpoint was the progression pattern; the secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety data. From baseline to time of progression, there was a progression from nodal to other sites of disease in cohort A and from skin and nodal to other sites in cohort B. In both the cohorts, the number of involved organs and metastases at each location decreased. The median OS was 32.4 months (95% CI: 20.1 months (not estimable)) for cohort A, and 10.5 months (95% CI: 8.3–14.4 months) for cohort B; median PFS was 12.4 months (95% CI: 10.9–17.0 months) for cohort A, and 8.1 months (95% CI: 6.3–9.4 months) for cohort B. No new safety signals were reported. This study describes the patterns of first-line treatment progression with dabrafenib and trametinib in Italian clinical practice. The effectiveness and safety data were consistent with previous trials and extended to a real-world heterogeneous population.