Identifying high-risk features and improving follow-up strategies in thin melanoma: a retrospective cohort study Antonella Vecchiato, Claudia Cozzolino, Paolo Del Fiore, Fortunato Cassalia, PierPaola Vallese, et al. Clinical and Experimental Dermatology, 2026 Background Thin melanomas (TMs) are typically associated with favourable outcomes, but a subset of patients experience recurrence and worse survival. Prognostic factors for recurrence in TM remain inadequately characterized. Objectives To identify clinical and histopathological factors associated with recurrence and explore implications for follow-up strategies in TM. Methods A retrospective cohort study included 308 patients with TM (Breslow thickness 0.1–1 mm) treated at two medical institutions between 1998 and 2017. Patients were stratified into groups with recurrence (n = 53) and no recurrence (n = 255). Clinical and histopathological variables were analysed, and survival outcomes were assessed. Results Recurrence (vs. no recurrence) was associated with nodular histology (13% vs. 3.1%, P = 0.02), presence of ulceration (17% vs. 2.7%, P < 0.001) and higher mitotic rate (mean 2.1 vs. 0.6 mitoses mm−2, P < 0.001). Ultrathin melanoma (Breslow ≤ 0.5 mm) was protective against recurrence (hazard ratio 0.08, P < 0.001). Recurrence (vs. no recurrence) reduced 10-year overall survival (62% vs. 95.7%, P < 0.001) and melanoma-specific survival (64% vs. 100%, P < 0.001). Conclusions Prognostic factors such as ulceration, mitotic rate and histological subtype should guide individualized follow-up strategies. Ultrathin melanomas may require less intensive monitoring, while melanomas > 0.5 mm could benefit from extended follow-up beyond current guidelines. Tailoring surveillance based on recurrence risk could improve outcomes and quality of care for patients with TM.
Molecular Basis of BRAF Inhibitor Resistance in Melanoma: A Systematic Review Ilaria Cosci, Valentina Salizzato, Paolo Del Fiore, Jacopo Pigozzo, Valentina Guarneri, et al. Pharmaceuticals, 2025 Background: Melanoma, the deadliest human skin cancer, frequently harbors activating BRAF mutations, with V600E being the most prevalent. These alterations drive constitutive activation of the MAPK pathway, promoting uncontrolled cell proliferation, survival, and dissemination. The advent of BRAFi and MEKi has significantly improved outcomes in BRAF V600-mutant melanoma. However, therapeutic resistance remains a major clinical barrier. Methods: This review integrates recent findings from preclinical and clinical studies to delineate resistance mechanisms to BRAF-targeted therapy. It categorizes resistance into primary (intrinsic), adaptive, and acquired forms, and analyzes their molecular underpinnings, including genetic and epigenetic alterations, pathway reactivation, and microenvironmental interactions. Results: Primary resistance is linked to pre-existing genetic and epigenetic changes that activate alternative signaling pathways, such as PI3K-AKT. Adaptive and acquired resistance includes secondary BRAF mutations, pathway redundancy, phenotype switching, and immune and stromal interactions. High-throughput sequencing has revealed novel mutations, including NRAS, NF1, and PTEN alterations, that contribute to resistance. Discussion: Understanding the multifaceted nature of resistance is critical to improving outcomes in advanced melanoma. This review highlights emerging strategies to overcome resistance, including combinatorial therapies, metabolic targeting, and biomarker-driven approaches, aiming to inform future therapeutic development and precision oncology strategies.
Sex-related differences in serum biomarker levels predict the activity and efficacy of immune checkpoint inhibitors in advanced melanoma and non-small cell lung cancer patients Giulia Pasello, Aline S. C. Fabricio, Paola Del Bianco, Valentina Salizzato, Adolfo Favaretto, et al. Journal of Translational Medicine, 2024 Background Immune Checkpoint Inhibitors (ICIs) lead to durable response and a significant increase in long-term survival in patients with advanced malignant melanoma (MM) and Non-Small Cell Lung Cancer (NSCLC). The identification of serum cytokines that can predict their activity and efficacy, and their sex interaction, could improve treatment personalization. Methods In this prospective study, we enrolled immunotherapy-naïve patients affected by advanced MM and NSCLC treated with ICIs. The primary endpoint was to dissect the potential sex correlations between serum cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, GM-CSF, MCP-1, TNF-ɑ, IP-10, VEGF, sPD-L1) and the objective response rate (ORR). Secondly, we analyzed biomarker changes during treatment related to ORR, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Blood samples, collected at baseline and during treatment until disease progression (PD) or up to 2 years, were analyzed using Luminex xMAP or ELLA technologies. Results Serum samples from 161 patients (98 males/63 females; 92 MM/69 NSCLC) were analyzed for treatment response. At baseline, IL-6 was significantly lower in females (F) versus males (M); lower levels of IL-4 in F and of IL-6 in both sexes significantly correlated with a better ORR, while higher IL-4 and TNF-ɑ values were predictive of a lower ORR in F versus M. One hundred and sixty-five patients were evaluable for survival analysis: at multiple Cox regression, an increased risk of PD was observed in F with higher baseline values of IL-4, sPD-L1 and IL-10, while higher IL-6 was a negative predictor in males. In males, higher levels of GM-CSF predict a longer survival, whereas higher IL-1β predicts a shorter survival. Regardless of sex, high baseline IL-8 values were associated with an increased risk of both PD and death, and high IL-6 levels only with shorter OS. Conclusions Serum IL-1β, IL-4, IL-6, IL-10, GM-CSF, TNF-ɑ, and sPD-L1 had a significant sex-related predictive impact on ORR, PFS and OS in melanoma and NSCLC patients treated with ICIs. These results will potentially pave the way for new ICI combinations, designed according to baseline and early changes of these cytokines and stratified by sex.
Cytokine and soluble programmed death-ligand 1 levels in serum and plasma of cancer patients treated with immunotherapy: Preanalytical and analytical considerations Elia Cappelletto, Laura Tiozzo Fasiolo, Valentina Salizzato, Luisa Piccin, Alessio Fabozzi, et al. International Journal of Biological Markers, 2024 Aim To evaluate cytokine and soluble programmed death ligand-1 (sPD-L1) levels in the serum and plasma of cancer patients treated with immunotherapy, and to test different assays. Methods Three Luminex xMAP assays and two ELLA microfluidic cartridges were used to screen 28 immune-related biomarkers in 38 paired serum and citrate-theophylline-adenosine-dipyridamole (CTAD) plasma samples collected from 10 advanced melanoma or non-small cell lung cancer (NSCLC) patients at different time points during immunotherapy. Results Twenty-three of 28 biomarkers were detected both in serum and plasma by at least one of the assays, including IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, GM-CSF, IFN-γ, TNF-α, VEGF, IP-10, MCP-1, eotaxin, fractalkine, G-CSF, IFN-α, IL-1RA, IL-13, IL-17A, MIP-1β and sPD-L1. Conversely, FGF-2 and IL-1α were not detected in both matrices; GRO-α factor and EGF were detected only in serum and MIP-1α only in plasma. sPD-L1, MCP-1, IFN-γ, IL-8, MIP-1β and VEGF were, respectively, 1.15-, 1.44-, 1.83-, 2.43-, 2.82-, 6.72-fold higher in serum, whereas IL-10, IL-4, IL-2 and IL-5 were 1.05-, 1.19-, 1.92- and 2.17-fold higher, respectively, in plasma. IP-10 levels were higher in plasma but, as well as for VEGF, the bias serum versus plasma varied depending on the assay used (IP-10: −5.7% to −145%; VEGF: 115% to 165%). No significant differences were found for the remaining nine analyzed cytokines. Conclusion The cytokine and sPD-L1 levels may differ between serum and plasma samples collected from cancer patients treated with immunotherapy, and the results obtained can be influenced by the different characteristics of the tested assays. The standardization of pre-analytical and analytical procedures is therefore needed for the future implementation of these circulating biomarkers in clinical practice.
Protein kinase CK2 subunits exert specific and coordinated functions in skeletal muscle differentiation and fusogenic activity Valentina Salizzato, Sofia Zanin, Christian Borgo, Elisa Lidron, Mauro Salvi, et al. FASEB Journal, 2019 Casein kinase 2 (CK2) is a tetrameric protein kinase composed of 2 catalytic (α and α′) and 2 regulatory β subunits. Our study provides the first molecular and cellular characterization of the different CK2 subunits, highlighting their individual roles in skeletal muscle specification and differentiation. Analysis of C2C12 cell knockout for each CK2 subunit reveals that: 1) CK2β is mandatory for the expression of the muscle master regulator myogenic differentiation 1 in proliferating myoblasts, thus controlling both myogenic commitment and subsequent muscle‐specific gene expression and myotube formation; 2) CK2α is involved in the activation of the muscle‐specific gene program; and 3) CK2α′ activity regulates myoblast fusion by mediating plasma membrane translocation of fusogenic proteins essential for membrane coalescence, like myomixer. Accordingly, CK2α′ overexpression in C2C12 cells and in mouse regenerating muscle is sufficient to increase myofiber size and myonuclei content via enhanced satellite cell fusion. Consistent with these results, pharmacological inhibition of CK2 activity substantially blocks the expression of myogenic markers and muscle cell fusion both in vitro in C2C12 and primary myoblasts and in vivo in mouse regenerating muscle and zebrafish development. Overall, our work describes the specific and coordinated functions of CK2 subunits in orchestrating muscle differentiation and fusogenic activity, highlighting CK2 relevance in the physiopathology of skeletal muscle tissue.—Salizzato, V., Zanin, S., Borgo, C., Lidron, E., Salvi, M., Rizzuto, R., Pallafacchina, G., Donella‐Deana, A. Protein kinase CK2 subunits exert specific and coordinated functions in skeletal muscle differentiation and fusogenic activity. FASEB J. 33, 10648–10667 (2019). www.fasebj.org
