Jos[Eacute] Luis Rodr[Iacute]Guez-Peralto

Purpose: Melanoma is a highly metastatic tumor responsible for 90% of skin cancer deaths. Despite established clinical guidelines, certain areas of its management in Spain remain heterogeneous, particularly in complex scenarios such as neoadjuvant therapy, metastatic sequencing, and follow-up. This project aimed to generate expert-informed recommendations to standardize care in areas of clinical uncertainty. Materials and methods: A two-round Delphi process was conducted. Following a systematized review, a multidisciplinary panel of 35 specialists (oncology, dermatology, surgery, and pathology) evaluated 59 statements on uncertain areas of melanoma management. Consensus was defined as ≥ 80% agreement using a 5-point Likert scale. Results: Overall, 52 statements achieved consensus (3 unanimous, 49 by agreement). Key findings support the use of neoadjuvant immunotherapy in resectable stage III melanoma, particularly in patients with clinically detectable nodal disease, due to its benefit in reducing recurrence risk. A major pathological response was considered a key factor to individualize subsequent surgical and adjuvant decisions. In metastatic disease, therapeutic sequencing algorithms were defined according to BRAF mutational status, prior treatments, and timing of progression. The panel agreed that PD-L1 expression should not be used as the sole factor to exclude patients from anti-PD-1 therapy. Marked variability in follow-up practices was identified, highlighting the need for standardized approaches and quality indicators. Conclusion: This Delphi consensus reflects the views of a multidisciplinary panel of Spanish melanoma experts on key areas of uncertainty in melanoma management. By integrating evidence and expert experience, the findings may help support clinical decision-making and serve as a complementary reference for clinical practice.

Analysis of ENG expression and plasma circulating sEVs in human PNSTs.

ENG knockdown leads to downregulation of pro-angiogenic and pro-metastatic gene signatures in MPNST cells.

ENG knockdown does not affect MPNST cell apoptosis in vivo.

Significant deregulated genes in shENG versus shScramble STS26T cells.

Combined anti-ENG/anti-MEK therapy inhibits MPNST growth without toxicity in vivo.

Dual inhibition of ENG and MEK efficiently blocks ENG-Smad1/5 and MAPK/ERK pathway activation in ST88-14 cells.

Taqman probes used for quantitative PCR.

Anti-ENG therapy is active against MPNST xenografts.

Dual inhibition of ENG and MEK efficiently blocks ENG-Smad1/5 and MAPK/ERK pathway activation in ST88-14 cells.