Electrochemotherapy (ECT) is an effective locoregional therapy for cutaneous melanoma metastases and has been safely combined with immune checkpoint inhibitors in preliminary experiences. Since ECT is known to induce immunogenic cell death, its combination with immune checkpoint inhibitors might be beneficial. In this study, we aimed to investigate the effectiveness of ECT on cutaneous melanoma metastases in combination with pembrolizumab. We undertook a retrospective matched cohort analysis of stage IIIC–IV melanoma patients, included in the International Network for sharing practices of ECT (InspECT) and the Slovenian Cancer Registry. We compared the outcome of patients who received the following treatments: (a) pembrolizumab alone, (b) pembrolizumab plus ECT, and (c) ECT. The groups were matched for age, sex, performance status, and size of skin metastases. The local objective response rate (ORR) was higher in the pembrolizumab-ECT group than in the pembrolizumab group (78% and 39%, p < 0.001). The 1 year local progression-free survival (LPFS) rates were 86% and 51% (p < 0.001), and the 1 year systemic PFS rates were 64% and 39%, respectively (p = 0.034). The 1 year overall survival (OS) rates were 88% and 64%, respectively (p = 0.006). Our results suggest that skin-directed therapy with ECT improves superficial tumor control in melanoma patients treated with pembrolizumab. Interestingly, we observed longer PFS and OS in the pembrolizumab-ECT group than in the pembrolizumab group. These findings warrant prospective confirmation.

Background: Metastatic uveal melanoma (MUM) is a highly aggressive, therapy-resistant disease. Driver mutations in Gα-proteins GNAQ and GNA11 activate MAP-kinase and YAP/TAZ pathways of oncogenic signalling. MAP-kinase and MEK-inhibitors do not significantly block MUM progression, likely due to persisting YAP/TAZ signalling. Statins inhibit YAP/TAZ activation by blocking the mevalonate pathway, geranyl-geranylation, and subcellular localisation of the Rho-GTPase. We investigated drugs that affect the YAP/TAZ pathway, valproic acid, verteporfin and statins, in combination with MEK-inhibitor trametinib. Methods: We established IC50 values of the individual drugs and monitored the effects of their combinations in terms of proliferation. We selected trametinib and cerivastatin for evaluation of cell cycle and apoptosis. Synergism was detected using isobologram and Chou–Talalay analyses. The most synergistic combination was tested in vivo. Results: Synergistic concentrations of trametinib and cerivastatin induced a massive arrest of proliferation and cell cycle and enhanced apoptosis, particularly in the monosomic, BAP1-mutated UPMM3 cell line. The combined treatment reduced ERK and AKT phosphorylation, increased the inactive, cytoplasmatic form of YAP and significantly impaired the growth of UM cells with monosomy of chromosome 3 in NSG mice. Conclusion: Statins can potentiate the efficacy of MEK inhibitors in the therapy of UM.

Although several studies have explored the molecular landscape of metastatic melanoma, the genetic determinants of therapy resistance are still largely unknown. Here, we aimed to determine the contribution of whole-exome sequencing and circulating free DNA (cfDNA) analysis in predicting response to therapy in a consecutive real-world cohort of 36 patients, undergoing fresh tissue biopsy and followed during treatment. Although the underpowered sample size limited statistical analysis, samples from non-responders had higher copy number variations and mutations in melanoma driver genes compared to responders in the BRAF V600+ subset. In the BRAF V600− subset, Tumor Mutational Burden (TMB) was twice that in responders vs. non-responders. Genomic layout revealed commonly known and novel potential intrinsic/acquired resistance driver gene variants. Among these, RAC1, FBXW7, GNAQ mutations, and BRAF/PTEN amplification/deletion were present in 42% and 67% of patients, respectively. Both Loss of Heterozygosity (LOH) load and tumor ploidy were inversely associated with TMB. In immunotherapy-treated patients, samples from responders showed higher TMB and lower LOH and were more frequently diploid compared to non-responders. Secondary germline testing and cfDNA analysis proved their efficacy in finding germline predisposing variants carriers (8.3%) and following dynamic changes during treatment as a surrogate of tissue biopsy, respectively.

Background/Objectives: During the pandemic, access to healthcare was severely disrupted, inevitably affecting melanoma diagnosis. While this was clearly evident during the pandemic itself, it is less clear whether clinical presentation has returned to baseline levels in subsequent years. Our study aimed to compare the current clinical presentation of melanoma with that in the pre-pandemic setting. Methods: We conducted a retrospective multicenter study involving Italian melanoma referral centers within the SICO network. Patients with a newly diagnosed primary cutaneous melanoma were included in the study and were grouped into four time periods: pre-pandemic (March 2019 to February 2020); pandemic (March 2021 to February 2022); the first post-pandemic year (March 2022 to February 2023); and the second post-pandemic year (March 2023 to February 2024). Our focus was on clinically relevant features at diagnosis, including Breslow thickness, ulceration, stage and sentinel lymph node status. We evaluated differences across periods using regression models that accounted for the multicenter design. Results: A total of 4938 patients were included in the study. Compared with the pre-pandemic period, melanomas diagnosed during and after the pandemic were thicker, more frequently ulcerated and more likely to be in stages II–III. The rate of sentinel lymph node positivity also increased. Notably, these patterns did not normalize over time, remaining evident even in the second post-pandemic year. The results were consistent after adjusting for age and sex. Conclusions: In this large Italian study, melanoma continues to be diagnosed at a later stage than in the pre-pandemic period. This persistent shift may reflect a combination of delayed access to care and ongoing system-level constraints. These findings emphasize the importance of restoring timely access to dermatological evaluation and reinforcing early detection strategies.

The association between breast cancer and non-Hodgkin lymphoma of the spleen is extremely rare, with very few cases documented in the medical literature. We present the case of a 39-year-old woman in good health but with a family history of breast cancer, who, in 2017, developed invasive lobular carcinoma in her right breast, which was treated with mastectomy followed by hormonal therapy. In 2024, she presented with a suspicious right axillary mass, suspected of recurrence, which was confirmed by fine-needle aspiration biopsy. The patient received neoadjuvant chemotherapy, followed by axillary lymph node dissection and bilateral adnexectomy. CT and PET scans showed suspicious splenic lesions suggestive of metastases. Infectious and hematological tests were negative, leading to the decision to perform laparoscopic splenectomy. Histological examination revealed follicular B-cell non-Hodgkin lymphoma. The patient is now in good general condition and is on a biannual follow-up. The case highlights the diagnostic complexity of tumor recurrences and the need to consider alternative diagnoses other than metastasis in oncological patients.

Background/Objectives: The indirect impact of the pandemic on the diagnosis and treatment of new primary melanoma has been carefully evaluated in recent years. The aim of the present study was to investigate if the indirect impact of the pandemic in Italy could be detectable also in the second year of the pandemic, as suggested by the characteristics of melanoma at diagnosis. Methods: Retrospective analysis of 1640 diagnoses of cutaneous melanoma in pre-pandemic period and 1292 diagnoses in the pandemic period from 10 centers (from 1 March 2019 to 28 February 2022). Results: Our findings confirmed an indirect impact of the pandemic on characteristics of incident melanoma, also in the second year of the pandemic in Italy (Breslow thickness p < 0.0001, tumor stage p = 0.002, ulceration p = 0.04, SNLB p = 0.03), without statistically significant differences between centers. A statistically significant reduction in the time interval from diagnosis to surgical treatment was observed, but only in centers that had to modify their case mix to address the needs of treating COVID-19 patients (p = 0.0002). Conclusions: Our study confirmed the indirect impact of the pandemic on melanoma characteristics at the diagnosis in the second year of the pandemic in Italy. We also found no differences in melanoma characteristics between hospitals with different organization. Diagnostic delays may be related to a delayed access of the patient to the entire diagnostic pathway, and therefore, especially in the case of a pandemic, policies to support early diagnosis are crucial.