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Introduction/Objective. Epidemiology of melanoma including the number of new cases and mortality have been established in most developed countries, but data on pathohistological features are mostly missing. The objective of the study was to investigate epidemiological, clinical, and pathohistological features of melanoma patients and compare the results with trends in other countries. Methods. Our sample comprised patients surgically treated for skin melanoma at the Hospital for Burns, Plastic and Reconstructive Surgery during the 2015–2017 period. Pathohistological, clinical, and demographic features of melanoma were studied. Results. The retrospective study comprised 201 patients (109 men and 92 women) aged 25–87 years. Melanoma was more common in men than in women (54.2% vs. 45.8%). Melanoma in male population most commonly presented on the trunk, while in females presentation on the trunk and lower extremities was almost equal. Superficial spreading melanoma was the most common type of melanoma (68.7%), without correlation to the sex. No correlation was observed in relation to the stage of the disease and the patient’s sex (p = 0.294). A statistical difference was observed in relation to the type of melanoma and the Breslow classification (p < 0.001). Breslow’s thickness correlated with neither age nor sex. In relation to tumor invasiveness, 12.4% of the lesions were classified as in situ lesions, while 87.6% of the lesions were invasive. The majority of patients were identified as stage pT1a. Conclusion. This study can help to identify patients at high risk for melanoma and contribute to optimize screening efforts in a defined target population.

METTL3 has emerged as a promising therapeutic target in cancer treatment, although its oncogenic functions in melanoma development and potential for therapeutic targeting drug have not been fully explored. In this study, we define the oncogenic role of METTL3 in melanoma development and progression. Building on this insight, we examine our recently designed peptide inhibitor RM3, which targets the binding interface of METTL3/14 complex for disruption and subsequent ubiquitin-mediated proteasomal degradation via the E3 ligase STUB1. RM3 treatment reduces proliferation, migration, and invasion, and induces apoptosis in melanoma cells in vitro and in vivo. Subsequent transcriptomic analysis identified changes in immuno-related genes following RM3-mediated suppression of METTL3/14 N 6 -methyladenosine (m 6 A) methyltransferase activity, suggesting a potential for interaction with immunotherapy. A combination treatment of RM3 with anti-PD-1 antibody results in significantly higher beneficial tumor response in vivo, with a good safety profile. Collectively, these findings not only delineate the oncogenic role of METTL3 in melanoma but also showcase RM3, acting as a peptide degrader, as a novel and promising strategy for melanoma treatment., (© 2024 Wiley-VCH GmbH.)

Purpose: Nivolumab plus relatlimab and nivolumab plus ipilimumab have been approved for advanced melanoma on the basis of the phase II/III RELATIVITY-047 and phase III CheckMate 067 trials, respectively. As no head-to-head trial comparing these regimens exists, an indirect treatment comparison was conducted using patient-level data from each trial., Methods: Inverse probability of treatment weighting (IPTW) adjusted for baseline characteristic differences. Minimum follow-ups (RELATIVITY-047, 33 months; CheckMate 067, 36 months) were selected to best align assessments. Outcomes included progression-free survival (PFS), confirmed objective response rate (cORR), and melanoma-specific survival (MSS) per investigator; overall survival (OS); and treatment-related adverse events (TRAEs). A Cox regression model compared PFS, OS, and MSS. A logistic regression model compared cORRs. Subgroup analyses were exploratory., Results: After IPTW, key baseline characteristics were balanced for nivolumab plus relatlimab (n = 339) and nivolumab plus ipilimumab (n = 297). Nivolumab plus relatlimab demonstrated similar PFS (hazard ratio [HR], 1.08 [95% CI, 0.88 to 1.33]), cORR (odds ratio, 0.91 [95% CI, 0.73 to 1.14]), OS (HR, 0.94 [95% CI, 0.75 to 1.19]), and MSS (HR, 0.86 [95% CI, 0.67 to 1.12]) to nivolumab plus ipilimumab. Subgroup comparisons showed larger numerical differences favoring nivolumab plus ipilimumab with acral melanoma, BRAF -mutant melanoma, and lactate dehydrogenase >2 × upper limit of normal, but were limited by small samples. Nivolumab plus relatlimab was associated with fewer grade 3-4 TRAEs (23% v 61%) and any-grade TRAEs leading to discontinuation (17% v 41%)., Conclusion: Nivolumab plus relatlimab demonstrated similar efficacy to nivolumab plus ipilimumab in the overall population, including most-but not all-subgroups, and improved safety in patients with untreated advanced melanoma. Results should be interpreted with caution.

We probed the mechanism by which the Parkinson's disease-associated protein α-synuclein (α-syn)/SNCA promotes the pathogenesis and progression of melanoma. We found that the human melanoma cell line SK-MEL-28 in which SNCA is knocked out (SNCA-KO) has low levels of tetraspanin CD81, which is a cell-surface protein that promotes invasion, migration, and immune suppression. Analyzing data from the Cancer Genome Atlas, we show that SNCA and CD81 mRNA levels are positively correlated in melanoma; melanoma survival is inversely related to the levels of SNCA and CD81; and SNCA/CD81 are inversely related to the expression of key cytokine genes (IL12A, IL12B, IFN, IFNG, PRF1 and GZMB) for immune activation and immune cell-mediated killing of melanoma cells. We propose that high levels of α-syn and CD81 in melanoma and in immune cells drive invasion and migration and in parallel cause an immunosuppressive microenvironment; these contributing factors lead to aggressive melanomas., Competing Interests: Declaration of competing interest The authors have nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Melanoma is a highly aggressive tumor, predominantly found in the skin, recognized as skin cutaneous melanoma (SKCM). Lymph node metastasis is commonly used as the route of metastasis in SKCM, necessitating the discovery of prognostic genes associated with this process for improved prognosis., Methods: The prognostic significance of lymph node metastasis in SKCM was assessed through Kaplan-Meier analysis in SEER and TCGA-SKCM datasets. Prognostic genes were identified and a prognostic risk model was constructed Enrichment analysis and immune cell infiltration analysis were also carried out.Moreover, a validation in vitro and in vivo were conducted by CCK8,flow cytometry, transwell and animal study., Results: The Kaplan-Meier survival curve revealed that patients with lymph node metastasis had a worse prognosis compared to those without. FCGR3B and PRF1 were screened by TCGA analysis.Additionally, significant differences in nine immune cell types were observed between the two risk groups. Notably, a strong positive association with CD8 T cells and a negative relationship with M2 macrophages were exhibited by PRF1. The validation of our nomogram were conducted in vitro and in vivo, and the results showed the correlations between CD8 + T cell and PRF1., Conclusion: In summary, two prognostic genes (FCGR3B and PRF1) were identified, and a prognostic risk model was developed for SKCM. These findings provide a novel approach for the diagnosis and treatment of SKCM., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Choroidal nevi are common benign melanocytic lesions often incidentally found during routine ophthalmic examinations. Patients with choroidal nevi are frequently referred to ocular oncology centers to differentiate these from choroidal melanoma and to exclude a malignant transformation which rarely occurs. However, this causes a high workload for referral centers and may delay diagnosis and treatment of patients with potentially severe conditions. To overcome this, the MOLES score was previously developed which may empower non-specialists to differentiate choroidal nevi from melanoma. In this retrospective study, the performance of the MOLES score was assessed in 695 patients with choroidal nevi and 53 with choroidal melanoma. With a specificity of 96% (choroidal nevi) and a sensitivity of 100% (melanoma) the MOLES score was highly successful in differentiating choroidal nevi from melanoma and may offer great potential to optimize monitoring and referral decisions, and for teleophthalmology applications. Furthermore, the TFSOM-DIM score using risk factors for determining tumor progression was applied and showed a good correlation with MOLES. A complementary use of MOLES and TFSOM-DIM may be beneficial for clinical routine: MOLES for screening by non-experts with limited diagnostic tools and TFSOM-DIM in a referral setting to counsel also regarding potential transformation., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Objective: Many investigation have sought to identify therapeutic targets and treatment strategies for skin cutaneous melanoma (SKCM). Numb, an endocytic adaptor protein, is known to act as a tumor suppressor in various human cancers. However, the roles of Numb and its homolog NumbL in immune microenvironment, and their effect on melanoma remain largely unexplored., Methods: We analyzed the expression levels of Numb and NumbL, as well as immune signatures of SKCM patients by UCSCXenaShiny v1 database. We also constructed animal model using Numb and NumbL conditional knockout (cKO) mice. Distribution analysis of immune cells in tumors was performed by flow cytometry and pathology staining., Results: Numb and NumbL were found to be consistently expressed at low levels in SKCM patients. In addition, alterations in tumor immune microenvironment were identified. The CD8 + T, CD19 + B, and NK1.1 + CD49 + cells were decreased in tumors of Numb and NumbL cKO mice, confirming previous bioinformatics analysis of immune signatures. Additionally, we observed CD68 + macrophages to be increased as judged by tumor pathology staining., Conclusion: Numb and NumbL were found to inhibit melanoma cell growth by modulating immune cell activity. These results suggested that Numb and NumbL may be potential therapeutic targets for SKCM patient immunotherapy., Competing Interests: Declarations Ethics approval and consent to participate Animal involved in this study were in accordance with the Animal Care Committee, and approved by the Institutional Animal Care of Xi’an Jiaotong University (No. 2022-0069). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Melanoma, recognized as the most aggressive type of skin cancer, has experienced a notable increase in cases, especially within populations with fair skin. This highly aggressive cancer is largely driven by UV radiation exposure, resulting in the uncontrolled growth and malignant transformation of melanocytes. The cGAS-STING pathway, an immune signaling mechanism responsible for detecting double-stranded DNA in the cytoplasm, is essential for mediating the immune response against melanoma. This pathway serves a dual purpose: it enhances antitumor immunity by activating immune cells, but it can also promote tumor growth when chronically activated by creating an immunosuppressive environment. This review comprehensively examines the multifaceted implication of the cGAS-STING pathway in melanoma pathogenesis and treatment. We explore its molecular mechanisms, including epigenetic regulation, interaction with signaling pathways such as AR signaling, and modulation by various cellular effectors like TG2 and activin-A. The therapeutic potential of modulating the cGAS-STING pathway is highlighted, with promising results from STING agonists, combination therapies with immune checkpoint inhibitors, and novel drug delivery systems, including nanoparticles and synthetic drugs. Our findings underscore the importance of the cGAS-STING pathway in melanoma, presenting it as a critical target for enhancing anti-tumor immunity. By leveraging this pathway, future therapeutic strategies can potentially convert 'cold' tumors into 'hot' tumors, making them more susceptible to immune responses., Competing Interests: Declarations Ethics approval and consent to participate Not applicable (Review Study). Informed consent to consent for publication Not applicable (Review Study). Declaration of generative AI and AI-assisted technologies in the writing process During the preparation of this work, the authors used ChatGPT by OpenAI to improve paper readability. After using this tool/service, the authors reviewed and edited the content as needed and took full responsibility for the publication’s content. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Research suggests that a high proportion of melanoma in situ (MIS) may be overdiagnosed, potentially contributing to overtreatment, patient harm and inflated costs for individuals and healthcare systems. However, Australia-wide estimates of the magnitude of melanoma overdiagnosis are potentially outdated and there has been no estimation of the cost to the healthcare system., Objectives: To estimate the magnitude and cost of overdiagnosed MIS and thin invasive melanomas in Australia., Methods: Using two different methods to calculate lifetime risk, we used routinely collected national-level data to estimate overdiagnosed MIS and thin invasive melanomas (stage IA) in Australia in 2017 and 2021, separately for men and women. We multiplied the number of overdiagnosed melanomas by the estimated annual cost of a MIS or thin invasive melanoma, to quantify the financial burden of melanoma overdiagnosis to the Australian healthcare system in the year following diagnosis., Results: We estimated that 67-70% of MIS were overdiagnosed in 2017, rising to 71-76% in 2021, contributing to between 19 829 [95% confidence interval (CI) 19 553-20 105] and 20 811 (95% CI 20 528-21 094) cases of overdiagnosed MIS. In 2021, the estimated costs in Australia ranged between $17.7 million Australian dollars (AUD; 95% CI 17.4-17.9 million) and AUD$18.6 million (95% CI 18.3-18.8 million). We estimated that 22-29% of thin invasive melanomas were overdiagnosed in 2017, rising to 28-34% in 2021, contributing to between 2831 (95% CI 2726-2935) and 3168 (95% CI 3058-3279) overdiagnosed thin invasive melanomas. In 2021, the estimated costs from thin invasive melanoma overdiagnoses ranged between AUD$2.5 million (95% CI 2.4-2.6 million) and AUD$2.8 million (95% CI 2.7-2.9 million)., Conclusions: Melanoma overdiagnosis is a growing clinical and public health problem in Australia, producing significant economic costs in the year following overdiagnosis. Limiting melanoma overdiagnosis may prevent unnecessary healthcare resource use and improve financial sustainability within the Australian healthcare system., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Cutaneous melanoma incidence varies consistently across body sites between men and women, but the underlying causes of these differences remain unclear. To date, no prospective studies have examined risk factors for melanoma separately for men and women according to body site., Objectives: We aimed to examine the association between identified constitutional, genetic and environmental risk factors for invasive melanoma of different body sites among men and women., Methods: We compared the association between constitutional, genetic and environmental risk factors for invasive melanoma on different body sites separately for men and women in a population-based prospective cohort study of 17 774 men and 21 070 women aged between 40 and 69 years who were residents of Queensland, Australia at baseline in 2011. Participants were followed until December 2021. We examined risk factors including hair colour, tanning ability, naevus density and proxies for high cumulative sun exposure, all self-reported at baseline. We also examined polygenic risk score (PRS) derived from summary statistics from a melanoma genome-wide association study meta-analysis., Results: During a median 10.4 years of follow-up, 455 men and 331 women developed an incident invasive melanoma; the mean age at diagnosis was lower in women than in men (62.6 vs. 65.0 years). The most common body site was the trunk in men (45.1%), and the upper (36.8%) and lower limbs (27.4%) in women. High naevus density and proxy measures of high cumulative sun exposure were similarly associated with melanoma at all sites in men and women. In both sexes, high genetic risk was associated with melanoma on all body sites except the head and neck. We observed differences between men and women in the association between PRS and melanoma of the trunk [highest vs. lowest tertile of PRS: hazard ratio (HR) 2.78, 95% confidence interval (CI) 1.64-4.69 for men; HR 1.55, 95% CI 0.63-3.80 for women] and nonsignificant but large differences for the lower limbs (HR 5.25, 95% CI 1.80-15.27 for men; HR 1.75, 95% CI 0.88-3.47 for women)., Conclusions: While there are a number of potential explanations for these findings, this raises the possibility that genetic factors other than those related to pigmentation and naevus phenotypes may play a role in the predilection for melanoma to arise on different sites in men and women., Competing Interests: Conflicts of interest The authors declare they have no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Melanoma arising in association with a blue nevus (BN) is rare but has molecular similarities to uveal melanoma (UM), including GNAQ/11 mutations. Tebentafusp was recently approved for UM based on improved overall survival in a phase 3 study. We hypothesized that tebentafusp may be active in BN-associated melanoma. Here, we present a case of metastatic BN-associated melanoma with rapid response and ~1 year of disease control on tebentafusp. We also explore molecular and histological features of secondary resistance. Our case highlights that PD-1-resistant melanomas should be screened for GNAQ/11 mutations, as tebentafusp may be a treatment option in this extremely rare disease., Competing Interests: Competing interests: ANS reports grants and personal fees from Bristol-Myers Squibb, Immunocore, Novartis, and Castle Biosciences, and institutional grants from Bristol-Myers Squibb, Immunocore, Novartis, Targovax, Pfizer, Mural Oncology, Checkmate Pharmaceuticals, Foghorn Therapeutics, Linnaeus Therapeutics, Prelude Therapeutics, Iovance Biotherapeutics, Obsidian Therapeutics. PF reports equity in GE Healthcare, Iovance, Gilead. JDW is a consultant for Apricity, Ascentage Pharma, Bicara Therapeutics, Daiichi Sankyo, Dragonfly, Imvaq, Larkspur, Takeda, Tizona, Trishula Therapeutics, Immunocore (on their Data Safety Board), Scancell. JDW received grant/research support from Bristol Myers Squibb, Enterome. JDW has equity in Apricity, Arsenal IO/CellCarta, Ascentage, Imvaq, Linneaus, Larkspur, Georgiamune, Maverick, Tizona Therapeutics, Xenimmune. JDW is an inventor on the following patents: Xenogeneic DNA Vaccines, Newcastle Disease viruses for Cancer Therapy, Myeloid-derived suppressor cell (MDSC) assay, Prediction of Responsiveness to Treatment with Immunomodulatory Therapeutics and Method of Monitoring Abscopal Effects During Such Treatment, Anti-PD1 Antibody, Anti-CTLA4 antibodies, Anti-GITR antibodies and methods of use thereof. The remaining authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Brain metastases (BrM) affect up to 60% of patients with metastatic melanoma and are associated with poor prognosis. While combined immune checkpoint blockade of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) demonstrates intracranial efficacy in a proportion of patients with melanoma, the responses are rarely durable, particularly in patients with symptomatic BrM. The brain is an immune-specialized organ and immune responses are regulated differently to the periphery. Methods Using our previously established two-site model of melanoma BrM with concomitant intracranial and extracranial tumors, in which clinically observed efficacy of the combined PD-1/CTLA-4 (PC) blockade can be reproduced, we here explored the role of natural killer (NK) cells in BrM, using functional studies, immunophenotyping and molecular profiling. Results We demonstrate that NK cells are required for the intracranial efficacy of PC blockade. While both perforin and interferon gamma were necessary for the PC blockade-dependent control of intracranial tumor growth, NK cells isolated from intracranial tumors demonstrated only a limited cancer cell killing ability, and PC blockade did not alter the abundance of NK cells within tumors. However, the depletion of NK cells in PC blockade-treated mice led to tumor molecular profiles reminiscent of those observed in intracranial tumors that failed to respond to therapy. Furthermore, the depletion of NK cells resulted in a strikingly reduced abundance of CD8+ T cells within intracranial tumors, while the abundance of other immune cell populations including CD4+ T cells, macrophages and microglia remained unaltered. Adoptive T cell transfer experiments demonstrated that PC blockade-induced trafficking of CD8+ T cells to intracranial tumors was chemokine-dependent. In line with this, PC blockade enhanced intratumoral expression of several T cell-attracting chemokines and we observed high expression levels of cognate chemokine receptors on BrM-infiltrating CD8+ T cells in mice, as well as in human BrM. Importantly, the depletion of NK cells strikingly reduced the intratumoral expression levels of T cell attracting chemokines and vascular T cell entry receptors that were upregulated following PC blockade. Conclusion Our data demonstrate that NK cells underpin the efficacy of PC blockade in BrM by orchestrating the "responder" molecular profile in tumors, and by controlling the intratumoral abundance of CD8+ T cells through regulation of multiple key molecular mediators of T cell trafficking., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Aberrant Ras homologous (Rho) GTPase signalling is a major driver of cancer metastasis, and GTPase-activating proteins (GAPs), the negative regulators of RhoGTPases, are considered promising targets for suppressing metastasis, yet drug discovery efforts have remained elusive. Here, we report the identification and characterization of adhibin, a synthetic allosteric inhibitor of RhoGAP class-IX myosins that abrogates ATPase and motor function, suppressing RhoGTPase-mediated modes of cancer cell metastasis. In human and murine adenocarcinoma and melanoma cell models, including three-dimensional spheroid cultures, we reveal anti-migratory and anti-adhesive properties of adhibin that originate from local disturbances in RhoA/ROCK-regulated signalling, affecting actin-dynamics and actomyosin-based cell-contractility. Adhibin blocks membrane protrusion formation, disturbs remodelling of cell-matrix adhesions, affects contractile ring formation, and disrupts epithelial junction stability; processes severely impairing single/collective cell migration and cytokinesis. Combined with the non-toxic, non-pathological signatures of adhibin validated in organoids, mouse and Drosophila models, this mechanism of action provides the basis for developing anti-metastatic cancer therapies., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Histone deacetylase 6 (HDAC6) inhibition is associated with an increased pro-inflammatory tumor microenvironment and antitumoral immune responses. Here, we show that the HDAC6 inhibitor AVS100 (SS208) had an antitumoral effect in SM1 melanoma and CT26 colon cancer models and increased the efficacy of anti-programmed cell death protein 1 treatment, leading to complete remission in melanoma and increased response in colon cancer. AVS100 treatment increased pro-inflammatory tumor-infiltrating macrophages and CD8 effector T cells with an inflammatory and T cell effector gene signature. Acquired T cell immunity and long-term protection were evidenced as increased immunodominant T cell clones after AVS100 treatment. Last, AVS100 showed no mutagenicity, toxicity, or adverse effects in preclinical good laboratory practice studies, part of the package that has led to US Food and Drug Administration clearance of an investigational new drug application for initiating clinical trials. This would be a first-in-human combination therapy of pembrolizumab with HDAC6 inhibition for locally advanced or metastatic solid tumors.

This study investigated whether adjuvant treatments in stage III cutaneous melanoma (CM) influenced patterns of recurrence. Patients with primary (n = 1033) or relapsed CM (n = 350) who received adjuvant therapies with Nivolumab (N), Pembrolizumab (P), or Dabrafenib and Trametinib (D + T) were extracted from the prospective multicenter real-world skin cancer registry ADOReg. Endpoints were progression-free survival (PFS), distant metastasis-free survival (DMFS), organ-specific DMFS, and overall survival (OS). For primary cases, D + T indicated an improved PFS (1- and 2-year PFS: 90.9%; 82.7%) as compared to P (81.0%, 73.9%; p = .0208), or N (83.8%, 75.2%; p = .0539). BRAF-mutated(mut) CM demonstrated significantly lower PFS (p = .0022) and decreased DMFS (p = .0580) when treated with immune checkpoint inhibitor (ICI) instead of D + T. Besides, NRAS-mut CM tended to perform worse than wt CM upon ICI (PFS: p = .1349; DMFS: p = .0540). OS was similar between the groups. Relapsed cases showed decreased PFS, DMFS, and OS in comparison to primary (all: p < .001), without significant differences between the subgroups. Organ-specific DMFS was significantly altered for primary cases with bone (p = .0367) or brain metastases (p = .0202). In relapsed CM, the frequency of liver (D + T: 1.5%; P: 12%; N: 9%) and LN metastases (D + T: 1.5%; P: 12%; N: 10.2%) was significantly lower with adjuvant D + T than ICI. NRAS-mut CM showed increased recurrence in primary and relapsed cases. These data show that adjuvant D + T is superior to ICI in primary BRAF-mut CM., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Despite advancements in treating cutaneous melanoma, patients with acral and mucosal (A/M) melanomas still have limited therapeutic options and poor prognoses. We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer-gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A/M melanomas. Using novel pre-clinical models of A/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A/M melanomas. Other alterations, including MYC and CRKL amplifications, were unique to A/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src/ABL inhibitor dasatinib, respectively. We further identified new, actionable A/M-specific alterations, including an inactivating NF2 fusion in a mucosal melanoma responsive to dasatinib in vivo. Our study highlights new molecular differences between cutaneous and A/M melanomas, and across different anatomic sites within A/M, which may change clinical testing and treatment paradigms for these rare melanomas., (© 2024 UICC.)

The patient was a 79-year-old male. At three years and eight months after his initial presentation, upper gastrointestinal endoscopy revealed a black-flattened elevated lesion in the middle third of the esophagus, which was diagnosed as malignant melanoma on biopsy. No lymph node or distant metastasis was found. A diagnosis of cT1bN0M0 Stage I was thus made. We performed a robot-assisted, minimally invasive esophagectomy and D2 dissection. The postoperative diagnosis was pT1a-MM, N0, M0, vascular invasion+, stage 0. The patient was recurrence-free for 14 months after surgery. We presume that an aggressive biopsy diagnosis is important for the early detection of malignant melanoma.

Purpose: Uveal melanoma (UM), although a rare malignancy, stands as the most prevalent intraocular malignancy in adults. Controversies persist regarding the dose dependency of local control (LC) through radiation therapy. This study sought to elucidate the significance of the prescription dose by employing time-dose-response models for patients with UM receiving photon-based stereotactic radiosurgery (SRS)., Methods and Materials: The analysis included patients with UM treated between 2005 and 2019. All patients underwent single-fraction SRS. Datapoints were separated into 3 dose groups, with Kaplan-Meier analysis performed on each group, from which time-dose-response models for LC were created at 2, 4, and 7 years after SRS using maximum-likelihood fitted logistic models., Results: Outcomes from 594 patients with 594 UMs were used to create time-dose-response models. The prescribed doses and the number of patients were as follows: 17 to 19 Gy (24 patients), 20 Gy (122 patients), 21 Gy (442 patients), and 22 Gy (6 patients). Averaged over all patients and doses, LC rates at 2, 4, and 7 years were 94.4%, 88.2%, and 69.0%, respectively. Time-dose-response models for LC demonstrated a dose-dependent effect, showing 2-year LC rates of more than 90% with 20 Gy and 95% with 22 Gy. For 4 years and a LC of 90%, a dose of approximately 21 Gy was required. After 7 years, the 21 Gy prescription dose was predicted to maintain a LC above 70%, sharply declining to less than 60% LC with 19 Gy and less than 40% with 18 Gy., Conclusions: In contrast to prior findings, the time-dose-response models for UM undergoing photon-based SRS emphasize the critical role of the prescription dose in achieving lasting LC. The dose selection must be carefully balanced against toxicity risks, considering tumor geometry and individual patient characteristics to tailor treatments accordingly., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Melanoma is a malignant tumour with a poorer prognosis in stage III and IV patients. Development of effective therapies for the treatment of advanced melanoma has led to an improvement in survival. Furthermore, the French population is ageing, and treatment of melanoma in this population has several specific limitations. This descriptive, retrospective, single-centre study collected data on the diagnostic and therapeutic management of patients with melanoma of Breslow ≥ 1 mm or of unknown primary and metastatic spread, at Limoges University Hospital, between 2018 and 2022, and compared the results obtained between 2 groups: under 80 and over 80 years of age; 344 patients were included. The extension work-up was more frequently complete and the sentinel lymph node technique more frequently performed in patients under 80. Wide excision was more frequently in accordance with guidelines in patients over 80. Adjuvant or first-line metastatic treat-ment was more frequently instituted in patients under 80, but no difference was found as regards the second and third lines, the frequency of adverse events, and the reason for stopping treatment. Our study supports similar management of elderly and young subjects, given the safety profile and efficacy of treatments.

In the last 5 decades there has been a steady increase in skin cancer incidence globally. As patients wait for treatment before or after referral, the prognosis for those with melanoma worsens. Teledermatology was introduced to help reduce waiting times. The objective of this study was to investigate how the introduction of teledermatology affected management of skin tumours, from primary care physicians to dermatologists. A retrospective cohort study was performed 1 year before and 1 year after introduction of teledermatology in Östergötland County, Sweden. Patients were included from 3 primary healthcare centres by 3 independent observers. A total of 2,139 patients were included in the study. The 2 cohorts were well matched. At 2 of the 3 primary healthcare centres there was a significant increase in the use of dermoscopy, and almost 66% of all referrals were teledermatological in the year following its introduction. There was a trend towards higher diagnostic accuracy in the post-teledermatology cohort. No apparent effect on melanoma referral times was observed. The results of this study confirm previous findings showing the value of teledermatology as well as a novel finding of an increase in dermoscopy use in primary healthcare settings.

Melanoma is the most aggressive type of skin cancer and can metastasize during primary tumor formation. This research aimed to determine the relationship between the prevention of melanoma development in a mouse model treated with liposomes loaded with soybean lunasin and amaranth unsaponifiable matter (UM + LunLip) and cell cycle arrest. Tumors excised from C57BL/6 mice treated topically or subcutaneously with UM + LunLip were subjected to immunohistochemistry. Markers related to cell cycle inhibition (p16, p21, p27, and p53) and markers involved in cell cycle progression (cyclin-dependent kinase, CDK6, and cyclin D1) were assessed. The results showed that UM + LunLip had antitumor activity in C57BL/6 mice treated either topically or subcutaneously by p16, p21, p27, and p53 overexpression (up to 572-, 134-, 30-, and 57-fold change, FC, respectively) in the tumors of mice treated with 30 mg UM + LunLip/kg body weight compared with the tumor-bearing untreated control. However, CDK6 and cyclin D1 expression was not inhibited (up to 1.37 FC and 2.09 FC, respectively), which is a typical behavior of cyclin D in melanoma. Therefore, melanoma tumor development was prevented by the overexpression of cell cycle inhibitors p16, p21, p27, and p53 due to UM + LunLip treatments. Since the topical application was effective, less invasive, and more practical for the user, this application will be recommended for future steps in in vivo studies., Competing Interests: Declarations Competing interests The authors declare no competing interests. Conflicts of interest The author reports no conflicts of interest in this work., (© 2024. The Author(s).)

Background: While the prognostic role of tertiary lymphoid structures (TLS) has been well studied in solid cancers, the prevalence and impact of immature precursor lymphoid structures known as lymphoid aggregates (LA) remain unresolved in relation to the disease process. In this study, we examined characteristics and the prognostic utility of LA and TLS status in histological samples from patients with melanoma., Methods: We assessed The Cancer Genomic Atlas-skin cutaneous melanoma digital slides and melanoma specimens from the University of Pittsburgh for the presence of LA and TLS using H&E staining, multiplex immunofluorescence (mIF) and transcriptomic analyses. Cox proportional hazard regression models were used to assess the prognostic value associated with the presence of lymphoid structures in melanomas., Results: A total of 278 evaluable samples were analyzed and split into primary melanomas in skin (N=195) and metastatic melanomas involving skin/subcutaneous/soft tissue sites (N=83). 72% of tumor specimens contained histologically defined LA located in peritumoral (34%), intratumoral (5.6%) or stromal (6.1%) locations, with the remaining samples (54.3%) exhibiting LA in multiple locations. In contrast to LA which tended to form more commonly in primary melanoma samples, TLS with germinal centers predominantly formed in peritumoral (45.2%) or stromal (35.5%) locations in metastatic melanomas (p=0.02), with TLS observed in 11% of all melanoma specimens evaluated. mIF analyses revealed cellular heterogeneity of lymphoid structures, with CD20 + (B) cells present in nodule-shaped and stromal locations where they exhibited a high degree of colocalization with CD4 + and CD8 + T cells. A previously defined 12-chemokine gene expression score was significantly higher in samples with evidence of LA versus none (p<0.001), and samples without LA/TLS were enriched with pigmentation/neural network gene signatures. The presence of LA was significantly associated with tumor-free regional lymph node status (p=0.002). In multivariable analysis, after adjusting for age, sex, sample type, and stage, the presence of LA was associated with improved patient overall survival (OS) (HR=0.52, 95% CI 0.31 to 0.87, p=0.01)., Conclusion: Melanoma frequently contains LA, which tends to form in diverse locations in the tumor microenvironment in association with improved overall survival and tumor-free regional lymph node status in patients with primary disease., Competing Interests: Competing interests: JMK: consultation with Amgen (with Davar and Najjar), Ankyra Therapeutics, Applied Clinical Intelligence, Axio Research, Becker Pharmaceutical Consulting, Bristol Myers Squibb, Cancer Network, Cancer Study Group, Checkmate Pharmaceuticals, CytomX Therapeutics, DermTech, Fenix Group International, Harbour BioMed, Immunocore, iOnctura, Iovance Biotherapeutics, IQVIA, Istari Oncology, Jazz Pharmaceuticals, Lytix Biopharma AS, Magnolia Innovation, Merck, Natera, Novartis Pharmaceuticals, OncoCyte Corporation, OncoSec Medical, PathAI, Pfizer, Piper Sandler & Co., PyrOjas Corporation, Regeneron Pharmaceuticals, Replimune, Scopus BioPharma, SR One Capital Management, Takeda, Valar Labs. JJM is Associate Center Director at Moffitt Cancer Center, has ownership interest in Aleta Biotherapeutics, CG Oncology, Turnstone Biologics, Ankyra Therapeutics, and AffyImmune Therapeutics, and is a paid consultant/paid advisory board member for ONCoPEP, CG Oncology, Turnstone Biologics, Vault Pharma, Ankyra Therapeutics, AffyImmune Therapeutics, UbiVac, Vycellix, and Aleta Biotherapeutics., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Insufficient influx of T cells into the tumor microenvironment, including brain metastasis, dramatically limits efficacy of conventional immunotherapy. In this issue of Immunity, Messmer et al. interrogate spatiotemporal dependencies of melanoma brain metastasis T cell infiltration by intravital microscopy. They find that T cells enter these brain tumors through peritumoral venous vessels and can be stimulated with immunotherapy., Competing Interests: Declaration of interests J.R. and A.B. are inventors of provisional patent applications related to leptomeningeal metastasis. A.B. is an inventor of patents related to treatment of brain and leptomeningeal metastases., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Myc-associated Zinc-finger Protein (MAZ) has been implicated in the malignant progression of various tumors. However, its expression and functional relationship of MAZ in melanoma have not been previously investigated. This study confirms elevated expression of MAZ in melanoma, correlating with poor patient prognosis. Furthermore, our findings demonstrate that MAZ enhances melanoma progression by promoting proliferation, migration and invasion. It is worth noting that we found that MAZ can target and regulate the transcription of NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3), a core subunit of mitochondrial complex I, to enhance mitochondrial metabolism and thus promote malignant progression of melanoma. Predictive modeling indicates that the co-expression of MAZ and NDUFS3 could serve as a potential prognostic marker for melanoma patients., Competing Interests: Competing interests The authors declare no competing interests. Ethics All animal procedures were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of Kunming Medical University (permit number: K2020-0006)., (© 2024. The Author(s).)

Intravenous pembrolizumab 400 mg every 6 weeks was approved across tumor types based on pharmacokinetic modeling, which showed exposures consistent with previous standard dosing of 200 mg or 2 mg/kg every 3 weeks, and early results of cohort B of the phase 1 KEYNOTE-555 study. Results after ≥1 year of potential follow-up for all patients in cohort B of KEYNOTE-555 are presented. Patients aged ≥18 years with previously untreated stage III/IV melanoma received pembrolizumab 400 mg every 6 weeks for ≤18 cycles. The primary endpoint was objective response rate per RECIST v1.1 by blinded independent central review. Secondary endpoints included duration of response, progression-free survival, pharmacokinetics, and safety. Overall, 101 patients received pembrolizumab. Median projected follow-up was 21.9 months (range, 17.0-25.7). The objective response rate was 50.5% (95% CI: 40.4-60.6; 19 complete responses, 32 partial responses). Median duration of response was not reached (NR; range, 2.4+ to 21.0+ months). Median progression-free survival was 13.8 months (95% CI: 4.1-NR). Observed pharmacokinetic exposures were consistent with model predictions for pembrolizumab 400 mg every 6 weeks and other approved and tested schedules (2 mg/kg or 200 mg every 3 weeks). Grade 3-4 treatment-related adverse events occurred in 13 patients (12.9%). No deaths were considered treatment related. These results support the pharmacokinetic modeling and demonstrate that the benefit-risk profile of pembrolizumab 400 mg Q6W is consistent with that of 200 mg or 2 mg/kg every 3 weeks. Clinically meaningful objective response rate and durable progression-free survival within the expected range for first-line pembrolizumab were observed. Clinical trial registry: ClinicalTrials.gov, NCT03665597., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: BR reports honoraria, advisory/consultancy, and speakers bureau from MSD, Roche South Africa, and AstraZeneca South Africa; research grant/funding from Roche South Africa; and travel/accommodations/expenses from MSD. PR reports honoraria, advisory/consultancy, speakers bureau, research grant/funding, and travel/accommodations/expenses from Charlotte Maxeke Johannesburg Academic Hospital to their institution. AA reports honoraria, speakers bureau, research grant/funding, and travel/accommodations/expenses from Pierre-Fabre, Novartis, MSD, Bristol Myers Squibb, Roche, Merck, and Sanofi. MPB reports honoraria and advisory/consultancy from MSD, Bristol Myers Squibb, and Novartis to their institution; research grant/funding from MSD and BMS to their institution; and travel/accommodations/expenses from MSD. RMZ reports advisory/consultancy for AstraZeneca; speakers bureau for Limbic Oncology; and researching grant/funding to their institution from Bristol Myers Squibb and Roche. EMC reports consulting fees from Bristol Myers Squibb, Merck Serono, Amgen, Pierre-Fabre, Sanofi, and Roche; honoraria from Bristol Myers Squibb, Novartis, Sanofi, Merck Serono, and Pierre-Fabre; travel/accommodations/expenses from Bristol Myers Squibb, Novartis, Merck Serono, and Sun Pharmaceuticals; and participation on data safety monitoring board or advisory board for Bristol Myers Squibb. ML reports advisory/consultancy from Bristol Myers Squibb, MSD, Novartis, and Roche; speakers bureau from BMS and MSD; and travel/accommodations/expenses from Pierre-Fabre and Merck. JRA is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stockholder of Merck & Co., Inc., Rahway, NJ, USA. LJ and DDA are a stockholders of Merck & Co., Inc., Rahway, NJ, USA. ML, OA, and EC are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, stockholders of Merck & Co., Inc., Rahway, NJ, USA, and hold patents/licensing/royalties/other intellectual property at Merck & Co., Inc., Rahway, NJ, USA. All remaining authors (GC, SWC, KME, BH, and CJ) have declared no conflicts of interest., (Copyright: © 2024 Cohen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Recent studies have uncovered that TIPE2 is involved in the development of cancer. However, less research has been conducted on the role of TIPE2 in melanoma. Our study aims to elucidate the mechanism of action of TIPE2 in the development of melanoma. We examined TIPE2 expression in paracarcinoma tissue and melanoma tissues and found that TIPE2 expression was downregulated in melanoma tissue compared with paracarcinoma tissue. Overexpression of TIPE2 significantly inhibited the proliferation of melanoma cells in vitro and even inhibited tumor formation in vivo. The CCK8 assay results indicated that TIPE2 overexpression suppressed the proliferation of melanoma cells. The colony-forming ability and wound healing ability of TIPE2-overexpressing melanoma cells were significantly reduced compared with those of control cells. Moreover, immunohistochemistry experiments using a nude mouse tumor model showed consistent results. TIPE2 inhibited the phosphorylation of MEK and ERK. In summary, TIPE2 suppresses the proliferation and migration of melanoma cells by affecting proliferation-related factors and possibly by regulating the MEK/ERK pathway. TIPE2 could be used to inhibit melanoma growth and is a potential drug target for future drug development., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Uveal melanoma (UM) is a rare and deadly eye cancer with high metastatic potential. Despite the predominance of malignant cells within the tumor microenvironment, the heterogeneity and underlying molecular features remain to be fully characterized., Methods: We analyzed single-cell transcriptomic profiling of 37,660 malignant cells from 17 UM tumors. A consensus non-negative factorization algorithm was used to decipher transcriptional programs underlying tumor cell-intrinsic heterogeneity. Tumor-infiltrated immune cells were computationally estimated from bulk transcriptomes and bioinformatics methods. A gene signature was derived for subtyping and prognostic stratification and validated in multicenter cohorts., Results: ScRNA-seq analysis revealed the existence of diverse subpopulations and transcriptional variability among malignant cells within and between tumors. Furthermore, we observed that the heterogeneity of malignant cell states and compositions correlated with genomic, immunological, and clinical characteristics. By identifying gene expression programs associated with malignant cell heterogeneity at the single cell level, UM samples were classified into two distinct intra-tumoral subtypes (ITMH lo and ITMH hi ) with different prognoses and immune microenvironments. Finally, a machine learning-derived 9-gene signature was developed to translate single-cell information into bulk tissue transcriptomes for patient stratification and was validated in multicenter cohorts., Conclusions: Our study provides insight into understanding the intra-tumoral heterogeneity of UM and its potential impact on patient stratification., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing financial interests., (© 2024. The Author(s).)

Surgical excision remains the principal treatment for melanoma, while tumor recurrence and delayed wound healing often occur due to the residual tumor cells and hypoxic microenvironment in the postoperative skin wounds. Herein, we present a living photosynthetic microneedle (MN) patch (namely MA/CM@MN) loaded with microalgae (MA) and cuttlefish melanin (CM) for postsurgical melanoma therapy and skin wound healing. Benefiting from the oxygenic photosynthesis of the alive MA in the MN base, the MA/CM@MN can generate oxygen under light exposure, thus facilitating skin cell proliferation and protecting cells against hypoxia-induced cell death. In addition, with CM nanoparticles embedded in the MN tips, the MA/CM@MN can be effectively heated up under near-infrared (NIR) irradiation, contributing to a strong tumor killing efficacy on melanoma cells in vitro. Further experiments demonstrate that the NIR-irradiated MA/CM@MN effectively prevents local tumor recurrence and simultaneously promotes the healing of tumor-induced wounds after incomplete tumor resection in melanoma-bearing mice, probably because the MA/CM@MN can inhibit tumor cell proliferation, stimulate tumor cell apoptosis, and mitigate tissue hypoxia in light. These results indicate that the living photosynthetic MN patch offers an effective therapeutic strategy for postoperative cancer therapy and wound healing applications., Competing Interests: Declarations Ethics approval and consent to participate This study has been approved by the ethics committee of the Wenzhou Institute of University of Chinese Academy of Sciences (Wenzhou, China) and conducted in accordance with ethical guidelines. Consent for publication All authors have provided consent for the manuscript to be published in Journal of Nanobiotechnology. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Mesenchymal epithelial transition factor (MET) variant is an independent prognostic factor for worse prognosis in patients with lung cancer or gastroesophageal adenocarcinoma. MET gene variants can be regarded as a subtype of melanoma but there is a lack of studies regarding the frequency of MET genetic alterations and the efficacy of immunotherapy in melanoma patients. The purpose of this study is to explore potential therapeutic strategies for melanoma subtypes with MET alterations., Methods: A total of 1751 malignant melanomas were analyzed to illustrate the landscape of MET mutations. We collected 55 melanoma cases from multicenter for a retrospective cohort from 2010 to 2023. We analyzed the impact of MET amplification on the efficacy of immunotherapy in the retrospective cohort after propensity score matching (PSM) and a pancancer cohort. CIBERSORT was used to evaluate the immune infiltration., Results: There were no instances of MET 14 exon skipping, and only instances of MET amplification were found in the 1751 melanomas and our retrospective cohort. Cox proportional hazards model analysis showed that MET amplification (P = 0.006) was significantly associated with poorer overall survival (OS) in patients who received immunotherapy as the first-line treatment. Compared with patients with MET amplification, patients in the negative control (NC) group had a significantly better OS (P = 0.022) after PSM. Analysis of 1661 pancancer cases with the MSK-IMPACT assay showed that patients receiving immunotherapy in the MET amplification group had a trend toward worse OS than those without MET amplification (P = 0.025)., Conclusions: This database analysis showed that the main type of MET mutation is amplification in malignant melanoma. MET-amplified solid tumors might be considered for targeted therapy, as MET amplification can be regarded as a risk factor affecting the prognosis of patients with tumors treated with immunotherapy., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the Ethical Committee of Fujian Cancer Hospital (K2023-097–01) in accordance with the Declaration of Helsinki. The patients in this manuscript have given written informed consent to publication of their case details. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Combinatorial immunotherapy may improve the efficacy of neoadjuvant checkpoint inhibitors in locoregionally advanced melanoma. In this issue of Cancer Cell, Davar and colleagues report a promising phase 2 neoadjuvant trial of the TLR9 agonist vidutolimod in combination with nivolumab. Analyses suggest a unique myeloid expression signature is associated with response., Competing Interests: Declaration of interests J.W.S. reports research funding from IO Biotech (Inst), Regeneron (Inst), and Daiichi Sankyo (Inst) and a consulting or advisory role from IO Biotech. M.A.P. reports a consulting or advisory role from Bristol-Myers Squibb; Cancer Expert Now; Chugai Pharma; Eisai; Erasca, Inc; Intellisphere; Merck; MJH Associates; Nektar; Novartis; Pfizer; and WebMD and research funding from Array BioPharma (Inst); Bristol-Myers Squibb (Inst); Infinity Pharmaceuticals (Inst); Merck (Inst); Novartis (Inst); and Rgenix (Inst)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

One of the most dangerous aspects of cancers is their ability to metastasize, which is the leading cause of death. Hence, it holds significance to develop therapies targeting the eradication of cancer cells in parallel, inhibiting metastases in cells surviving the applied therapy. Here, we focused on two melanoma cell lines─WM35 and WM266-4─representing the less and more invasive melanomas. We investigated the mechanisms of cellular processes regulating the activation of actomyosin as an effect of colchicine treatment. Additionally, we investigated the biophysical aspects of supplement therapy using Rho-associated protein kinase (ROCK) inhibitor (Y-27632) and myosin II inhibitor ((-)-blebbistatin), focusing on the microtubules and actin filaments. We analyzed their effect on the proliferation, migration, and invasiveness of melanoma cells, supported by studies on cytoskeletal architecture using confocal fluorescence microscopy and nanomechanics using atomic force microscopy (AFM) and microconstriction channels. Our results showed that colchicine inhibits the migration of most melanoma cells, while for a small cell population, it paradoxically increases their migration and invasiveness. These changes are also accompanied by the formation of stress fibers, compensating for the loss of microtubules. Simultaneous administration of selected agents led to the inhibition of this compensatory effect. Collectively, our results highlighted that colchicine led to actomyosin activation and increased the level of cancer cell invasiveness. We emphasized that a cellular pathway of Rho-ROCK-dependent actomyosin contraction is responsible for the increased invasive potential of melanoma cells in tubulin-targeted therapy.

Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. This study dissects the intra-tumoral diversity of CAFs in basal cell carcinoma, squamous cell carcinoma, and melanoma using molecular and spatial single-cell analysis. We identify three distinct CAF subtypes: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs), and immunomodulatory CAFs (iCAFs). Large-cohort tissue analysis reveals significant shifts in CAF subtype patterns with increasing malignancy. Two CAF subtypes exhibit immunomodulatory properties via different mechanisms. mCAFs sythesize extracellular matrix and may restrict T cell invasion in low-grade tumors via ensheathing tumor nests, while iCAFs are enriched in late-stage tumors, and express high levels of cytokines and chemokines to aid immune cell recruitment and activation. This is supported by the induction of an iCAF-like phenotype with immunomodulatory functions in primary healthy fibroblasts exposed to skin cancer cell secretomes. Thus, targeting CAF variants holds promise to enhance immunotherapy efficacy in skin cancers., (© 2024. The Author(s).)

Colonic melanoma is a rarely detected aetiology of small bowel obstruction. This is a case of a male in his 80s with a history of treated stage IIIA melanoma on his trunk 7 years prior who presented with small bowel obstruction. He underwent urgent surgical intervention, where a partial colectomy was performed. Pathology revealed a 4.6 cm melanoma causing intussusception. This case highlights the insidious nature of metastatic melanomas and discusses an uncommon location of melanoma metastasis that evaded detection until a late stage., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Mucosal melanoma (MucM) is a rare cancer with a poor prognosis and low response rate to immune checkpoint inhibition (ICI) compared with cutaneous melanoma (CM). To explore the immune microenvironment and potential drivers of MucM's relative resistance to ICI drugs, we characterized 101 MucM tumors (43 head and neck [H&N], 31 female urogenital, 13 male urogenital, 11 anorectal, and 3 other gastrointestinal) using bulk RNA-Seq and immunofluorescence. RNA-Seq data show that MucM has a significantly lower IFN-γ signature levels than CM. MucM tumors of the H&N region show a significantly greater abundance of CD8+ T cells, cytotoxic cells, and higher IFN-γ signature levels than MucM from lower body sites. In the subcohort of 35 patients with MucM treated with ICI, hierarchical clustering reveals clusters with a high and low degree of immune infiltration, with a differential ICI response rate. Immune-associated gene sets were enriched in responders. Signatures associated with cancer-associated fibroblasts, macrophages, and TGF-β signaling may be higher in immune-infiltrated, but ICI-unresponsive tumors, suggesting a role for these resistance mechanisms in MucM. Our data show organ region-specific differences in immune infiltration and IFN-γ signature levels in MucM, with H&N MucM displaying the most favorable immune profile. Our study might offer a starting point for developing more personalized treatment strategies for this disease.

Background and Purpose: In patients with metastatic melanoma who respond to anti-PD-1 therapy, the proliferation of intra-tumour CD8+ T cells is directly correlated with the clinical response, making tumour-infiltrating lymphocytes (TILs) a treatment of interest in combination with a PD-1 inhibitor, which is the undisputed gold standard in the management of metastatic melanoma. The aim of this trial was, therefore, to evaluate the safety and efficacy of sequential combination therapy consisting of nivolumab (a PD-1 inhibitor) and TILs adoptive T cells in patients with metastatic melanoma., Materials and Methods: We performed an exploratory, prospective, single-centre, open-label, non-randomised, uncontrolled phase I/II study. We enrolled 10 previously untreated patients with advanced melanoma. The treatment regimen was neoadjuvant anti-PD-1 therapy followed by 2 injections of TILs and a second sequence of anti-PD-1 therapy., Results and Interpretation: Among the four patients who received the autologous TILs + nivolumab combination, three (75%) achieved an objective response (two achieved a partial response [PR] at the end of the study, two achieved a complete response [CR]), and one achieved a CR at the end of the study. Among these three patients, one had a PR, and two had stable disease (SD) after the nivolumab course and before any TILs administration, reinforcing the importance of the tumour response after TILs injection. These responses were persistent, ranging from 9 months to 3.4 years.

The Parkinson's disease protein, alpha-synuclein (α-syn/SNCA), is highly expressed in neurons and melanomas. The goal of this study was to reveal the mechanism(s) of α-syn's involvement in melanoma pathogenesis. To decipher the genes and pathways affected by α-syn, we conducted an RNA sequencing analysis of human SK-MEL-28 cells and several SK-MEL-28 SNCA-KO clones. We identified 1098 significantly up-regulated genes and 660 significantly down-regulated genes. Several of the upregulated genes are related to the immune system, i.e., the inflammatory response and the matrisome. We validated five upregulated genes (IL-1β, SAA1, IGFBP5, CXCL8, and CXCL10) by RT-qPCR and detected IGFBP5 and IL-1β in spent media of control and SNCA-KO cells. The levels of each of these secreted proteins were significantly higher in the spent media of the SNCA-KO clones than control cells. These secreted proteins quite likely activate the immune response against SNCA-KO cells. We suggest that, conversely, high levels of α-syn expression in melanoma cells helps the cells evade the immune system by inhibiting the secretion of these immune activating factors., (© 2024. The Author(s).)

Background: The 5-year results of this trial showed that adjuvant therapy with dabrafenib plus trametinib resulted in longer relapse-free survival and distant metastasis-free survival than placebo among patients with BRAF V600-mutated stage III melanoma. Longer-term data were needed, including data regarding overall survival., Methods: We randomly assigned 870 patients with resected stage III melanoma with BRAF V600 mutations to receive 12 months of dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Here, we report the final results of this trial, including results for overall survival, melanoma-specific survival, relapse-free survival, and distant metastasis-free survival., Results: The median duration of follow-up was 8.33 years for dabrafenib plus trametinib and 6.87 years for placebo. Kaplan-Meier estimates for overall survival favored dabrafenib plus trametinib over placebo, although the benefit was not significant (hazard ratio for death, 0.80; 95% confidence interval [CI], 0.62 to 1.01; P = 0.06 by stratified log-rank test). A consistent survival benefit was seen across several prespecified subgroups, including the 792 patients with melanoma with a BRAF V600E mutation (hazard ratio for death, 0.75; 95% CI, 0.58 to 0.96). Relapse-free survival favored dabrafenib plus trametinib over placebo (hazard ratio for relapse or death, 0.52; 95% CI, 0.43 to 0.63), as did distant metastasis-free survival (hazard ratio for distant metastasis or death, 0.56; 95% CI, 0.44 to 0.71). No new safety signals were reported, a finding consistent with previous trial reports., Conclusions: After nearly 10 years of follow-up, adjuvant therapy with dabrafenib plus trametinib was associated with better relapse-free survival and distant metastasis-free survival than placebo among patients with resected stage III melanoma. The analysis of overall survival showed that the risk of death was 20% lower with combination therapy than with placebo, but the benefit was not significant. Among patients with melanoma with a BRAF V600E mutation, the results suggest that the risk of death was 25% lower with combination therapy. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: In phase 1-2 trials in patients with resectable, macroscopic stage III melanoma, neoadjuvant immunotherapy was more efficacious than adjuvant immunotherapy., Methods: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma to two cycles of neoadjuvant ipilimumab plus nivolumab followed by surgery or surgery followed by 12 cycles of adjuvant nivolumab. Only patients in the neoadjuvant group with a partial response or nonresponse received adjuvant treatment. The primary end point was event-free survival., Results: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% in patients in the neoadjuvant group who had a major pathological response, 76.1% among those with a partial response, and 57.0% among those with a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of patients in the neoadjuvant group and in 14.7% in the adjuvant group., Conclusions: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.)., (Copyright © 2024 Massachusetts Medical Society.)

Early detection and treatment of skin cancer are important for patient recovery and survival. Dermoscopy images can help clinicians for timely identification of cancer, but manual diagnosis is time-consuming, costly, and prone to human error. To conduct this, an innovative deep learning-based approach has been proposed for automatic melanoma detection. The proposed method involves preprocessing dermoscopy images to remove artifacts, enhance contrast, and cancel noise, followed by feeding them into an optimized Convolutional Neural Network (CNN). The CNN is trained using an innovative metaheuristic called the Improved Chameleon Swarm Algorithm (CSA) to optimize its performance. The approach has been validated using the SIIM-ISIC Melanoma dataset and the results have been confirmed through rigorous evaluation metrics. Simulation results demonstrate the efficacy of the proposed method in accurately diagnosing melanoma from dermoscopy images by highlighting its potential as a valuable tool for clinicians in early cancer detection., (© 2024. The Author(s).)

Uveal melanoma (UM) is a rare aggressive intraocular tumour that spreads most commonly to the liver in tumours with loss of one copy of chromosome 3 (HR-M3); current treatments for metastatic disease remain largely ineffective. Pre-clinical research is increasingly using three-dimensional models that better recapitulate the tumour microenvironment (TME). One aspect of the TME is the acellular extracellular matrix (ECM) that influences cell proliferation, migration and response to therapy. Although commercial matrices are used in culture, the composition and biochemical properties may not be representative of the tumour ECM in vivo. This study identifies UM metastatic risk specific ECM proteins by developing methodology for decellularisation of low- and high- metastatic risk tissue samples (LR-D3 vs. HR-M3). Proteomic analysis revealed a matrisome signature of 34 core ECM and ECM-associated proteins upregulated in HR-M3 UM. Combining additional UM secretome and whole cell iTRAQ proteomic datasets revealed enriched GO and KEGG pathways including 'regulating ECM binding' and 'PI3K/Akt signalling'. Structural analyses of decellularised matrices revealed microarchitecture of differing fibre density and expression differences in collagen 4, collagen 6A1 and nidogen 1, between metastatic risk groups. This approach is a powerful tool for the generation of ECM matrices relevant to high metastatic risk UM., (© 2024. The Author(s).)

Herein, we designed and synthesized a series of novel 2-methylthieno [3,2-d]pyrimidine analogues as tubulin inhibitors with antiproliferative activities at low nanomolar levels. Among them, compound DPP-21 displayed the most potent anti-proliferative activity against six cancer cell lines with an average IC 50 of ∼6.23 nM, better than that of colchicine (IC 50  = 9.26 nM). DPP-21 exerted its anti-cancer activity by suppressing the polymerization of tubulin with an IC 50 of 2.4 μM. Furthermore, the crystal structure of DPP-21 in complex with tubulin was solved by X-ray crystallography to 2.94 Å resolution, confirming the direct binding of DPP-21 to the colchicine site. Moreover, DPP-21 arrested the cell cycle in the G2/M phase of mitosis, subsequently inducing tumor cell apoptosis. Additionally, DPP-21 was able to effectively inhibit the migration of cancer cells. Besides, DPP-21 exhibited significant in vivo anti-tumor efficacy in a B16-F10 melanoma tumor model with a TGI of 63.3 % (7 mg/kg) by intraperitoneal (i.p.) injection. Notably, the combination of DPP-21 with NP-19 (a PD-L1-targeting small molecule inhibitor reported by our group before) demonstrated enhanced anti-cancer efficacy in vivo. These results suggest that DPP-21 is a promising lead compound deserving further investigation as a potential anti-cancer agent., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jianjun chen reports a relationship with Southern Medical University that includes: non-financial support. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Despite a great progress in identifying treatment options for patients with malignant melanoma, novel therapies tend to be costly and, in some cases, produce adverse effects forcing the melanoma patients to withdraw drugs. There is a strong need for less expensive drugs with a more favorable spectrum of anticancer actions. This study was designed to assess whether LY-2183240 (a potent inhibitor of both, anandamide cellular reuptake and fatty acid amide hydrolase (FAAH), an enzyme that degrades anandamide) has antiproliferative and cytotoxic effects on various human malignant melanoma cell lines (primary A375 and FM55P, metastatic SK-MEL28 and FM55M2) when administered alone or in combination with docetaxel, paclitaxel, mitoxantrone and cisplatin via the MTT assay. The MTT, LDH and BrdU assays were used to evaluate the potency and safety of LY-2183240, whereas isobolographic analysis of interactions was applied to characterize the interactions of LY-2183240 with the studied chemotherapeutics (docetaxel, paclitaxel, mitoxantrone and cisplatin). The isobolography confirmed that the combinations of LY-2183240 with docetaxel, paclitaxel and mitoxantrone produced additive interactions in all the tested melanoma cell lines. Only two antagonistic interactions for LY-2183240 combined with cisplatin in the A375 and FM55P cell lines were observed by the MTT assay. In conclusion, LY-2183240 can be considered an add-on drug for the treatment of melanoma, when combined with docetaxel, paclitaxel, or mitoxantrone, but not with cisplatin., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript or in the decision to publish the results., (Copyright © 2024 Elsevier B.V. All rights reserved.)

With an increasing incidence of malignant melanoma, new prognostic biomarkers for clinical decision making have become more important. In this study, we evaluated the role of ecto-NOX disulfide-thiol exchanger 2 (ENOX2/tNOX), a cancer- and growth-associated protein, in the prognosis and therapy of primary malignant melanoma. We conducted a tissue microarray analysis of immunohistochemical ENOX2 protein expression and The Cancer Genome Atlas (TCGA) ENOX2 RNA expression analysis, as well as viability assays and Western blots of melanoma cell lines treated with the ENOX2 inhibitor phenoxodiol (PXD) and BRAF inhibitor (BRAFi) vemurafenib. We discovered that high ENOX2 expression is associated with decreased overall (OS), disease-specific (DSS) and metastasis-free survival (MFS) in primary melanoma (PM) and a reduction in electronic tumor-infiltrating lymphocytes (eTILs). A gradual rise in ENOX2 expression was found with an increase in malignant potential from benign nevi (BNs) via PMs to melanoma metastases (MMs), as well as with an increasing tumor thickness and stage. These results highlight the important role of ENOX2 in cancer growth, progression and metastasis. The ENOX2 expression was not limited to malignant cell lines but could also be found in keratinocytes, fibroblasts and melanocytes. The viability of melanoma cell lines could be inhibited by PXD. A reduced induction of phospho-AKT under PXD could prevent the development of acquired BRAFi resistance. In conclusion, ENOX2 may serve as a potential prognostic marker and therapeutic target in malignant melanoma.

Purpose: We aimed to assess imaging findings and detection sensitivity for melanoma liver metastases on gadoxetic acid-enhanced magnetic resonance imaging (MRI)., Methods: This retrospective study included patients with melanoma liver metastasis who underwent gadoxetic acid-enhanced MRI. Two abdominal radiologists independently evaluated signal characteristics of liver metastases on morphologic imaging (precontrast T1- and T2-weighted imaging), diffusion-weighted imaging (DWI), dynamic imaging, and hepatobiliary phase (HBP). Imaging findings were compared according to detection on HBP and the primary site of the melanoma using logistic regression with the generalized estimating equation (GEE). Detection sensitivity for metastases was compared among different MR imaging sets using logistic regression with GEE., Results: A total of 67 patients with 254 liver metastases were included (44 women; mean age ± standard deviation, 65.6 ± 13.0 years). On HBP, 76.0% of metastases were detected, and 55.5% (141/254) showed hypointensity. Most of the metastases that were not detected on HBP originated from ocular melanomas (98.4%, 60/61), ≤1 cm (90.2%, 55/61) and showed T1 hyperintensity (98.4%, 60/61). Metastases from non-ocular melanomas more frequently showed T1 hypointensity, T2 hyperintensity, diffusion restriction, arterial enhancement, and HBP hypointensity than those from ocular melanomas (Ps ≤ 0.019). The detection sensitivity of HBP (76.0%) was significantly higher than DWI (65.7%, P = 0.006), but lower than morphologic imaging (98.8%, P < 0.001) and dynamic imaging (97.6%, P < 0.001)., Conclusion: The detection sensitivity of HBP for melanoma liver metastasis was 76.0%, which was lower than that of morphologic or dynamic imaging. HBP of gadoxetic acid-enhanced MRI has little advantage in detecting melanoma liver metastases., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chung et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Immune checkpoint inhibitors (ICI) have dramatically improved the life expectancy of patients with metastatic melanoma. However, about half of the patient population still present resistance to these treatments. We have previously shown Notch1 contributes to a non-inflamed TME in melanoma that reduces the response to ICI. Here, we addressed the therapeutic effects of a novel anti-Notch1 neutralizing antibody we produced, alone and in combination with immune checkpoint inhibition in melanoma models., Methods: Anti-Notch1 was designed to interfere with ligand binding. Mice were immunized with a peptide encompassing EGF-like repeats 11-15 of human Notch1, the minimal required region that allows ligand binding and Notch1 activation. Positive clones were expanded and tested for neutralizing capabilities. Anti-Notch1-NIC was used to determine whether anti-Notch1 was able to reduce Notch1 cleavage; while anti-SNAP23 and BCAT2 were used as downstream Notch1 and Notch2 targets, respectively. K457 human melanoma cells and the YUMM2.1 and 1.7 syngeneic mouse melanoma cells were used. Cell death after anti-Notch1 treatment was determined by trypan blue staining and compared to the effects of the gamma-secretase inhibitor DBZ. 10 mg/kg anti-Notch1 was used for in vivo tumor growth of YUMM2.1 and 1.7 cells. Tumors were measured and processed for flow cytometry using antibodies against major immune cell populations., Results: Anti-Notch1 selectively inhibited Notch1 but not Notch2; caused significant melanoma cell death in vitro but did not affect normal melanocytes. In vivo, it delayed tumor growth without evident signs of gastro-intestinal toxicities; and importantly promoted an inflamed TME by increasing the cytotoxic CD8 + T cells while reducing the tolerogenic Tregs and MDSCs, resulting in enhanced efficacy of anti-PD-1., Conclusions: Anti-Notch1 safely exerts anti-melanoma effects and improves immune checkpoint inhibitor efficacy. Thus, anti-Notch1 could represent a novel addition to the immunotherapy repertoire for melanoma., (© 2024. The Author(s).)

Purpose: Conjunctival melanoma (CJM) is a rare malignant ocular surface tumor, which often leads to local recurrences and metastases. In murine models of subcutaneous tumors, treatment with a novel virus-like drug conjugate (VDC; Bel-sar) showed a dual mechanism of action with direct tumor cell killing as well as stimulation of an antitumoral immune response. Bel-sar is currently being evaluated for the treatment of primary uveal melanoma and indeterminate nevi in a phase III clinical trial. We determined whether Bel-sar also has direct antitumor efficiency and a potential immunostimulatory capacity in CJM cells., Methods: Three human tumor-derived CJM lines were used. Bel-sar's subcellular and intracellular locations were determined with tracers. Following light activation of Bel-sar, cytotoxicity and exposure of damage-associated molecular patterns (DAMPs) were assessed. Treated tumor cells were co-cultured with THP-1 derived macrophages to assess tumor-cell phagocytosis., Results: Bel-sar was bound and internalized by CJM cells and subsequently found in the cell membrane, lysosome, Golgi apparatus, and mitochondria. Bel-sar activation induced near complete cell death with half-maximal inhibitory concentration (IC50) values between 30 pM and 60 pM. Finally, light-activated Bel-sar enhanced exposure of DAMPs, including calreticulin, heat shock protein 90, and stimulated phagocytosis by macrophages., Conclusions: Treatment with a novel VDC (Bel-sar) induced pro-immunogenic cell death in all three CJM cell lines. The in vitro cytotoxicity was accompanied by exposure of DAMPs, suggesting Bel-sar is a potential treatment for CJM by a dual mechanism of action. This dual mechanism may provide a targeted and direct killing of tumor cells and induce an immune response which might decrease local recurrences and metastasis.

Melanoma is an aggressive skin cancer notorious for high levels of drug resistance. Additionally, current treatments such as immunotherapies are often associated with numerous adverse side effects. The use of nitric oxide (NO) may represent an attractive treatment for melanoma due to NO's various anticancer properties, unlikeliness to foster resistance, and limited toxicity toward healthy tissues. The anticancer effects of chemical NO donors have been explored previously but with limited understanding of the needed characteristics for exerting optimal antimelanoma activity. Herein, the in vitro therapeutic efficacy of three macromolecular NO donor systems (i.e., cyclodextrin, mesoporous silica nanoparticles, and hyaluronic acid) with tunable NO-release kinetics was explored by evaluating skin permeation along with toxicity against melanoma and healthy skin cells. Cytotoxicity against melanoma cells was dependent on NO payload and not donor identity or NO-release kinetics. In contrast, cytotoxicity against healthy cells was primarily influenced by the macromolecular NO donor, with cyclodextrin- and hyaluronic acid-based NO donors having the highest therapeutic indices. In vitro skin permeation was influenced by both the size and charge of the NO donor, with smaller, more neutral donors resulting in greater permeation. A Pluronic F127 organogel was optimized for the delivery of a cyclodextrin-based NO donor. Delivery of the NO donor in this manner resulted in increased in vitro skin permeation and reduced tumor growth in an in vivo model.

Background: We aim to provide survival scenario estimates for patients with advanced melanoma starting targeted therapies and immunotherapies., Materials and Methods: We sought randomized trials of targeted therapies and immunotherapies for advanced melanoma and recorded the following percentiles (represented survival scenario) from each overall survival (OS) curve: 90th (worst-case), 75th (lower-typical), 50th (median), 25th (upper-typical), and 10th (best-case). We tested whether these scenarios can be estimated for each OS curve by multiplying its median by 4 multiples: 0.25 (worst-case), 0.5 (lower-typical), 2 (upper-typical), and 3 (best-case)., Results: We identified 15 trials with 8025 patients. For first-line combination targeted therapy treatment groups, the median (interquartile range, IQR) in months for each percentile was: 90th, 6.2 (6.0-6.5); 75th, 11.3 (11.3-11.4); and median, 24.4 (23.5-25.3). For the first-line combination immunotherapy treatment group, the percentiles in months were: 90th, 3.9 (2.8-4.5); 75th, 13.4 (10.1-15.4), median 73 (not applicable). In targeted therapy groups, simple multiples of the median OS were accurate for estimating the 90th percentile in 80%; 75th percentile in 40%; 25th percentile in 100%. In immunotherapy groups, these multiples were accurate at 0% for the 90th percentile, and 43% for the 75th percentile. The 90th percentile (worst-case scenario) was better estimated as 1/6× median OS, and the 75th percentile (lower-typical) as 1/3× median OS., Conclusions: Simple multiples of the median OS are a useful framework to estimate scenarios for survival for patients receiving targeted therapies, not immunotherapy. Longer follow-up is required to estimate upper-typical and best-case scenarios., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Encorafenib plus binimetinib (EB) is a standard-of-care treatment for advanced BRAFV600-mutant melanoma. We assessed the efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600-mutant melanoma and brain metastasis (BM) and explored if radiotherapy improves the duration of response., Methods: E-BRAIN/GEM1802 was a prospective, multicenter, single-arm, phase II trial that enrolled patients with melanoma BRAFV600-mutant and BM. Patients received encorafenib 450 mg once daily plus binimetinib 45 mg BID, and those who achieved a partial response or stable disease at first tumor assessment were offered radiotherapy. Treatment continued until progression. Primary endpoint was intracranial response rate (icRR) after 2 months of EB, establishing a futility threshold of 60%., Results: The study included 25 patients with no BM symptoms and 23 patients with BM symptoms regardless of using corticosteroids. Among them, 31 patients (64.6%) received sequential radiotherapy. After 2 months, icRR was 70.8% (95% CI: 55.9-83.1); 10.4% complete response. Median intracranial progression-free survival (PFS) and OS were 8.5 (95% CI: 6.4-11.8) and 15.9 (95% CI: 10.7-21.4) months, respectively (8.3 months for icPFS and 13.9 months OS for patients receiving RDT). Most common grades 3-4 treatment-related adverse event was alanine aminotransferase (ALT) increased (10.4%)., Conclusions: Encorafenib plus binimetinib showed promising clinical benefit in terms of icRR, and tolerable safety profile with low frequency of high-grade TRAEs, in patients with BRAFV600-mutant melanoma and BM, including those with symptoms and need for steroids. Sequential radiotherapy is feasible but it does not seem to prolong response., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Malignant melanoma is a difficult-to-treat skin cancer with increasing incidence worldwide. Although type-I interferon (IFN) is no longer part of guidelines, several melanoma patients are treated with type-I interferon (IFN) at some point of the disease, potentially affecting its genetic progression. We run genome-wide copy number variation (CNV) analysis on previously type-I IFN-treated (n = 17) and control (n = 11) visceral metastases of melanoma patients. Results were completed with data from the TCGA and MM500 databases. We identified metastasis- and brain metastasis-specific gene signatures mostly affected by CN gains. Some cases were genetically resistant to IFN showing characteristic gene alterations (e.g. ABCA4 or ZEB2 gain and alterations of DNA repair genes). Analysis of a previously identified type-I IFN resistance gene set indicates that only a proportion of these genes was exclusive for the IFN-treated metastases reflecting a possible selective genomic pressure of endogenous IFNs during progression. Our data suggest that previous type-I IFN treatment and/or endogenous IFN production by immune response affect genomic progression of melanoma which may have clinical relevance, potentially influence immune checkpoint regulation in the tumor microenvironment., (© 2024. The Author(s).)