Melanoma Research最新文献

Phosphodiesterase type 5 (PDE5) inhibitors are the first-line treatment for erectile dysfunction, with modest adverse effects. Since 2011, concerns have arisen about increased melanoma risk in PDE5 inhibitor users. PDE5 inhibitors affect the rat sarcoma virus oncogene-rapidly accelerated fibrosarcoma-mitogen-activated protein kinase-extracellular signal-regulated kinase signaling cascade, which is involved in melanoma formation. This systematic review and meta-analysis investigates melanoma risk in PDE5 inhibitor users. PubMed, Cochrane, and Embase were searched to examine the relationship between PDE5 inhibitors and melanoma. A random-effects model estimated pooled odds ratios (ORs) and hazard ratios (HRs), with the I ² statistic assessing heterogeneity. RStudio v4.4.2 was used for the meta-analysis, and a P value less than 0.05 was deemed significant. Eight studies including 7 620 765 patients were analyzed, with 2 123 165 (27.86%) comprising the PDE5 inhibitor-exposed group. The meta-analysis found a relationship between PDE5 inhibitor use and increased melanoma risk [OR: 1.60, 95% confidence interval (CI): 1.13-2.27, P = 0.009, I ² = 98%] and [HR: 1.10, 95% CI: 1.03-1.17, P = 0.005, I ² = 43%]. When each PDE5 inhibitor was examined separately, increased melanoma incidence was observed, though not statistically significant. The OR for sildenafil was 1.85 (95% CI: 0.97-3.51, P = 0.059, I ² = 99%), tadalafil 1.54 (95% CI: 0.79-3.00, P = 0.203, I ² = 96%), and vardenafil 1.16 (95% CI: 0.82-1.64, P = 0.391, I ² = 89%). This study suggests PDE5 inhibitor users have a higher chance of developing potentially fatal melanoma. Patients with a history of skin cancer, a family history of melanoma, or other risk factors should avoid these medications.

To explore the functional role of thrombospondin 2 (THBS2) in the metastasis of skin cutaneous melanoma (SKCM), with a focus on its regulation of angiogenesis and extracellular matrix (ECM) remodeling. THBS2 expression was assessed in normal melanocytes and SKCM cell lines with varying metastatic potential. Functional analyses were conducted after THBS2 knockdown in A375 cells and overexpression in G-361 cells. Effects on migration, invasion, endothelial tube formation, and angiogenesis- and ECM-related factors were evaluated. Tumor IMmune Estimation Resource database was used for correlation analyses in SKCM samples. A liver metastasis model was established by intrasplenic injection of B16-F10 cells into Thbs2 knockout and wild-type mice, followed by quantification of hepatic metastases and molecular analysis of peritumoral liver tissue. THBS2 was highly expressed in invasive melanoma cell lines and was positively associated with VEGFA, PECAM1, and MMPs in both databases and experimental models. Knockdown of THBS2 significantly suppressed VEGFA, PECAM1, FGF2, FLT1, MMP2, MMP9, and ECM components (LAMA4, COL1A1, and COL4A1) at mRNA and protein levels, inhibited melanoma cell migration and invasion, and reduced tube formation in human umbilical vein endothelial cells. Overexpression had opposite effects. In vivo , Thbs2 knockout mice exhibited significantly fewer hepatic metastases and reduced metastatic area compared with wild-type controls. Expression of Lama4, Pecam1, Vegfa, Mmp2, and Mmp9 was markedly lower in peritumoral liver tissue of knockout mice. THBS2 promotes SKCM metastasis by enhancing angiogenesis and ECM remodeling. Targeting THBS2 may represent a promising strategy for inhibiting melanoma progression and distant organ colonization.

Inflammation, well-known as one of the hallmarks of cancer, has been demonstrated to have a key role in the incidence and growth of different tumors. However, its role as a prognostic factor for melanoma has not yet been clarified. Our study aimed to evaluate the correlation of neutrophil to lymphocyte ratio (NLR), platelet to monocyte ratio (PMR), systemic inflammation index (SII), and aggregate index of systemic inflammation (AISI) with clinical stages of disease, to define whether higher values of these markers correlate with a more aggressive disease. We retrospectively analyzed NLR, PMR, SII, and AISI in a total of 129 newly diagnosed melanoma patients. All values were calculated using the complete blood count data. Higher NLR was associated with advanced stages ( P  < 0.001). Mean NLR among patients with early stage disease (IB and IIA) was 2.01, while the mean NLR for patients with advanced stage disease (from stage IIB to IV) was 3.22. Mean PMR among patients with early stage disease (IB and IIA) was 520, while the mean PMR for patients with advanced stage disease was 479 ( P  = 0.049). Mean AISI in the early stage was 247 and 482 in advanced stages ( P  < 0.001). Mean SII was 480 in the early stage and 747 in advanced stages ( P  = 0.004). Our data confirmed the association between NLR and newly reported the association of PMR, AISI, and SII with high-risk and aggressive melanoma. Further investigations are required to define a meaningful prognostic system for patients with advanced melanoma. This could help classify patients with advanced stages of disease, demanding a short follow-up.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and are increasingly used, also in the adjuvant and neoadjuvant settings. ICIs, however, can induce immune-related adverse events (irAEs), which range from mild to life-threatening. As the use of ICIs expands, prompt identification and management of especially severe and life-threatening irAEs are crucial. We report a case of grade 4 steroid-refractory immune-related mucositis in a 60-year-old male treated with pembrolizumab following complete resection of stage IIIC melanoma. The patient received seven courses of adjuvant pembrolizumab without adverse events until 2 weeks after the seventh dose, when he presented with acute respiratory distress, dysphagia, and dyspnea. Examination revealed significant throat swelling and mucosal edema. Despite initial treatment with high-dose steroids, the patient's condition deteriorated, and he was admitted to the ICU for intubation and close monitoring. Infliximab was administered for steroid-refractory mucositis, resulting in rapid symptom resolution and successful extubation 5 days later. This case highlights the challenges in managing severe steroid-refractory irAEs. The rapid response to infliximab suggests the benefit of early intervention with alternative immunosuppressive agents in severe irAEs. Increased awareness of rare irAEs is essential for optimizing treatment and improving outcomes for patients receiving ICIs.

Identification of effective systemic therapies for the treatment of metastatic uveal melanoma remains an ongoing challenge. While immune checkpoint inhibitors are frequently used to treat this disease, response rates and survival outcomes remain poor. In this case report, we present two heavily pretreated patients with metastatic uveal melanoma who had robust responses to combination nivolumab (PD-1 inhibitor) with relatlimab (LAG-3 inhibitor) as salvage treatment. We highlight the ongoing research of the uveal melanoma tumor immune microenvironment and the potential role of LAG-3 inhibition as an effective treatment strategy.

The objective of this study was to investigate the clinical characteristics of lipodystrophy induced by immune checkpoint inhibitors (ICIs). Domestic and international databases were searched as of 28 February 2025 and case reports of ICI-associated lipodystrophy were collected. Relevant information including patients' basic information, ICI application, the occurrence of lipodystrophy, etc., were extracted and descriptively analyzed. A total of 11 patients were included in the analysis, including two males and nine females, age from 34 to 76 years, with an average age of 55 years. The primary diseases were mainly lung cancer, melanoma and renal cell carcinoma. The latency period from ICI initiation to lipodystrophy diagnosis ranged from 42 to 540 days. Clinical manifestations included facial fat pad depletion and subcutaneous fat loss in trunk and extremities. Treatment regimens included pembrolizumab ( n  = 3), nivolumab ( n  = 6), cadonilimab ( n  = 1), and nivolumab/ipilimumab combination ( n  = 1). Serum leptin levels were tested in seven patients, and two had serum leptin concentrations <0.5 ng/ml, the others ranged from 0.6 to 61.1 ng/ml. Eight cases had records of glycated hemoglobin testing, of which five cases had glycated hemoglobin ≥6.5%. After being diagnosed with lipodystrophy, seven patients discontinued ICIs while four continued treatment. Four patients received steroid therapy and seven cases had no relevant records. Among the 11 patients, only one patient demonstrated subcutaneous fat improvement, and seven patients' prognosis was not reported. None of the eight patients who discontinued treatment resumed immunotherapy. ICI-associated lipodystrophy presents similar clinical features to conventional lipodystrophy but shows limited reversibility with treatment cessation or steroid intervention, necessitating increased clinical awareness.

Nomograms are commonly used in oncology to assist clinicians in individualized decision-making processes, such as considering sentinel node biopsy (SNB) for melanoma patients. Concurrently, artificial intelligence (AI) is increasingly being utilized in medical predictions. This study aims to compare the predictive accuracy of nomograms and AI platforms for SNB positivity in a real-world cohort of melanoma patients. A retrospective analysis of melanoma patients who underwent SNB from 2020 to 2024 in a single institution was performed. Three open-access nomograms and three public AI platforms were employed to assess SNB positivity based on comprehensive clinical and pathological characteristics. Our cohort comprised 62 melanoma patients who have undergone SNB, of whom 12 (19.4%) were positive. There was no concordance among the three nomograms, nor among AI platforms ( P  < 0.001). Only the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram scored statistically different between positive and negative SNB ( P  = 0.04), and ChatGPT was the only AI platform that was also statistically significant ( P  = 0.02). Only ChatGPT score was statistically significant for SNB positivity after univariate logistic regression (odds ratio: 1.05; 95% confidence interval: 1.004-1.108; P = 0.03). A receiver operating characteristic curve based on ChatGPT predictions generated a model with an area under the curve (AUC) of 0.702. Integrating MSKCC predictions marginally improved the model's predictive performance, enhancing the AUC to 0.715. In conclusion, SNB positivity could be better performed by an AI platform in this cohort of patients. Enhancing AI platforms could provide better populations for nomogram validation, which would lead to better predictive models.

Tinostamustine is a first-in-class alkylating deacetylase inhibitor that facilitates access to cancer cell DNA, resulting in its damage and counteracting DNA repair systems. We hypothesize that the addition of tinostamustine to immune checkpoint inhibitors (ICIs) improves melanoma treatment. This open-label, nonrandomized phase IB study characterized dose-limiting toxicity (DLT) and the recommended dose (RD) of 2-weekly intravenous tinostamustine at escalating doses of 15 and 30 mg/m 2 when administered with 2-weekly nivolumab 3 mg/kg added in cycle 2 in patients with melanoma. We included 17 patients (four at 15 mg/m 2 and 13 at 30 mg/m 2 tinostamustine). A total of 13/17 (77%) patients were ICI-resistant, 7/17 (41%) had unfavorable melanoma subtypes. No DLT was identified. Tinostamustine RD was 30 mg/m 2 every 2 weeks. One patient experienced grade 2 nivolumab-associated immune-related pneumonitis. Tinostamustine-associated grade 3 leukocytopenia was documented in one patient, grade 2 leukocytopenia in five patients, and grade 1 thrombocytopenia in three patients. Treatment discontinuation occurred in one patient for nivolumab-associated immune-related pneumonitis and in another patient for tumor-related hemorrhage. A total of 7/13 (54%) evaluable patients had at least stable disease as best treatment response, including 3/13 (23%) patients with a confirmed partial response. Median progression-free survival was 8.3 weeks [95% confidence interval (CI): 2.4-15.4 weeks), median overall survival was 19.1 weeks (95% CI: 2.4-41 weeks). Two-weekly intravenous tinostamustine at an immune-modulatory dose of 30 mg/m 2 is safe when coadministered with nivolumab 3 mg/kg and resulted in 54% disease stabilization and 23% confirmed partial responses in patients with predominantly ICI-resistant, advanced melanoma.

The National Comprehensive Cancer Network (NCCN) recommended surveillance imaging intervals for uveal melanoma (UM) based on the risk of distant metastasis. The objective of this research is to evaluate if patients, treated at our tertiary cancer center, who had scans consistent with these guidelines, had improved overall survival (OS). This was a single-center, retrospective study of UM patients, who developed metastatic disease. Patients were grouped into risk-of-metastasis cohorts (low, medium, and high-risk) based on the UM NCCN guidelines v1.2023. The frequency of scans was reported within annual intervals for 5 years within the low-risk cohort and for 10 years within the medium-risk cohort, and within 6-month intervals for the first 5 years and then annually in years 6-10 within the high-risk cohort. Conditional landmark analyses were used to evaluate the relationship between OS and consistency with guidelines. Scan frequency was evaluated against socioeconomic status. Of the 740 UM patients identified (1997-2020), 110 experienced metastasis and comprised our analysis population (20 low-risk; 67 medium-risk; and 23 high-risk). The median time to death (95% confidence interval) from diagnosis of metastasis was similar between the low, medium, and high-risk cohorts at 1.2 (1.0, 2.0), 2.0 (1.7, 2.6), and 1.6 (1.3, 2.3) years, respectively. For each cohort, the OS results were similar between those who followed guidelines vs. not at each annual landmark time. Living in disadvantaged areas did not impact imaging frequency (all P > 0.05). Imaging at intervals outlined by the NCCN guidelines v1.2023 did not impact OS for patients who developed metastatic UM.

Goal of this study was to examine the impact of immunotherapy on overall survival (OS) in patients with female genital tract melanoma (GTM). This retrospective cohort study utilized the National Cancer Database to identify individuals with invasive vulvar or vaginal melanoma diagnosed between 2004 and 2019. Kaplan-Meier plots and multivariate Cox regression were used to describe the impact of immunotherapy on OS and to examine predictors of OS among those who received immunotherapy for those with vulvar or vaginal melanoma. Of the 870 patients with vaginal melanoma, 23.6% received immunotherapy. Receiving immunotherapy for treatment of vaginal melanoma was associated with improved OS (median: 21.8 versus 18.9 months; P  = 0.01); this association remained after adjustment for other prognostic factors [hazard ratio (HR), 0.77; 95% confidence interval (CI), 0.62-0.95; P  = 0.01]. The survival advantage was more pronounced among those who did not receive primary surgical resection (median: 18.6 versus 12.2 months; P  = 0.0009). Among 3123 patients with vulvar melanoma, 15.3% received immunotherapy. Receiving immunotherapy for treatment of vulvar melanoma was associated with an improvement in OS (median: 43.6 versus 57.7 months; P  = 0.06; HR, 0.86; 95% CI, 0.74-1.00; P  = 0.04). Survival benefit was more pronounced when restricted to patients with advanced or unknown stage disease (median OS, 31.6 versus 24.2 months; P  = 0.002; adjusted HR, 0.74; 95% CI, 0.61-0.89; P  = 0.002) and among the small subset who did not receive primary surgical resection (median: 19.8 versus 9.6 months; P  = 0.0005). Immunotherapy was associated with improved OS in patients with female GTM, with some subsets particularly benefitting.