This study focuses on a green and sustainable nanoplatform for the delivery of therapeutic agents, based on gold nanoparticles (AuNPs) synthesized using PEO-PPO block copolymers (F127, F68, P85, and their F127:P85 combination) as dual-function reducing and stabilizing agents. This eco-friendly approach eliminates the need for toxic chemical reductants, adheres to green chemistry principles, and yields highly stable, biocompatible nanosystems. The resulting polymer-stabilized AuNPs were associated with doxycycline (DOXY), a mitochondrial biogenesis inhibitor with radiosensitizing properties, and characterized using UV-Vis spectroscopy, dynamic light scattering (DLS), transmission electron microscopy (TEM), and X-ray fluorescence (XRF). The nanoparticles exhibited high colloidal stability, with tunable hydrodynamic diameters modulated by the copolymer composition. In vitro studies on A-375 and IIB-MEL-J melanoma cell lines revealed that DOXY-associated AuNPs, combined with gamma radiation (2 Gy, 137Cs), significantly enhanced radiosensitivity, reducing both cell viability and clonogenic survival. The physicochemical features of the nanosystems, particularly particle size and surface composition, influenced cellular uptake and therapeutic response. Notably, AuNPs stabilized with F127:P85 copolymer combination (∼19 nm) outperformed those with F127 (∼30 nm), despite displaying slightly higher polydispersity. Compared to Turkevich AuNPs, our copolymer-coated nanosystems demonstrated superior colloidal stability and cellular internalization. These findings highlight the potential of green-synthesized AuNPs as multifunctional, biocompatible platforms for therapeutic delivery, supporting the development of effective and environmentally responsible multimodal cancer therapies. Moreover, the simplicity, scalability, and cost-effectiveness of the synthesis process support its potential for future translational applications.

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/m2 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/m2 and 13 at 30 mg/m2 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/m2 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/m2 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 dysregulation of matrix metalloproteinases (MMPs) in skin cutaneous melanoma (SKCM) represents a critical aspect of tumorigenesis. In this study, we investigated the diagnostic, prognostic, and therapeutic aspects of the MMPs in SKCM. Thirteen SKCM cell lines and seven normal skin cell lines were cultured under standard conditions for experimental analyses. RNA and DNA were extracted, followed by RT-qPCR to assess MMP expression and promoter methylation analysis to determine methylation levels. Functional assays, including cell proliferation, colony formation, and wound healing, were conducted post-MMP7 knockdown using siRNA in A375 cells. Databases like GEPIA2, HPA, MEXPRESS, and miRNet were employed for expression, survival, methylation, and miRNA-mRNA network analyses. We investigated the expression and promoter methylation landscape of MMPs in SKCM cell lines, revealing significant (p-value < 0.05) up-regulation of MMP1, MMP7, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, and MMP25, alongside down-regulation of MMP2, MMP3, and MMP21. Furthermore, our analysis demonstrated a significant (p-value < 0.05) inverse correlation between MMP expression levels and promoter methylation status, suggesting a potential regulatory role of DNA methylation in MMP dysregulation. Notably, MMP7, MMP11, and MMP14 exhibited significant (p-value < 0.05) associations with the overall survival of SKCM patients, emphasizing their prognostic significance. Additionally, Receiver operating characteristic (ROC) curve analysis highlighted the significant (p-value < 0.05) diagnostic potential of MMP7, MMP11, and MMP14 in distinguishing SKCM from normal individuals. Subsequent validation across multiple cohorts confirmed significant (p-value < 0.05) elevated MMP expression levels in SKCM tissues, particularly in advanced disease stages, further emphasizing their role in tumor progression. Furthermore, we elucidated potential regulatory pathways involving miR-22-3p, which targets MMP7, MMP11, and MMP14 genes in SKCM. Our findings also revealed associations between MMP expression and immune modulation, drug sensitivity, and functional states of SKCM cells. Lastly, MMP7 knockdown in A375 cells significantly significant (p-value < 0.05) impacted several characteristics, including cell proliferation, colony formation, and wound healing. Our findings highlight the diagnostic, prognostic, and therapeutic potential of MMP7, MMP11, and MMP14 in SKCM. These MMPs could serve as biomarkers for early detection and targets for therapy. Future efforts should focus on preclinical and clinical validation to translate these insights into personalized diagnostic and therapeutic strategies.

Melanoma is a highly lethal form of skin cancer, and effective treatment remains a significant challenge. SPP86 is a novel potential therapeutic drug. Nonetheless, the specific influence of SPP86 on autophagy, particularly its mechanisms in the context of DNA damage and apoptosis in human melanoma cells, remains inadequately understood. Thus, this study aims to explore the effects of SPP86 on autophagy and to elucidate its association with cell proliferation, apoptosis, and DNA damage in melanoma cells.

This study assessed the anti-tumor effects of SPP86 on cell viability, colony formation, apoptosis, and DNA damage in two melanoma cell lines, A375 and A2058. Concurrently, the underlying mechanisms, including the PI3K/AKT signaling pathway and autophagy modulation, were also elucidated.

The study demonstrated that SPP86 exerts anti-tumor effects in melanoma cells through multiple mechanisms: it induces apoptosis, causes DNA damage, inhibits cell proliferation, and suppresses the PI3K/AKT signaling pathway. Importantly, the inhibition of autophagy appears to be a critical component of SPP86' s mode of action, with the modulation of autophagic processes influencing the cytotoxicity against melanoma cells.

These promising findings suggest that SPP86 is a potential drug candidate for the treatment of melanoma, warranting further research and development.

Melanoma is a malignant skin cancer type with a high lethality rate due to active metastasis. Among the risk factors for its development is exposure to ultraviolet radiation (UV) and phenotypical characteristics such as clear skin and eyes. Given the difficulties of the conventional therapy, the high cost of the treatment and the low bioavailability of drugs, it is important to develop new therapeutic methods to circumvent this situation. Nanosystems such as micelles, liposomes and nanoparticles present advantages when compared to conventional treatments. The objective of this paper is to carry out a literature review based on articles that dealt with the use of siRNA-loaded nanosystems for the treatment of melanoma, with trials carried out in vivo to assess tumor size. The search was conducted in the Web of Science and PubMed databases considering the last 5 years, that is, the period between January 2017 to December 2021. The "SiRNA and Drug Delivery Systems and Melanoma" keywords were used in both databases, and the articles were analyzed using the inclusion and exclusion criteria established for this paper. The results obtained indicated that using siRNA transported via nanosystems was capable of silencing the BRAF tumor genes and of reducing tumor size and weight, not presenting in vitro and/or in vivo toxicity. Such being the case, the development of these systems becomes a non-invasive and promising option for the treatment of melanoma.

Malignant melanoma is one of the most important dermatological neoplasms. The high mortality rate associated with this skin disease is primarily due to the occurrence of metastases, while the diagnosis and treatment of melanoma in its early stages has a favorable prognosis. Early detection is crucial because the success of treatment is directly related to the depth of cancerous growth. The family of matrix metalloproteinases (MMPs) plays a critical role in the initiation and progression of melanoma. Prominent MMPs, including MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, and MMP-14, have been shown to significantly contribute to the development of melanoma. The tumor microenvironment, particularly the extracellular matrix (ECM), has emerged as a critical factor in modulating cancer progression. This review focuses on the role of matrix metalloproteinases and their inhibitors in ECM degradation and the subsequent progression of melanoma, as well as their potential as therapeutic targets.

Immunotherapy offers a novel and promising option in the treatment of late-stage melanoma. By utilizing the immune system to assist in tumor destruction, patients have additional options after tumor progression. Immune checkpoint inhibitors reduce the ability for tumors to evade the immune system by inhibiting key surface proteins used to inactivate T-cells. Without these surface proteins, T-cells can induce cytotoxic responses against tumors. Tumor infiltrating lymphocyte therapy is a form of adoptive cell therapy that takes advantage of a small subset of T-cells that recognize and infiltrate tumors. Isolation and rapid expansion of these colonies assist the immune system in mounting a charged response that can induce remission. Tumor vaccines deliver a high dose of unique antigens expressed by tumor cells to the entire body. The introduction of large quantities of tumor antigens upregulates antigen presenting cells and leads to effective activation of the immune system against tumors. Cytokine therapy introduces high amounts of chemical messengers that are endogenous to the immune system and support T-cell expansion. While other methods of immunotherapy exist, immune checkpoint inhibitors, tumor infiltrating lymphocytes, tumor vaccines, and cytokine therapy are commonly used to treat melanoma. Like many other cancer treatments, immunotherapy is not without adverse effects, as toxicities represent a major obstacle. However, immunotherapy has been efficacious in the treatment of melanoma.

Melanoma is a deadly type of skin cancer that develops from melanocytes and can manifest on the skin or other regions of the body. Its incidence is increasing rapidly, with approximately 100,000 diagnoses and 7000 deaths per year in the US alone. We conducted a cross-sectional study with the aim of determining an association between the cost of care for invasive melanoma and the specialty involved in the treatment to adequately guide future treatment.

We analyzed data from 3817 patients (2013-2018) using the Florida inpatient/outpatient dataset, CMS cost reports, and the National Plan and Provider Enumeration System. Covariates included age, sex, race/ethnicity, insurance type, region, county rurality, the number of procedures, the comorbidity index, obesity, metastatic cancer presence, hospital size, and physician volume. Multivariable mixed linear regression was used to analyze the data, and the cost was adjusted to the 2019 USD.

Dermatology had the largest decrease in the overall and outpatient costs compared to general surgery, followed by plastic surgery. The inpatient costs for dermatology and plastic surgery were lower than those for general surgery, but not significantly so.

The costs associated with surgical procedures may vary depending on the specialty of the physician treating the patient. Dermatology was associated with lower treatment costs for invasive melanoma compared to other specialties, indicating that physician specialty influences the cost of care.

Several studies have described how the restrictive measures due to COVID-19 have delayed melanoma diagnoses, resulting in an increased rate of more severe cases. Summarizing the sparse results in this context might help to understand the real impact of the COVID-19 pandemic on melanoma. We conducted a systematic review and meta-analysis to investigate how the clinical and prognostic factors of new melanoma diagnoses changed after COVID-19.

A literature search in MEDLINE, EMBASE, and Scopus was conducted in September 2023. We included studies published in peer-reviewed journals reporting histopathological data on new diagnoses of cutaneous melanoma in adult patients during and/or after the lockdown compared to those diagnosed before the COVID-19 pandemic. A meta-analysis was conducted utilizing a random effects model. The between-study heterogeneity was assessed via Higgins's I2 statistic. Publication bias was assessed using the Begg and Egger test. This study adhered to the updated PRISMA guidelines. The primary outcome was a comparison of melanoma thickness between the pre-COVID-19 and post-lockdown periods. The secondary outcomes were evaluations of the histopathological subtype, stage, and presence of ulceration and mitosis in melanomas diagnosed in these two pandemic phases.

The study included 45 articles. We found a significantly higher proportion of all factors indicating worse prognosis in the post-lockdown period compared to the pre-COVID-19 phase, including high thickness (SOR = 1.14, 95%CI 1.08-1.20 for 1-2 mm; SOR = 1.62, 95%CI 1.08-2.40, for >2 mm), the presence of ulcerations (SOR = 1.35, 95%CI 1.18-1.54), nodular subtype (SOR = 1.19, 95%CI 1.07-1.32), the presence of mitosis (SOR = 1.57, 95% CI 1.17-2.11), and stage III (SOR = 1.39, 95%CI 1.19-1.52) and IV (SOR = 1.44, 95%CI 1.26-1.63). Limitations include the limited studies' geographical distribution and moderate heterogeneity affecting meta-analysis estimates.

Our meta-analysis provided evidence of more advanced melanomas diagnosed in the post-COVID-19 pandemic period, emphasizing the importance of creating and updating pandemic preparedness plans to limit the impact of any future events on oncological care.

Basal cell carcinoma (BCC) is a slowly progressive, locally aggressive and rarely metastasizing cancer, and although its mortality is low, its morbidity and cost of disease are high. While BCC is more common, cutaneous malignant melanoma (CMM) is significant due to its higher mortality rate. These patients can be treated, but recurrence, metastasis and mortality may occur in such patients. Various environmental, phenotypic and genotypic factors, especially ultraviolet (UV) radiations, play a role in the etiology of BCC and CMM. Histopathological examination continues to be the "gold standard" in their diagnosis. Spexin (SPX) and DARS2 are newly discovered proteins linked to many diseases, including cancer. These proteins may have an effect on the development and expression of skin cancers such as BCC and CMM. In this study, we evaluated the potential of SPX and DARS2 expressions as immunohistochemical biomarkers in the differential diagnosis of BCC and CMM. This study was conducted retrospectively using samples taken from the pathology laboratory. A total of 180 patient samples were used. The control group consisted of healthy skin tissues of the patients, and the other groups consisted of BCC and CMM tissues of the same patients. Tissue samples of all three groups were evaluated immunohistochemically with SPX and DARS2. The immunoreactivity of SPX was found to be higher in BCC and CMM tissue samples than in healthy skin tissues in the control group. DARS2 immunoreactivity was found to be higher in CMM tissues compared to the other two groups, and statistically significant in BCC tissues when compared with healthy control group tissues. SPX can be used as an immunohistochemical biomarker in the diagnosis of BCC and CMM. Since DARS2 expression is statistically more significant in CMM tissues than in BCC tissues, it can be used in differential diagnosis.

Melanoma is an aggressive cancer with poor response to traditional therapies. A combination of photothermal therapy and topical immunotherapy may enhance elimination of melanoma..

C57BL/6 mice with early stage and metastatic melanoma were treated with laser immunotherapy (LIT), combining near-infrared laser-based photothermal therapy (PTT) and topical imiquimod (IMQ)-based immunotherapy. The volume of primary and abscopal melanoma, animal survival, tissue temperature, transcriptome, and immune cell response were investigated to evaluate the effect of LIT.

LIT could eliminate primary tumors, inhibite abscopal tumors, and prolong animal survival. The tumor tissues were selectively destroyed under a photothermal gradient between 38.2 ± 3.7 °C and 73.0 ± 2.3 °C. Gene expression analysis showed a significant increase in the expression of damage associated molecular patterns. Additionally, the population of mature dendritic cells, CD4+ T cells, and CD8+ T cells were increased, while myeloid-derived suppressor cells were downregulated after LIT.

The study showed that LIT inhibited the growth of both primary and abscopal melanoma by activating systemic antitumor immune responses and reversing the immunosuppressive tumor microenvironment, making LIT a potential method for advanced melanoma treatment.

In this proof-of-concept study, we propose a new method for automated digital quantification of PRAME (PReferentially expressed Antigen of MElanoma) as a diagnostic aid to distinguish between benign and malignant melanocytic lesions. The proposed method utilizes immunohistochemical virtual double nuclear staining for PRAME and SOX10 to precisely identify the melanocytic cells of interest, which is combined with digital image analyse to quantify a PRAME-index.

Our study included 10 compound nevi, 3 halo nevi, and 10 melanomas. Tissue slides were stained with PRAME, scanned, the cover glass removed, stained with SOX10, scanned again, and finally analysed digitally. The digitally quantified PRAME-index was compared with a manual qualitative assessment by a dermatopathologist using the standard PRAME-scoring system.

The digitally quantified PRAME-index showed a sensitivity of 70 % and a specificity of 100 % for separating melanomas from benign lesions. The manual qualitative PRAME-score showed a sensitivity of 60 % and a specificity of 100 %. Comparing the two methods using ROC-analyses, our digital quantitative method (AUC: 0.931, 95 % CI: 0.834;1.00, SD: 0.050) remains on par with the manual qualitative method (AUC: 0.877, 95 % CI: 0.725;1.00, SD: 0.078).

We found our novel digital quantitative method was at least as precise at classifying lesions as benign or malignant as the current manual qualitative assessment. Our method has the advantages of being operator-independent, objective, and replicable. Furthermore, our method can easily be implemented in an already digitalized pathology department. Given the small cohort size, more studies are to be done to validate our findings.

Skin cutaneous melanoma (SKCM) is a highly fatal form of skin cancer that develops from the malignant transformation of epidermal melanocytes. There is substantial evidence linking autophagy to cancer etiology and immunotherapy efficacy. This study aimed to conduct a comprehensive analysis of autophagy-related genes (ARGs) using TCGA datasets and further explore the potential function of critical ARGs in SKCM progression. We performed comprehensive bioinformatics analysis uses the TCGA dataset. RT-PCR was applied to examine the expression of CAPNS1 in SKCM cells. Lost-of-function experiments were performed to detect the expression of the related proteins. In this search, we screed 70 differentially expressed autophagy-related genes (DE-ARGs), including 33 up-DE-ARGs and 37 down-DE-ARGs. Enrichment assays revealed that these 70 DE-ARGs may exert influence on critical cellular processes such as autophagy, protein kinase activity, and signaling pathways, impacting cell growth, differentiation, survival, and tumor development. Then, we further explore the prognostic value of 70 DE-ARGs and confirmed 18 survival-related DE-ARGs in SKCM patients. Nearly all the 18 DE-ARGs' methylation was negatively correlated with their corresponding expression in SKCM. The 12 survival-related DE-ARGs were used to develop a unique predictive model that effectively classified SKCM patients into high- and low-risk groups with regard to overall survival. Furthermore, tumor environment analysis indicated that the risk score was associated with several immune cells. Among the 12 survival-related DE-ARGs, our attention focused on CAPNS1 which was highly expressed in SKCM patients and predicted a poor prognosis. In addition, we confirmed that knockdown of CAPNS1 distinctly suppressed the proliferation, metastasis and EMT of SKCM cells, and promoted autophagy via regulating Notch signaling pathway. Overall, this study enhances our understanding of the intricate molecular landscape of SKCM progression and presents promising avenues for future research and clinical applications.

BRAF (v-raf murine sarcoma viral oncogene homolog B1)/MEK (mitogen-activated protein kinase kinase) inhibitors are used for melanoma treatment. Unfortunately, patients treated with this combined therapy develop resistance to treatment quite quickly, but the mechanisms underlying this phenomenon are not yet fully understood. Here, we report and characterize two melanoma cell lines (WM9 and Hs294T) resistant to BRAF (vemurafenib) and MEK (cobimetinib) inhibitors.

Cell viability was assessed via the XTT test. The level of selected proteins as well as activation of signaling pathways were evaluated using Western blotting. The expression of the chosen genes was assessed by RT-PCR. The distribution of cell cycle phases was analyzed by flow cytometry, and confocal microscopy was used to take photos of spheroids. The composition of cytokines secreted by cells was determined using a human cytokine array.

The resistant cells had increased survival and activation of ERK kinase in the presence of BRAF/MEK inhibitors. The IC50 values for these cells were over 1000 times higher than for controls. Resistant cells also exhibited elevated activation of AKT, p38, and JNK signaling pathways with increased expression of EGFR, ErbB2, MET, and PDGFRβ receptors as well as reduced expression of ErbB3 receptor. Furthermore, these cells demonstrated increased expression of genes encoding proteins involved in drug transport and metabolism. Resistant cells also exhibited features of epithelial-mesenchymal transition and cancer stem cells as well as reduced proliferation rate and elevated cytokine secretion.

In summary, this work describes BRAF/MEK-inhibitor-resistant melanoma cells, allowing for better understanding the underlying mechanisms of resistance. The results may thus contribute to the development of new, more effective therapeutic strategies.

The aim of this study is to correlate the diagnostic criteria described in dermoscopy, ultrasonography (US), and histology of the most common types of cutaneous melanoma (CM).

We conducted a prospective study including 40 CM cases, which were analyzed by dermoscopy using the Delta 30 dermatoscope and Vidix 4.0 videodermoscope, by ultrasound (US) using a high-resolution 20 MHz linear probe, along with histopathological analysis.

The study involved 40 patients with histopathologically confirmed CM, comprising 10 nodular melanomas (NM), 21 superficial spreading melanomas (SSM), and nine in situ melanomas (MIS). US measurements of tumor thickness exhibited strong correlations with the histopathological Breslow index (BI), particularly in the NM and SSM groups. A notable correlation was observed between the presence of ulceration in histopathology and ultrasonography. Dermoscopic analysis revealed significant associations between specific features and CM types. For instance, the presence of an atypical network, irregular globules, irregular dots, prominent skin margins, angulated lines/polygons, dotted and short linear vessels, and negative network correlated with a median BI ≤ 0.5 mm. Conversely, the presence of blue-white veil, atypical vessels, blue-black color, and milky red color were associated with a median BI ≥ 2.3 mm. Furthermore, regression observed in histopathology correlated with regression identified in dermoscopy, we also found statistical correlations between the presence of vascularization at US with the high Clark level, and the presence of prominent skin markings at dermoscopy. The presence of histopathological regression was more frequently associated with tumors that had precise margins, absent vascularization and with those that did not have ulceration on US. The high mitotic rate was associated with tumors that presented imprecise margins, increased vascularization and US detectable ulceration.

Innovative CM diagnosis using non-invasive methods like dermoscopy and ultrasound may enhance accuracy and treatment guidance by assessing lesion characteristics.

CD8+ T cells have been recognized as crucial factors in the prognosis of melanoma. However, there is currently a lack of gene markers that accurately describe their characteristics and functions in acral melanoma (AM), which hinders the development of personalized medicine.

Firstly, we explored the composition differences of immune cells in AM using single-cell RNA sequencing (scRNA-seq) data and comprehensively characterized the immune microenvironment of AM in terms of composition, developmental differentiation, function, and cell communication. Subsequently, we constructed and validated a prognostic risk scoring model based on differentially expressed genes (DEGs) of CD8+ T cells using the TCGA-SKCM cohort through Lasso-Cox method. Lastly, immunofluorescence staining was performed to validate the expression of four genes (ISG20, CCL4, LPAR6, DDIT3) in AM and healthy skin tissues as included in the prognostic model.

The scRNA-seq data revealed that memory CD8+ T cells accounted for the highest proportion in the immune microenvironment of AM, reaching 70.5%. Cell-cell communication analysis showed extensive communication relationships among effector CD8+ T cells. Subsequently, we constructed a prognostic scoring model based on DEGs derived from CD8+ T cell sources. Four CD8+ T cell-related genes were included in the construction and validation of the prognostic model. Additionally, immunofluorescence results demonstrated that ISG20 and CCL4 were downregulated, while LPAR6 and DDIT3 were upregulated in AM tissues compared to normal skin tissues.

Identifying biomarkers based on the expression levels of CD8+ T cell-related genes may be an effective approach for establishing prognostic models in AM patients. The independently prognostic risk evaluation model we constructed provides new insights and theoretical support for immunotherapy in AM.

Over the past decade, several strategies have revolutionized the clinical management of patients with cutaneous melanoma (CM), including immunotherapy and targeted tyrosine kinase inhibitor (TKI)-based therapies. Indeed, immune checkpoint inhibitors (ICIs), alone or in combination, represent the standard of care for patients with advanced disease without an actionable mutation. Notably BRAF combined with MEK inhibitors represent the therapeutic standard for disease disclosing BRAF mutation. At the same time, FDG PET/CT has become part of the routine staging and evaluation of patients with cutaneous melanoma. There is growing interest in using FDG PET/CT measurements to predict response to ICI therapy and/or target therapy. While semiquantitative values such as standardized uptake value (SUV) are limited for predicting outcome, new measures including tumor metabolic volume, total lesion glycolysis and radiomics seem promising as potential imaging biomarkers for nuclear medicine. The aim of this review, prepared by an interdisciplinary group of experts, is to take stock of the current literature on radiomics approaches that could improve outcomes in CM.

Cutaneous melanoma, a malignancy of melanocytes, presents a significant challenge due to its aggressive nature and rising global incidence. Despite advancements in treatment, the variability in patient responses underscores the need for further research into novel therapeutic targets, including the role of programmed cell death pathways such as necroptosis. The melanoma datasets used for analysis, GSE215120, GSE19234, GSE22153 and GSE65904, were downloaded from the GEO database. The melanoma data from TCGA were downloaded from the UCSC website. Using single-cell sequencing, we assess the heterogeneity of necroptosis in cutaneous melanoma, identifying distinct cell clusters and necroptosis-related gene expression patterns. A combination of 101 machine learning algorithms was employed to construct a necroptosis-related signature (NRS) based on key genes associated with necroptosis. The prognostic value of NRS was evaluated in four cohorts (one TCGA and three GEO cohorts), and the tumour microenvironment (TME) was analysed to understand the relationship between necroptosis, tumour mutation burden (TMB) and immune infiltration. Finally, we focused on the role of key target TSPAN10 in the prognosis, pathogenesis, immunotherapy relevance and drug sensitivity of cutaneous melanoma. Our study revealed significant heterogeneity in necroptosis among melanoma cells, with a higher prevalence in epithelial cells, myeloid cells and fibroblasts. The NRS, developed through rigorous machine learning techniques, demonstrated robust prognostic capabilities, distinguishing high-risk patients with poorer outcomes in all cohorts. Analysis of the TME showed that high NRS scores correlated with lower TMB and reduced immune cell infiltration, indicating a potential mechanism through which necroptosis influences melanoma progression. Finally, TSPAN10 has been identified as a key target for cutaneous melanoma and is highly associated with poor prognosis. The findings highlight the complex role of necroptosis in cutaneous melanoma and introduce the NRS as a novel prognostic tool with potential to guide therapeutic decisions.

Early detection and standardized treatment are crucial for enhancing outcomes for patients with cutaneous melanoma, the commonly diagnosed skin cancer. However, access to quality health care services remains a critical barrier for many patients, particularly the uninsured. Whereas Medicaid expansion (ME) has had a positive impact on some cancers, its specific influence on cutaneous melanoma remains understudied.

The National Cancer Database identified 87,512 patients 40-64 years of age with a diagnosis of non-metastatic cutaneous melanoma between 2004 and 2017. In this study, patient demographics, disease characteristics, and treatment variables were analyzed, and ME status was determined based on state policies. Standard univariate statistics were used to compare patients with a diagnosis of non-metastatic cutaneous melanoma between ME and non-ME states. The Kaplan-Meier method and log-rank tests were used to evaluate overall survival (OS) between ME and non-ME states. Multivariable Cox regression models were used to examine associations with OS.

Overall, 28.6 % (n = 25,031) of the overall cohort was in ME states. The patients in ME states were more likely to be insured, live in neighborhoods with higher median income quartiles, receive treatment at academic/research cancer centers, have lower stages of disease, and receive surgery than the patients in non-ME states. Kaplan-Meier analysis found enhanced 5-year OS for the patients in ME states across all stages. Cox regression showed improved survival in ME states for stage II (hazard ratio [HR], 0.84) and stage III (HR, 0.75) melanoma.

This study underscores the positive association between ME and improved diagnosis, treatment, and outcomes for patients with non-metastatic cutaneous melanoma. These findings advocate for continued efforts to enhance health care accessibility for vulnerable populations.

The diagnosis of malignant melanoma, often an inconspicuous but highly aggressive tumor, is most commonly done by histological examination, while additional diagnostic methods on the level of elements and molecules are constantly being developed. Several studies confirmed differences in the chemical composition of healthy and tumor tissue. Our study presents the potential of the LIBS (Laser-Induced-Breakdown Spectroscopy) technique as a diagnostic tool in malignant melanoma (MM) based on the quantitative changes in elemental composition in cancerous tissue. Our patient group included 17 samples of various types of malignant melanoma and one sample of healthy skin tissue as a control. To achieve a clear perception of results, we have selected two biogenic elements (calcium and magnesium), which showed a dissimilar distribution in cancerous tissue from its healthy surroundings. Moreover, we observed indications of different concentrations of these elements in different subtypes of malignant melanoma, a hypothesis that requires confirmation in a more extensive sample set. The information provided by the LIBS Imaging method could potentially be helpful not only in the diagnostics of tumor tissue but also be beneficial in broadening the knowledge about the tumor itself.

The goal was to explore the effect of interleukin-6 (IL6) and C reactive protein (CRP) on malignant melanoma (MM) using two-sample Mendelian randomization.

Data for this study were obtained from the IEU Open GWAS project website for genome-wide association study data (GWAS) on interleukin-6, C reactive protein levels and malignant melanoma. Inverse variance weighted (IVW) method was mainly used and supplemented with MR-Egger regression and weighted median. Finally, horizontal multivariate validity and heterogeneity tests were performed to assess the stability and reliability of the results.

The results of univariate two-sample MR analyses showed no significant effect of CRP on MM: inverse variance weighting method (OR=0.999, 95% CI: 0.998-1.001, P=0.343), MR-Egger regression (OR= 1.000, 95% CI: 0.998-1.001, P= 0.180), and weighted median method (OR= 0.999, 95% CI: 0.997 to 1.000, P= 0.583), and weighted model (OR= 0.999, 95% CI: 0.998 to 1.001, P= 0.328). Also,IL-6 had no significant effect on MM: inverse variance weighting method (OR= 1.001, 95% CI: 0.999 to 1.002, P=0.461), MR-Egger regression (OR= 1.000, 95% CI: 0.997 to 1.004, P= 0.910), weighted median method (OR= 1.000, 95% CI: 0.998 to 1.002, P= 0.749), and weighted mode (OR= 1.000, 95% CI: 0.998 to 1.002, P= 0.820).

There was no causal relationship between C-reactive protein and IL-6 on the risk of malignant melanoma.

Intratumor heterogeneity (ITH) is defined as differences in molecular and phenotypic profiles between different tumor cells and immune cells within a tumor. ITH was involved in the cancer progression, aggressiveness, therapy resistance and cancer recurrence. Integrative machine learning procedure including 10 methods was conducted to develop an ITH-related signature (IRS) in The Cancer Genome Atlas (TCGA), GSE54467, GSE59455 and GSE65904 cohort. Several scores, including tumor immune dysfunction and exclusion (TIDE) score, tumor mutation burden (TMB) score and immunophenoscore (IPS), were used to evaluate the role of IRS in predicting immunotherapy benefits. Two immunotherapy datasets (GSE91061 and GSE78220) were utilized to the role of IRS in predicting immunotherapy benefits of skin cutaneous melanoma (SKCM) patients. The optimal prognostic IRS constructed by Lasso method acted as an independent risk factor and had a stable and powerful performance in predicting the overall survival rate in SKCM, with the area under the curve of 2-, 3- and 4-year receiver operating characteristic curve being 0.722, 0.722 and 0.737 in TCGA cohort. We also constructed a nomogram and the actual 1-, 3- and 5-year survival times were highly consistent with the predicted survival times. SKCM patients with low IRS scores had a lower TIDE score, lower immune escape score and higher TMB score, higher PD1&CTLA4 IPS. Moreover, SKCM patients with low IRS scores had a lower gene sets score involved in DNA repair, angiogenesis, glycolysis, hypoxia, IL2-STAT5 signaling, MTORC1 signaling, NOTCH signaling and P53 pathway. The current study constructed a novel IRS in SKCM using 10 machine learning methods. This IRS acted as an indicator for predicting the prognosis and immunotherapy benefits of SKCM patients.

Malignant melanoma (MM) is a malignant tumor associated with high mortality rates and propensity for metastasis. Despite advancement in treatment, the incidence of MM continue to rise globally. GPR168, also known as MrgprF, is a MAS related GPR family member. The low expression of GPR168 has also been reported in many malignant tumors including MM. In the study, the statistical analysis from The Cancer Genome Atlas (TCGA) revealed a significant down regulation of GPR168 in melanoma compared to normal melanocytes, underscoring its importance in MM. The aim of the present study is to investigate the affect of GPR168 overexpression and elucidate its molecular mechanisms in MM cells. In addition, we used mouse melanoma B16-F10 cell line and xenograph tumor model to explore the function of GPR168 in melanoma. Our findings demonstrate that GPR168 overexpression could inhibit B16-F10 cell proliferation, migration, and xenografts tumor growth. Further, mechanistic studies revealed that GPR168 affected B16-F10 progress through Akt signal pathway with the decreased expression of p-Akt, p-GSK-3β, β-catenin, Myc, CyclinD1 and CDK4. In order to validate these findings, a rescue experiment was formulated employing GPR168 polyclonal antibody (Anti-GPR168 pAbs) to block GPR168 functionality. The addition of Anti-GPR168 pAbs into the culture medium restored both cell proliferation and migration. In conclusion, the overexpression of GPR168 in mouse melanoma B16-F10 cells suppressed proliferation and migration through the Akt signaling pathway. These findings collectively propose GPR168 as a promising novel tumor suppressor in MM, suggesting its potential as a therapeutic target in future interventions.

Annual melanoma incidence in the US is escalating.

Comprehensive evaluation of nivolumab alone or with ipilimumab for advanced melanoma treatment.

A systematic search was conducted across PubMed, Embase, Web of Science, and Cochrane databases, extending until August 2023. A range of outcomes were evaluated, encompassing overall survival (OS), recurrence-free survival (RFS), progression-free survival (PFS), disease-free survival (DFS), adverse events (both any and serious), complete response rate, mortality rate, and recurrence rate in patients with advanced melanoma.

This analysis was conducted on seven relevant studies, involving 2,885 patients. The baseline characteristics of both groups were found to be comparable across all outcomes, with the exception of tumor size. The pooled analysis did not reveal any significant disparities, except for PFS, where the nivolumab-ipilimumab treatment group demonstrated a significantly longer PFS compared to the nivolumab group. However, there was a notable discrepancy in any adverse events (Odds Ratio (OR): 2.69; 95% Confidence Interval (CI): 1.96, 3.69; p < 0.00001) and serious adverse events (OR: 3.59; 95% CI: 2.88, 4.49, p < 0.00001) between the two groups, suggesting that the safety profile of nivolumab combined with ipilimumab was inferior.

Given diversity and potential biases, oncologists should base immunotherapy decisions on professional expertise and patient characteristics.

PROSPERO registration number: CRD42023453484.

The incidence of cutaneous melanoma is rising, and Melanoma related deaths are highest among people aged 65-74. Herein, we aim to understand the impact of novel and established melanoma treatment methods on CM related mortality and all-cause mortality. We further compared these effects among Hispanic and non-Hispanic Whites (NHW).

The data was extracted from the Texas Cancer Registry from 2007 to 2017. A Cox Proportional Hazard regression analysis was performed to assess treatment effect on melanoma mortality and all-cause mortality, with race-ethnicity as an effect modifier.

A higher percentage of Hispanic patients presented with CM-related mortality (22.11%) compared to NHW patients (14.39%). In both the Hispanic and NHW, post-diagnosis radiation (HR = 1.610, 95% CI 0.984-2.634, HR = 2.348, 95% CI 2.082-2.648, respectively), post-diagnosis chemotherapy (HR = 1.899, 95% CI 1.085-3.322, HR = 2.035, 95% CI 1.664-2.489, respectively), and post-diagnosis immunotherapy (HR = 2.100, 95% CI 1.338-3.296, HR = 2.402, 95% CI 2.100-2.748) are each associated with an increased risk in CM-related mortality. Similar results were seen with post-diagnosis radiation (Hispanic HR = 1.640, 95% CI 1.121-2.400, NHW HR = 1.800, 95% CI 1.644-1.971), post-diagnostic chemotherapy (Hispanic HR = 1.457, 95% CI 0.898-2.364, NHW HR = 1.592, 95% CI 1.356-1.869), and post-diagnosis immunotherapy (Hispanic HR = 2.140, 95% CI 1.494-3.065, NHW HR = 2.190, 95% CI 1.969-2.435) with respect to all-cause mortality. Post-diagnosis surgery (HR = 0.581, 95% CI 0.395-0.856, HR = 0.622, 95% CI 0.571-0.678) had the opposite effect in CM-related mortality for Hispanics and NHWs respectively.

Our results propose differences in all-cause and CM-only related mortality with separate treatment modalities, particularly with chemotherapy, radiation therapy and immunotherapy. In addition, this retrospective cohort study showed that health disparities exist in the Hispanic Medicare population of Texas with CM.

Malignant melanoma (MM) is a highly aggressive tumour that can easily metastasize through the lymphatic system at the early stages. Lymph node (LN) involvement and lymphatic vessel (LV) density (LVD) represent a harbinger of an adverse prognosis, indicating a strong link between the state of the lymphatic system and the advancement of MM. Permeable capillary lymphatic vessels are the optimal conduits for melanoma cell (MMC) invasion, and lymphatic endothelial cells (LECs) can also release a variety of chemokines that actively attract MMCs expressing chemokine ligands through a gradient orientation. Moreover, due to the lower oxidative stress environment in the lymph compared with the blood circulation, MMCs are more likely to survive and colonize. The number of LVs surrounding MM is associated with tumour-infiltrating lymphocytes (TILs), which is crucial for the effectiveness of immunotherapy. On the other hand, MMCs can release various endothelial growth factors such as VEGF-C/D-VEGFR3 to mediate LN education and promote lymphangiogenesis. Tumour-derived extracellular vesicles are also used to promote lymphangiogenesis and create a microenvironment that is more conducive to tumour progression. MM is surrounded by a large number of lymphocytes. However, both LECs and MMCs are highly plastic, playing multiple roles in evading immune surveillance. They achieve this by expressing inhibitory ligands or reducing antigen recognition. In recent years, tertiary lymphoid structures have been shown to be associated with response to anti-immune checkpoint therapy, which is often a positive prognostic feature in MM. The present review discusses the interaction between lymphangiogenesis and MM metastasis, and it was concluded that the relationship between LVD and TILs and patient prognosis is analogous to a dynamically tilted scale.

Malignant tumors of the eyelid are much less frequent than benign eyelid alterations. These are frequently incidental findings without symptoms which are often overlooked or misinterpreted by patients.

This article gives an overview of clinical aspects, diagnostics and treatment of the five most common malignant eyelid tumors and exemplarily explains the essential principles of evidence-based treatment of malignant eyelid tumors.

This narrative review was prepared based on a selective literature search. The depiction of the treatment of eyelid tumors is supported by illustrations of clinical cases.

The medical history and inspection provide initial indications of malignancy. Every eyelid change suspected of being malignant should be examined histologically to confirm a diagnosis. By far the most common malignant eyelid tumor in Europe is basal cell carcinoma, which metastasizes only in exceptional cases. Squamous cell carcinomas, sebaceous adenocarcinomas, melanomas and Merkel cell carcinomas occur much less frequently. In these cases, potential metastasis in particular must be considered when making the diagnosis and staging has to be initiated. Surgical excision into healthy tissue with tumor-free margins is the gold standard for malignant eyelid tumors. Non-surgical adjuvant or neoadjuvant forms of evidence-based treatment can be initiated based on the individual case to minimize the risk of recurrence and metastasis.

It is essential to recognize eyelid changes at an early stage, to classify them correctly and to initiate the appropriate treatment. The interaction between the general condition and the personal needs of a patient as well as state of the art medicine are the keys to a good personalized treatment.

The goal of this study was to evaluate the global burden of malignant skin melanoma (MSM) from 1990 to 2019 using MSM-related data from the Global Burden of Disease study.

The incidences' relationships with the social-demographic index (SDI) and human developmental index (HDI) were investigated. To determine significant changes in incidence trends, the joinpoint regression model was used. To demonstrate trends in MSM mortality rates, an Age-Period-Cohort framework was conducted. For the projection of new cases and the age-standardized incidence rate (ASR) of MSM incidence to 2034, the Nordpred method was used.

In 2019, the ASR incidence per 100, 000 people for MSM was 3.6 (95% UI, 2.6-4.2). MSM prevalence increased in most countries between 1990 and 2019 (average annual percentage change >0). HDI and annual percentage change (APC) (ρ = .63, P < .001), as well as SDI and ASR, had a positive correlation. The total MSM mortality rate declined globally, with an APC of -.61%. Likewise, the mortality rate for the age group of people with ages <77.5 years declined. Predictive analysis demonstrated a declining trend in ASR incidence and a growing number of MSM.

There are significant differences in ASR incidence among regions and countries. Despite decreases in ASR incidence and fatality, MSM remains one of the leading sources of cancer mortality and morbidity globally. MSM necessitates more primary prevention measures and screening in high-risk areas.

Investigate the ability of frailty status to predict post-surgical outcomes in patients with cutaneous malignancies of the scalp and neck undergoing flap reconstruction.

National Surgical Quality Improvement Program database was used to isolate patients with cutaneous malignancies of the scalp and neck who underwent surgical resection between 2015 to 2019. Univariate and multivariate analyses were performed to determine if frailty score correlated with negative post-operative outcomes. Receiver operating characteristic (ROC) curves allowed testing of the discriminative performance of age versus frailty.

This study demonstrated an independent correlation between frailty and major complications as well as non-home discharge. In ROC curve analysis, frailty demonstrated superior discrimination compared to age for predicting major complications.

Our study demonstrated an association between increasing frailty and major complications as well as the likelihood of a non-home discharge. When compared to age, frailty was also shown to be a better predictor of major complications.

Human cutaneous melanoma (CM) is a highly invasive malignancy arising from melanocytes, and accompanied by ever-increasing incidence and mortality rates worldwide. Interestingly, microRNAs (miRNAs) possess the ability to regulate CM cell biological functions, resulting in the aggressive progression of CM. Nevertheless, a comprehensive understanding of the underlying mechanism remains elusive. Accordingly, the current study sought to elicit the functional role of miR-141-3p in human CM cells in association with fibroblast growth factor 13 (FGF13) and the MAPK pathway. First, miR-141-3p expression patterns were detected in human CM tissues and cell lines, in addition to the validation of the targeting relationship between miR-141-3p and FGF13. Subsequently, loss- and gain-of-function studies of miR-141-3p were performed to elucidate the functional role of miR-141-3p in the malignant features of CM cells. Intriguingly, our findings revealed that FGF13 was highly expressed, whereas miR-141-3p was poorly expressed in the CM tissues and cells. Further analysis highlighted FGF13 as a target gene of miR-141-3p. Meanwhile, overexpression of miR-141-3p inhibited the proliferative, invasive, and migratory abilities of CM cells, while enhancing their apoptosis accompanied by downregulation of FGF13 and the MAPK pathway-related genes. Collectively, our findings highlighted the inhibitory effects of miR-141-3p on CM cell malignant properties via disruption of the FGF13-dependent MAPK pathway, suggesting a potential target for treating human CM.

Patients with melanoma have been found to be at greater risk of adverse outcomes including mortality after contacting COVID-19. Management of postsurgical complications presented additional challenges by potentially increasing exposure to COVID-19 through repeated inpatient admissions to hospital during the pandemic. We report four cases for which skin flaps, lymph ligation, and split-thickness skin graft (STSG) were successfully used in the treatment of complications in the trunk and extremities after wide local excision (WLE). This study details the operative experience in management of postsurgical complications for melanoma in the trunk and extremities during a 6-month period at the height of the COVID-19 pandemic.

We present 4 cases detailing management of complications that occurred after wide local excisions performed for melanoma during Feb. to Oct. 2020. Case 1: A 90-year-old man who experienced wound dehiscence and necrosis on the shoulder after non-radical excision for an aggressive melanoma and underwent the side-to-side closure after ellipse formed WLE with modified tangent-to-circle method. Case 2: An 80-year-old man who had undergone excision for melanoma in his left upper arm and histopathology did not show radically. Two weeks after the excision, he underwent a WLE and direct reconstruction with double rotation skin flap. Case 3: A 55-year-old man that experienced a large wound dehiscence on his back due to WLE. He underwent an advanced double skin flap operation. Case 4: A 36-year-old woman who had a lymphorrhea and graft necrosis after WLE and STSG on the right lower leg. A combination of micro lymph ligation and re-STSG was performed. One month after the operation, all wounds had healed. There was no clinical evidence of tumor recurrence after 8 months post procedure.

Severe complications (e.g., large wound dehiscence, necrosis, or lymphorrhea) following wide local excision of melanoma are infrequent but must be swiftly and appropriately managed, especially during the COVID-19 pandemic to decrease the likelihood of COVID-19 infection and impaired oncology outcomes from delaying systemic cancer therapy due to the complications in primary interventions.

Objective The aim of this study is to evaluate the expression of the phosphatase and tensin homolog (PTEN), which is a tumor suppressor gene that is implicated in the pathogenesis of cutaneous malignant melanoma, in normal skin and melanoma tissue samples. The study also aimed to correlate PTEN expression levels with various clinicopathological parameters of melanoma lesions, thus highlighting the utility of PTEN expression as a prognostic biomarker for melanoma. Study design Immunohistochemistry (IHC) staining was performed on tissue microarray samples representing normal skin and melanoma biopsies of different clinicopathological parameters. Tissue photomicrographs were evaluated with Aperio ImageScope, which has a positive-pixel-counting algorithm built in. Subsequently, a histochemical score (H-score) was derived from the percentage of positive cells (%-staining) and their staining intensity. The H-scores were averaged in groups of tissue samples representing the different melanomas' tumor (T), node (N), and distant metastasis (M), also known as TNM parameters, as set forth by the American Joint Committee on Cancer (AJCC) classification. The mean H-scores were statistically compared using a two-tailed unpaired t-test. Results The PTEN protein expression was measured by IHC and found to be correlated with tumor thickness (T), which is a reliable indicator for survival rates. Specifically, PTEN was significantly downregulated in tumors with a thickness over 2 mm (T3+T4) compared to tumors with a thickness at or below 2 mm (T1+T2). Conclusions The PTEN protein expression, as measured by immunohistochemistry, helped differentiate between tumors with a thickness over 2 mm and tumors with a thickness at or below 2 mm, suggesting PTEN as a potential surrogate marker for the melanoma's invasion depth along with possible prognostic implications. Longitudinal studies evaluating risk stratification based on the expression of PTEN are needed to establish the utility of this promising biomarker in the clinic as an adjunct for pathological examination.

Melanoma is a serious and aggressive type of skin cancer with growing incidence, and it is the leading cause of death among those affected by this disease. Although surgical resection has been employed as a first-line treatment for the early stages of the tumor, noninvasive topical treatments might represent an alternative option. However, they can be irritating to the skin and result in undesirable side effects. In this context, the potential of topical polymeric hydrogels has been investigated for biomedical applications to overcome current limitations. Due to their biocompatible properties, hydrogels have been considered ideal candidates to improve local therapy and promote wound repair. Moreover, drug combinations incorporated into the polymeric-based matrix have emerged as a promising approach to improve the efficacy of cancer therapy, making them suitable vehicles for drug delivery. In this work, we demonstrate the synthesis and characterization of Pluronic F-127 hydrogels (PL) containing the nitric oxide donor S-nitrosoglutathione (GSNO) and copper oxide nanoparticles (CuO NPs) against melanoma cells. Individually applied NO donor or metallic oxide nanoparticles have been widely explored against various types of cancer with encouraging results. This is the first report to assess the potential and possible underlying mechanisms of action of PL containing both NO donor and CuO NPs toward cancer cells. We found that PL + GSNO + CuO NPs significantly reduced cell viability and greatly increased the levels of reactive oxygen species. In addition, this novel platform had a huge impact on different organelles, thus triggering cell death by inducing nuclear changes, a loss of mitochondrial membrane potential, and lipid peroxidation. Thus, GSNO and CuO NPs incorporated into PL hydrogels might find important applications in the treatment of skin cancer.

The synergy of superparamagnetic iron oxide nanoparticles (SPIONs) and ionizing radiation (IR), attributed to reactive oxygen species (ROS) and DNA double-strand breaks (DSBs) increase, was widely investigated in different cancers, but scarcely in melanoma. Herein, SPIONs were evaluated as radiosensitizers in A-375 human melanoma cells. Moreover, the effect of the combined treatment of SPIONs and gamma irradiation (SPIONs-IR) was assessed at the DNA level, where DSBs induction and their repair capacity were studied. SPIONs were synthesized, stabilized by poly(ethylene glycol) methyl ether and physicochemically characterized by high resolution-transmission electron microscopy (HR-TEM), X-ray diffraction and magnetometry and dynamic light scattering. The obtained nanoparticles showing superparamagnetic behavior and low dispersion in shape and sizes were tested in A-375 cells. The intracellular internalization of SPIONs was verified by HR-TEM and quantified by inductively coupled plasma atomic emission spectroscopy. Cells treated with SPIONs exhibited high ROS levels without associated cytotoxicity. Next, a significant radiosensitization in SPIONs-IR vs. control (IR) cells was demonstrated at 1 Gy of gamma radiation. Furthermore, a decreased DSBs repair capacity in SPIONs-IR vs. IR-treated cells was evidenced by the size increase of persistent phosphorylated H2AX foci at 24 h post-irradiation. In conclusion, these nanoparticles show the potential to radiosensitize melanoma cells by the induction of unrepairable DNA damage.

The aim of this study was to investigate angiopoietin-2 (Ang-2/ANGPT2) expression and its relationship with lymphangiogenesis and clinicopathological characteristics in cutaneous malignant melanoma (CMM).

Gene expression differences between metastatic melanoma and melanoma in situ in 472 patients from the TCGA database were analyzed. The target gene Ang-2 was screened. A clinical study was conducted to analyze the correlation between Ang-2 expression in CMM and tumor-associated lymphangiogenesis. A total of 42 patients with primary CMM who underwent extended tumor resection procedures at the Affiliated Hospital of Jiangsu University were included in this study. Clinical data (gender, age, lymph node metastasis, Breslow thickness, and clinical stage) were collected. The expression levels of both Ang-2 and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) proteins were detected by immunohistochemistry (IHC). Lymphatic vascular density (LVD) was counted by using LYVE-1 to label lymphatic endothelial cells (LECs) in peritumoral and intratumoral areas per high-magnification field of view. Statistical analysis was performed using the Pearson correlation test and Student's t-test.

Using the TCGA database, it was found that the gene expression level of Ang-2 in 368 cases of metastatic melanoma was significantly higher than that in 104 cases of melanoma in situ. Correlation analysis showed a significant relationship between Ang-2 and LYVE-1, and vascular endothelial growth factor receptor 3(VEGFR3) expression, respectively, in CMM. Moreover, the optimal cutoff value of survival analysis showed that high Ang-2 expression in CMM had a worse prognosis, based on data from the TCGA database. Our research showed that Ang-2 was more highly expressed in the group of patients with lymph node metastasis and in the group of stage 3C-4 patients than in the group of patients with no lymph node metastasis and in the group of stage 0-3B patients. Our research also showed that LVD in the group of patients with lymph node metastasis and in the group of stage 3C-4 patients was significantly higher than that in the group of no lymph node metastasis and in the group of stage 0-3B patients, respectively. Breslow thickness also correlated with Ang-2 expression and LVD. Ang-2 expression was not related to sex or age. Ang-2 expression was obviously correlated with LVD.

An evaluation of Ang-2 expression and LVD can be used to predict the risk of tumor lymphatic metastasis and determine the prognosis of CMM. These results may also provide a new clinical treatment strategy for CMM.

Skin cancers require a multidisciplinary approach. The updated guidelines introduce new insights into the management of these diseases. Melanoma (MM), the third most common skin cancer, a malignant melanocytic tumor, which is classified into four major histological subtypes, continues to have the potential to be a lethal disease. The mortality-incidence ratio is higher in Eastern European countries compared to Western European countries, which shows the need for better prevention and early detection in Eastern European countries. Basal cell carcinoma (BCC) and squamous cell carcinoma (cSCC) remain the top two skin cancers, and their incidence continues to grow. The gold standard in establishing the diagnosis and establishing the histopathological subtype in BCC and SCC is a skin biopsy. Sebaceous carcinoma (SeC) is an uncommon and potentially aggressive cutaneous malignancy showing sebaceous differentiation. It accounts for 0.7% of skin cancers and 3-6.7% of cancer-related deaths. Due to the rapid extension to the regional lymph nodes, SeC requires early treatment. The main treatment for sebaceous carcinoma is surgical treatment, including Mohs micrographic surgery, which has the advantage of complete margin evaluation and low recurrence rates. Primary cutaneous lymphomas (PCLs) are a heterogeneous group of lymphoproliferative diseases, with no evidence of extracutaneous determination at the moment of the diagnosis. PCLs have usually a very different evolution, prognosis, and treatment compared to the lymphomas that may secondarily involve the skin. The aim of our review is to summarize the important changes in the approach to treating melanoma, non-melanoma skin, cutaneous T and B cell lymphomas, and other types of skin cancers. For all skin cancers, optimal patient management requires a multidisciplinary approach including dermatology, medical oncology, and radiation oncology.

Skin cutaneous melanoma (SKCM) is an extremely malignant tumor and accounts for the majority of skin cancer deaths. Aspartate beta-hydroxylase domain containing 1 (ASPHD1) may participate in cancer progression through controlling α-ketoglutarate-dependent dioxygenases. However, its role in skin cutaneous melanoma (SKCM) has not been well studied.

The gene expression data of ASPDH1 and differentially expressed genes (DEGs) from TCGA and GTEx were evaluated, and verified via the GEO database. Then, we performed GO/KEGG, GSEA, PPI network analysis to analyze the functional implications of the DEGs related to ASPHD1. Then, the association between the ASPHD1 expression and clinical parameters was investigated by Cox regression analysis. Subsequently, the survival time of SKCM patients was evaluated by plotting Kaplan-Meier curves. Moreover, we investigated the correlation between the ASPHD1 expression and lymphocytic infiltration by using the data from TISIDB and TIMER 2.0. Next, we explored the association between ASPHD1 expression and drug sensitivity. Finally, we validate the expression differences by analyzing the results of qPCR, Western blot from human normal epidermal melanocytes and melanoma cells, and immunohistochemistry (IHC) from non-tumor skin as well as melanoma tissues.

The ASPHD1 expression level was significantly upregulated in several cancers, including SKCM especially SKCM-metastasis tissues, and patients with an increased ASPHD1 expression had longer overall survival time than low expression ones. The functional enrichment analysis of ASPHD1-related DEGs showed an association with cell development regulation and tumorigenic pathways. Furthermore, the increased ASPHD1 expression level was associated with the level of immunostimulors, immunoinhibitors, chemokines, and TILs, such as CD4⁺, CD8⁺ T cell, mast cell, Th2 cell, and dendritic cell. More interesting, we found that ASPHD1 expression was tightly associated with CTLA4 and CD276 which are immune checkpoint markers. Moreover, the upregulated expression of ASPHD1 exhibited higher IC50 values for 24 chemotherapy drugs, including doxorubicin, and masitinib. Finally, the differential expression of ASPHD1 in SKCM was validated by the results of qPCR, Western blot, and IHC.

The expression of ASPHD1 in SKCM patients is closely related to patient survival. ASPHD1 may participate in the regulation of tumor immune microenvironment. Additionally, it may serve as a prognostic biomarker for SKCM and future in-depth studies are necessary to explore its value.

Transmembrane emp24 domain containing (TMED) proteins are known to play pivotal roles in normal development, but have been reported to be implicated in pancreatic disease, immune system disorders, and cancers. As far as TMED3 is concerned, its roles in cancers are controversial. However, evidence describing TMED3 in the context of malignant melanoma (MM) is scarce.

In this study, we characterized the functional significance of TMED3 in MM and identified TMED3 as a tumor-promoting factor in MM development. Depletion of TMED3 arrested the development of MM in vitro and in vivo. Mechanistically, we found that TMED3 could interact with Cell division cycle associated 8 (CDCA8). Knocking down CDCA8 suppressed cell events associated with MM development. On the contrary, elevating CDCA8 augmented cell viability and motility and even reversed the inhibitory effects of TMED3 knockdown on MM development. On the other hand, we found that the levels of P-Akt and P-PI3K were decreased in response to TMED3 downregulation, which was partially abolished following SC79 treatment. Thus, our suspicion was that TMED3 exacerbates MM progression via PI3K/Akt pathway. More notably, previously decreased P-Akt and P-PI3K in TMED3-depleted cells were rescued after overexpressing CDCA8. Also, previously impaired cell events due to CDCA8 depletion were ameliorated after SC79 addition, implying that TMED3 regulates PI3K-AKT pathway via CDCA8, thereby promoting MM development.

Collectively, this study established the link between TMED3 and MM, and provides a potential therapeutic intervention for patients with MM harboring abundant TMED3.

This study obtained data on patients with cutaneous malignant melanoma (CMM) from the Surveillance, Epidemiology, and End Results (SEER) database, and used a deep learning and neural network (DeepSurv) model to predict the survival rate of patients with CMM and evaluate its effectiveness.

We collected information on patients with CMM between 2004 and 2015 from the SEER database. We then randomly divided the patients into training and testing cohorts at a 7:3 ratio. The likelihood that patients with CMM will survive was forecasted using the DeepSurv model, and its results were compared with those of the Cox proportional-hazards (CoxPH) model. The calibration curves, time-dependent area under the receiver operating characteristic curve (AUC), and concordance index (C-index) were used to assess the prediction abilities of the model.

This study comprised 37,758 patients with CMM: 26,430 in the training cohort and 11,329 in the testing cohort. The CoxPH model demonstrated that the survival of patients with CMM was significantly influenced by age, sex, marital status, summary stage, surgery, radiotherapy, chemotherapy, postoperative lymph node dissection, tumor size, and tumor extension. The C-index of the CoxPH model was 0.875. We also constructed the DeepSurv model using the data from the training cohort, and its C-index was 0.910. We examined how well the aforementioned two models predicted outcomes. The 1-, 3-, and 5-year AUCs were 0.928, 0.837, and 0.855, respectively, for the CoxPH model, and 0.971, 0.947, and 0.942 for the DeepSurv model. The DeepSurv model presented a greater predictive effect on patients with CMM, and its reliability was better than that of the CoxPH model according to both the AUC value and the calibration curve.

The DeepSurv model, which we developed based on the data of patients with CMM in the SEER database, was found to be more effective than the CoxPH model in predicting the survival time of patients with CMM.

Primary cutaneous melanoma (PCM) is the most aggressive skin malignancy, with an increasing incidence and significant mortality. Tumoral invasion, expressed as Breslow thickness, is routinely assessed on hematoxylin and eosin (HE), although this stain may sometimes underestimate the tumoral depth. The aim of this study was to compare the efficiency of the immunohistochemical (IHC) markers S-100, SOX10, Melan-A, and HMB-45 with HE for the evaluation of the Breslow thickness and staging of PCM. This retrospective study included 46 cases of PCM diagnosed between 2015 and 2022; for each case, the Breslow thickness using HE, S-100, SOX10, Melan-A, and HMB-45 was measured and the appropriate T category was recorded. The highest values of the Breslow thickness were observed for S-100. However, S-100, SOX10, and Melan-A provided statistically significant higher values of the Breslow thickness compared to HE, but no difference was noted between HMB-45 and HE. S-100 was most frequently involved in increasing the T category (26.1%), the majority of cases being upstaged from T1a to T1b. The IHC markers S-100, SOX10, and Melan-A contributed to better evaluation of the melanoma invasion, especially in thin melanomas, but their impact on staging and consecutive treatment remains to be confirmed by future studies.

Malignant tumors of the eyelid are much less frequent than benign eyelid alterations. These are frequently incidental findings without symptoms which are often overlooked or misinterpreted by patients.

This article gives an overview of clinical aspects, diagnostics and treatment of the five most common malignant eyelid tumors and exemplarily explains the essential principles of evidence-based treatment of malignant eyelid tumors.