A Review of Current and Pipeline Drugs for Treatment of Melanoma.

Malignant melanoma is the most aggressive form of skin cancer. Standard treatment options include surgery, radiation therapy, systemic chemotherapy, targeted therapy, and immunotherapy. Combining these modalities often yields better responses. Surgery is suitable for localized cases, sometimes involving lymph node dissection and biopsy, to assess the spread of the disease. Radiation therapy may be sometimes used as a standalone treatment or following surgical excision. Systemic chemotherapy, while having low response rates, is utilized as part of combination treatments or when other methods fail. The development of resistance to systemic chemotherapies and associated side effects have prompted further research and clinical trials for novel approaches. In the case of advanced-stage melanoma, a comprehensive approach may be necessary, incorporating targeted therapies and immunotherapies that demonstrate significant antitumor activity. Targeted therapies, including inhibitors targeting BRAF, MEK, c-KIT, and NRAS, are designed to block the specific molecules responsible for tumor growth. These therapies show promise, particularly in patients with corresponding mutations. Combination therapy, including BRAF and MEK inhibitors, has been evidenced to improve progression-free survival; however, concerns about resistance and cutaneous toxicities highlight the need for close monitoring. Immunotherapies, leveraging tumor-infiltrating lymphocytes and CAR T cells, enhance immune responses. Lifileucel, an FDA-approved tumor-infiltrating lymphocyte therapy, has demonstrated improved response rates in advanced-stage melanoma. Ongoing trials continue to explore the efficacy of CAR T-cell therapy for advanced melanoma. Checkpoint inhibitors targeting CTLA-4 and PD-1 have enhanced outcomes. Emerging IL-2 therapies boost dendritic cells, enhancing anticancer immunity. Oncolytic virus therapy, approved for advanced melanoma, augments treatment efficacy in combination approaches. While immunotherapy has significantly advanced melanoma treatment, its success varies, prompting research into new drugs and factors influencing outcomes. This review provides insights into current melanoma treatments and recent therapeutic advances.

Hypoxic transcriptomes predict survival and tumor-infiltrating immune cell composition in cutaneous melanoma.

Hypoxia has established associations with aggressive tumor phenotypes in many cancers. However, it is not currently understood whether tumor hypoxia levels map to distinct immune infiltrates in cutaneous melanoma, potentially unveiling novel therapeutic targets. To this end, we leveraged a previously identified seven-gene hypoxia signature to grade hypoxia levels of 460 cutaneous melanomas obtained from the Broad Institute GDAC Firehose portal. CIBERSORTx ( https://cibersortx.stanford.edu/ ) was employed to calculate the relative abundance of 22 mature human hematopoietic populations. Clinical outcomes and immune cell associations were assessed by computational means. Results indicated that patients with high-hypoxia tumors reported significantly worse overall survival and correlated with greater Breslow depth, validating the in-silico methodology. High-hypoxia tumors demonstrated increased infiltration of activated and resting dendritic cells, resting mast cells, neutrophils, and resting NK cells, but lower infiltration of gamma-delta T cells. These data suggest that high tumor hypoxia correlates with lower survival probability and distinct population differences of several tumor-infiltrating leukocytes in cutaneous melanomas.

Cutaneous Manifestations of Rheumatoid Arthritis: Diagnosis and Treatment.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder characterized by inflammatory arthritis and periarticular structural damage. Available evidence suggests that RA results from complex interactions between genetic susceptibility (e.g., HLA-DRB1), environmental factors (e.g., smoking), and immune dysregulation. Alongside joint-related symptoms, individuals with RA may also experience a wide array of skin issues, including the development of nodules, neutrophilic dermatoses, vasculitis, and vasculopathy. Treatment strategies for these manifestations vary but routinely involve corticosteroids, disease-modifying anti-rheumatic drugs, and biologics, with individualized approaches guided by disease severity. In this review, we provide comprehensive insights into the skin-related issues associated with RA, outlining their clinical characteristics and histopathological findings. Our aim is to facilitate early diagnosis and personalized treatment to improve the quality of life of affected individuals.

Genomic subtypes of cutaneous melanoma have distinct metabolic profiles: A single-cell transcriptomic analysis.

OBJECTIVE: Genomic profiling previously classified melanoma into distinct subtypes based on the presence or absence of mutations in driver genes, but metabolic differences between and within these groups have yet to be thoroughly analyzed. Thus, the objective of the present study is to provide the first effort to holistically characterize the metabolic landscape of qualified melanoma genomic subtypes at single-cell resolution. METHODS: Expression data for a total of 1145 malignant cells sourced from NRAS(Q61L), BRAF(V600E), and NRAS/BRAF WT melanomas were retrieved from the Broad Single Cell Portal. Metabolic activity was interrogated by pathway scoring and gene set enrichment analysis. RESULTS: A total of 53 metabolic pathways were differentially regulated in at least one melanoma genomic subtype. Some notable findings include: BRAF/NRAS WT cells were enriched for fatty acid biosynthesis and depleted for metabolism of alanine, aspartate, and glutamate; BRAF(V600E) melanoma cells were enriched for beta-alanine metabolism and depleted for phenylalanine metabolism; NRAS(Q61L) melanoma cells were enriched for steroid biosynthesis and depleted for linoleic acid metabolism. CONCLUSION: Primary limitations include the total quantity of single cells and breadth of available genomic subtypes plus inherent noisiness of the applied methodologies. Nonetheless, these findings nominate novel, testable therapeutic targets.

Nanoparticle-Based Treatment Approaches for Skin Cancer: A Systematic Review.

Nanoparticles have shown marked promise as both antineoplastic agents and drug carriers. Despite strides made in immunomodulation, low success rates and toxicity remain limitations within the clinical oncology setting. In the present review, we assess advances in drug delivery nanoparticles, for systemic and topical use, in skin cancer treatment. A systematic review of controlled trials, meta-analyses, and Cochrane review articles was conducted. Eligibility criteria included: (1) a primary focus on nanoparticle utility for skin cancer; (2) available metrics on prevention and treatment outcomes; (3) detailed subject population; (4) English language; (5) archived as full-text journal articles. A total of 43 articles were selected for review. Qualitative analysis revealed that nanoscale systems demonstrate significant antineoplastic and anti-metastasis properties: increased drug bioavailability, reduced toxicity, enhanced permeability and retention effect, as well as tumor growth inhibition, among others. Nanoformulations for skin cancers have largely lagged behind those tested in other cancers-several of which have commercialized formulae. However, emerging evidence has indicated a powerful role for these carriers in targeting primary and metastatic skin cancers.

Regulatory miRNAs and lncRNAs in Skin Cancer: A Narrative Review.

Non-coding RNAs (ncRNAs) have a significant regulatory role in the pathogenesis of skin cancer, despite the fact that protein-coding genes have generally been the focus of research efforts in the field. We comment on the actions of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in the current review with an eye toward potential therapeutic treatments. LncRNAs are remarkably adaptable, acting as scaffolding, guides, or decoys to modify key signaling pathways (i.e., the Wnt/ß-catenin pathway) and gene expression. As post-transcriptional gatekeepers, miRNAs control gene expression by attaching to messenger RNAs and causing their degradation or suppression during translation. Cell cycle regulation, cellular differentiation, and immunological responses are all affected by the dysregulation of miRNAs observed in skin cancer. NcRNAs also show promise as diagnostic biomarkers and prognostic indicators. Unraveling the complexity of the regulatory networks governed by ncRNAs in skin cancer offers unprecedented opportunities for groundbreaking targeted therapies, revolutionizing the landscape of dermatologic care.

Evidence-Based Utility of Adjunct Antioxidant Supplementation for the Prevention and Treatment of Dermatologic Diseases: A Comprehensive Systematic Review.

Skin conditions are a significant cause of fatal and nonfatal disease burdens globally, ranging from mild irritations to debilitating diseases. Oxidative stress, which is an imbalance between reactive oxygen species and the cells' ability to repair damage, is implicated in various skin diseases. Antioxidants have been studied for their potential benefits in dermatologic health, but the evidence is limited and conflicting. Herein, we conducted a systematic review of controlled trials, meta-analyses, and Cochrane review articles to evaluate the current evidence on the utility of antioxidant supplementation for adjunct prevention and treatment of skin disease and to provide a comprehensive assessment of their role in promoting dermatologic health. The Cochrane Library, PubMed, EMBASE, and Epistemonikos databases were queried. Eligibility criteria included (1) primary focus on nanoparticle utility for skin cancer; (2) includes measurable outcomes data with robust comparators; (3) includes a number of human subjects or cell-line types, where applicable; (4) English language; and (5) archived as full-text journal articles. A total of 55 articles met the eligibility criteria for the present review. Qualitative analysis revealed that topical and oral antioxidant supplementation has demonstrated preliminary efficacy in reducing sunburns, depigmentation, and photoaging. Dietary exogenous antioxidants (namely vitamins A, C, and E) have shown chemopreventive effects against skin cancer. Antioxidant supplementation has also shown efficacy in treating non-cancer dermatoses, including rosacea, psoriasis, atopic dermatitis, and acne vulgaris. While further studies are needed to validate these findings on a larger scale, antioxidant supplementation holds promise for improving skin health and preventing skin diseases.