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ABSTRACT Metabolic syndrome (MetS) remains a significant global public health concern. However, the relationship between MetS, its individual components and melanoma metastasis remains unexplored. We analysed the clinical data of 258 Chinese melanoma patients who had not undergo systemic therapy. Binary logistic regression, adjusted for sex and age, was employed to evaluate the connection between MetS and its components and melanoma metastasis. Of the 258 melanoma patients, 92 met the MetS criteria upon diagnosis. No direct association between MetS and melanoma metastasis was identified. However, specific components of MetS, namely low HDL‐cholesterol levels (OR = 2.85, 95% CI:1.50–5.41, p < 0.05) and dysglycaemia (OR = 4.23, 95% CI:1.80–8.96, p < 0.05), were associated with melanoma metastasis. In subgroup analysis, hypertriglyceridemia correlated with melanoma metastasis in non‐elderly patients (< 65 years) (OR = 2.69, 95% CI: 1.14–6.33, p < 0.05). Central obesity and hypertension showed no association. A dose–response analysis further indicated that melanoma metastasis risk escalated with increasing fasting blood glucose and blood triglyceride concentrations, and with decreasing blood HDL concentration. Our results suggest that monitoring and managing individual components of the MetS, particularly HDL‐cholesterol levels, fasting glucose and triglyceride levels, may have potential prognostic benefits for melanoma in the Chinese population. [ABSTRACT FROM AUTHOR]

Background/Objectives: The therapeutic management of melanoma, the most aggressive form of skin cancer, remains challenging. In the search for more effective therapeutic options, metal-based complexes are being investigated for their anticancer properties. Cisplatin was the first clinically approved platinum-based drug and, based on its success, other metals (e.g., gold) are being used to design novel compounds. Methods: the antimelanoma potential of a new organometallic cyclometalated Au(III) complex [[Au(CNOxN)Cl2] (CNOxN = 2-(phenyl-(2-pyridinylmethylene)aminoxy acetic acid))] (ST004) was evaluated in vitro and in vivo. Furthermore, the gold-based complex was incorporated in liposomes to overcome solubility and stability problems, to promote accumulation at melanoma sites and to maximize the therapeutic effect while controlling its reactivity. The antiproliferative activity of ST004 formulations was assessed in murine (B16F10) and human (A375 and MNT-1) melanoma cell lines after 24 and 48 h incubation periods. The proof-of-concept of the antimelanoma properties of ST004 formulations was carried out in subcutaneous and metastatic murine melanoma models. Results: the developed liposomal formulations showed a low mean size (around 100 nm), high homogeneity (with a low polydispersity index) and high incorporation efficiency (51 ± 15%). ST004 formulations exhibited antiproliferative activity with EC50 values in the μmolar range being cell-line- and incubation-period-dependent. On the opposite side, the benchmark antimelanoma compound, dacarbazine (DTIC), presented an EC50 > 100 μM. Cell cycle analysis revealed an arrest in G0/G1 phase for Free-ST004 in all cell lines. In turn, LIP-ST004 led to a G0/G1 halt in B16F10, and to an arrest in S phase in A375 and MNT-1 cells. Preliminary mechanistic studies in human red blood cells suggest that gold-based inhibition of glycerol permeation acts through aquaglyceroporin 3 (AQP3). In a metastatic murine melanoma, a significant reduction in lung metastases in animals receiving LIP-ST004, compared to free gold complex and DTIC, was observed. Conclusion: This study highlights the antimelanoma potential of a new gold-based complex. Additional studies, namely in vivo biodistribution profile and therapeutic validation of this organogold complex in other melanoma models, are expected to be performed in further investigations. [ABSTRACT FROM AUTHOR]

Summary The outcome of 221 patients with bulky (≥10 cm) classic Hodgkin lymphoma (cHL) treated with doxorubicin, bleomycin, vinblastine, dacarbazine and consolidative radiotherapy (RT) only in those with a positive end‐of‐treatment (EOT) positron emission tomography (PET) scan was evaluated. With a median follow‐up of 9.6 years, 5‐ and 10‐year progression‐free survival (PFS) in EOT PET‐negative cases were 94.0% and 90.4%, respectively, and in PET‐positive cases, 5/10‐year PFS was 64.6% (p < 0.001), with 15% overall receiving RT. Five‐year PFS for Deauville (D) score DX/D1–3 was 93.6%, compared with D4 66.7% (p < 0.001) and D5 33.3% (p < 0.001). Omission of RT in EOT PET‐negative cases is associated with excellent long‐term outcomes in bulky cHL. [ABSTRACT FROM AUTHOR]

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

Dacarbazine is an anticancer drug used in the treatment of skin melanoma. However, its systemic administration results in various side effects. These constraints might be alleviated by topical dacarbazine administration for the treatment of skin melanoma, although it is confined by the drug's limited skin permeability. To improve dacarbazine efficacy against skin cancer and minimize its systemic side effects, it was loaded in lipid polymer hybrid nanoparticle (LPHN)-based topical delivery system. LPHNs were prepared using emulsification solvent evaporation method employing experimental design for the optimization of independent variables. Optimized LPHNs showed particle size, entrapment efficiency, and zeta potential of 202.7 nm, 70.29 ± 0.97%, and − 24.89 mV, respectively. Further, optimized formulation was incorporated in gel and was evaluated for ex vivo permeability. Studies revealed enhanced permeability following Higuchi diffusion kinetics. Flux was observed to be 15.93 ± 1.61 μg·cm−2·h−1. Anticancer efficacy studies on melanoma cell line exhibited enhanced cytotoxicity of drug. Accelerated stability studies indicated stability of drug for at least six months. These results confirm the potential of topical dacarbazine LPHNs to enhance the efficacy against skin melanoma. [ABSTRACT FROM AUTHOR]

BackgroundMalignant glioma carries a poor prognosis despite current therapeutic modalities. Standard of care therapy consists of surgical resection, fractionated radiotherapy concurrently administered with temozolomide (TMZ), a DNA-alkylating chemotherapeutic agent, followed by adjuvant TMZ. O-6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylated lesions from tumor DNA, thereby promoting chemoresistance. MGMT promoter methylation status predicts responsiveness to TMZ; patients harboring unmethylated MGMT (~60% of glioblastoma) have a poorer prognosis with limited treatment benefits from TMZ.MethodsVia lentiviral-mediated delivery into LN18 glioma cells, we employed deactivated Cas9-CRISPR technology to target the MGMT promoter and enhancer regions for methylation, as mediated by the catalytic domain of the methylation enzyme DNMT3A. Methylation patterns were examined at a clonal level in regions containing Differentially Methylation Regions (DMR1, DMR2) and the Methylation Specific PCR (MSP) region used for clinical assessment of MGMT methylation status. Correlative studies of genomic and transcriptomic effects of dCas9/CRISPR-based methylation were performed via Illumina 850K methylation array platform and bulk RNA-Seq analysis.ResultsWe used the dCas9/DNMT3A catalytic domain to achieve targeted MGMT methylation at specific CpG clusters in the vicinity of promoter, enhancer, DMRs and MSP regions. Consequently, we observed MGMT downregulation and enhanced glioma chemosensitivity in survival assays in vitro, with minimal off-target effects.ConclusiondCas9/CRISPR is a viable method of epigenetic editing, using the DNMT3A catalytic domain. This study provides initial proof-of-principle for CRISPR technology applications in malignant glioma, laying groundwork for subsequent translational studies, with implications for future epigenetic editing-based clinical applications.

Cancer cell drug resistance hinders significantly therapeutic modalities in oncology. Dacarbazine is chemotherapeutic agent traditionally used for melanoma treatment although it's effectiveness insufficient. In the present study we performed NGS-based transcriptomic profiling of B16 melanoma tumors after Dacarbazine treatment in vivo. Whole transcriptome sequencing revealed 34 differentially expressed genes most of them associated with drug resistance and apoptosis evading. In accordance to bionformatic analysis, 6 signaling cascades: “D-Amino acid metabolism”, “NF-kappa B signaling pathway”, “Phosphatidylinositol signaling system”, “P53 signaling pathway”, “IL-17 signaling pathway” and “Bile secretion” were enriched by differentially expressed genes. Next we provided a combined treatment by Dacarbazine and miR-204-5p mimic as miR-204-5p was considered previously implicated in cancer drug resistance. This approach lead to an increase of miR-204-5p expression in B16 melanoma cells in vivo that was accompanied by subsequent decrease in the expression of miR-204-5p target genes – BCL2 and SIRT1 in the primary tumors. MiR-204-5p overexpression with Dacarbazine application resulted in increased the weight, and volume of primary tumors and diminished the proportion of β-Galactosidase expression in melanoma B16-bearing mice. Taking together, our study revealed that although miR-204-5p showed antiproliferative capacities in vitro, it's mimic in combination with Dacarbazine is able to potentiate tumor growth triggering probably a switch from senescent to proliferative phenotype of malignant cells.