HGF facilitates methylation of MEG3, potentially implicated in vemurafenib resistance in melanoma.

BACKGROUND: Melanoma, a frequently encountered cutaneous malignancy characterized by a poor prognosis, persists in presenting formidable challenges despite the advancement in molecularly targeted drugs designed to improve survival rates significantly. Unfortunately, as more therapeutic choices have developed over time, the gradual emergence of drug resistance has become a notable impediment to the effectiveness of these therapeutic interventions. The hepatocyte growth factor (HGF)/c-met signaling pathway has attracted considerable attention, associated with drug resistance stemming from multiple potential mutations within the c-met gene. The activation of the HGF/c-met pathway operates in an autocrine manner in melanoma. Notably, a key player in the regulatory orchestration of HGF/c-met activation is the long non-coding RNA MEG3. METHODS: Melanoma tissues were collected to measure MEG3 expression. In vitro validation was performed on MEG3 to prove its oncogenic roles. Bioinformatic analyses were conducted on the TCGA database to build the MEG3-related score. The immune characteristics and mutation features of the MEG3-related score were explored. RESULTS: We revealed a negative correlation between HGF and MEG3. In melanoma cells, HGF inhibited MEG3 expression by augmenting the methylation of the MEG3 promoter. Significantly, MEG3 exhibits a suppressive impact on the proliferation and migration of melanoma cells, concurrently inhibiting c-met expression. Moreover, a predictive model centered around MEG3 demonstrates notable efficacy in forecasting critical prognostic indicators, immunological profiles, and mutation statuses among melanoma patients. CONCLUSIONS: The present study highlights the potential of MEG3 as a pivotal regulator of c-met, establishing it as a promising candidate for targeted drug development in the ongoing pursuit of effective therapeutic interventions.

Optical and supramolecular properties of cyclometalated palladium nanostructures with tumor targeting properties in living mice: a quantum mechanics interpretation.

The recent discovery that metallophilic interactions between cyclometalated palladium supramolecular nanostructures - with efficient tumour accumulation rate in a skin melanoma model - maintain excellent photodynamic properties even in a hypoxic microenvironment has inspired the present study focused on the theoretical predictions of optical properties of the bis-cyclometalated palladium compound in different contexts. More specifically, structural and UV/Vis absorption properties of both monomeric and dimeric forms of this anticancer drug are well reproduced with a Time-Dependent Density Functional Theoretical (TD-DFT) approach based on Exchange-Correlation (XC) hybrid functionals in conjunction with conductor-like and polarization solvation effects. A further novelty is represented by a fine investigation of the supramolecular interactions between the different subunits of the drug via dispersion force correction and Quantum Theory of Atoms in Molecules (QTAIM). This contribution while supporting the photoexcitation properties derived in laboratory following the self-assembly of monomeric units when passing from dimethyl sulfoxide (DMSO) to a H2O/DMSO mixture at 298K, shed some light on the nature of the chemical interactions modulating the formation of nano-size aggregates.

Global, Regional, and National Incidence Trend Analysis of Malignant Skin Melanoma Between 1990 and 2019, and Projections Until 2034.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Lithium salts cytotoxicity and accumulation in melanoma cells in vitro.

Boron neutron capture therapy is a perspective selective technology for the destruction of cancer cells, while the use of lithium instead of boron may represent a new and promising vector for the development of neutron capture therapy (NCT). The aim of the study was a comparative assessment of the cytotoxicity of various lithium salts, as well as an analysis of the accumulation of lithium in tumor cells in vitro to determine the possibility of using lithium in NCT. The cytotoxicity of lithium salts was determined using MTT-test and colony forming assay on human fibroblasts BJ-5ta, human skin melanoma SK-Mel-28, and mouse skin melanoma B16 cell lines. An assessment of lithium concentration in cells was performed using inductively coupled plasma atomic emission spectrometry. Our results showed that three different lithium salts at a concentration of 40 µg/ml are not toxic for both tumor and normal cells. The highest uptake values were obtained on murine melanoma B16 cells when exposed to lithium carbonate (0.8 µg/106 cells); however, human melanoma SK-Mel-28 cells effectively accumulated both lithium carbonate and lithium citrate (about 0.46 µg/106 cells for two salts). Thus, our results demonstrate a range of non-toxic doses of lithium salts and a high uptake of lithium by tumor cells, which indicates the possibility to use the lithium in NCT.

Assessment of Autophagy in Tumor Cells of Human Skin Melanoma of Different Stages.

High levels of autophagy can increase the viability of tumor cells as well as their resistance to chemotherapy. Evaluation of the dynamics of autophagy processes at different stages of carcinogenesis can extend our understanding of melanoma pathogenesis to develop new therapeutic approaches. We performed a comparative study of tumor cell autophagy in stages II and III human skin melanoma. Tumor cells were characterized by high content of structures associated with autophagy (autophagosomes and autolysosomes). In stage III melanoma characterized by the presence of regional metastases in the lymph nodes, tumor cells showed higher expression of the autophagy marker protein LC3beta in comparison with stage II melanoma cells, which can indicate the involvement of autophagy processes in tumor progression and the formation of metastases in the lymph nodes.

Content-Based Medical Image Retrieval System for Skin Melanoma Diagnosis Based on Optimized Pair-Wise Comparison Approach.

Medical image analysis for perfect diagnosis of disease has become a very challenging task. Due to improper diagnosis, required medical treatment may be skipped. Proper diagnosis is needed as suspected lesions could be missed by the physician's eye. Hence, this problem can be settled up by better means with the investigation of similar case studies present in the healthcare database. In this context, this paper substantiates an assistive system that would help dermatologists for accurate identification of 23 different kinds of melanoma. For this, 2300 dermoscopic images were used to train the skin-melanoma similar image search system. The proposed system uses feature extraction by assigning dynamic weights to the low-level features based on the individual characteristics of the searched images. Optimal weights are obtained by the newly proposed optimized pair-wise comparison (OPWC) approach. The uniqueness of the proposed approach is that it provides the dynamic weights to the features of the searched image instead of applying static weights. The proposed approach is supported by analytic hierarchy process (AHP) and meta-heuristic optimization algorithms such as particle swarm optimization (PSO), JAYA, genetic algorithm (GA), and gray wolf optimization (GWO). The proposed approach has been tested with images of 23 classes of melanoma and achieved significant precision and recall. Thus, this approach of skin melanoma image search can be used as an expert assistive system to help dermatologists/physicians for accurate identification of different types of melanomas.

Lithium Enhances Autophagy and Cell Death in Skin Melanoma: An Ultrastructural and Immunohistochemical Study.

Lithium is an inhibitor of glycogen synthase kinase 3 beta, which is traditionally used in the treatment of bipolar disorders and has antitumor effects. The aim of the current study was to determine if lithium salt causes autophagy and apoptosis in skin melanoma cells to enhance cell death. Light microscopy, transmission electron microscopy, immunohistochemistry, and immunofluorescence were used to study the mechanism of action of lithium carbonate in B16 melanoma cells in vivo. Proliferating cell nuclear antigen immunofluorescence assay revealed that the proliferation of B16 melanoma cells was suppressed by lithium treatment for 7 days. Electron microscopy demonstrated a significant increase in the number of autophagic vacuoles in lithium-treated cells relative to control. In addition, levels of autophagy markers LC3 beta and LAMP1 found in lithium-treated tumor xenografts were higher than levels of these markers in the control tumors. Lithium induced caspase-3 expression and apoptotic cell death in tumor cells. Thus, lithium carbonate is the compound that inhibits cell proliferation and stimulates cell death in melanoma cells through induction of autophagy and apoptosis. Stimulation of autophagy by lithium could contribute to the development of autophagic cell death in tumor cells.

Molecular Pathology of Skin Melanoma: Epidemiology, Differential Diagnostics, Prognosis and Therapy Prediction.

Similar to other malignancies, TCGA network efforts identified the detailed genomic picture of skin melanoma, laying down the basis of molecular classification. On the other hand, genome-wide association studies discovered the genetic background of the hereditary melanomas and the susceptibility genes. These genetic studies helped to fine-tune the differential diagnostics of malignant melanocytic lesions, using either FISH tests or the myPath gene expression signature. Although the original genomic studies on skin melanoma were mostly based on primary tumors, data started to accumulate on the genetic diversity of the progressing disease. The prognostication of skin melanoma is still based on staging but can be completed with gene expression analysis (DecisionDx). Meanwhile, this genetic knowledge base of skin melanoma did not turn to the expected wide array of target therapies, except the BRAF inhibitors. The major breakthrough of melanoma therapy was the introduction of immune checkpoint inhibitors, which showed outstanding efficacy in skin melanoma, probably due to their high immunogenicity. Unfortunately, beyond BRAF, KIT mutations and tumor mutation burden, no clinically validated predictive markers exist in melanoma, although several promising biomarkers have been described, such as the expression of immune-related genes or mutations in the IFN-signaling pathway. After the initial success of either target or immunotherapies, sooner or later, relapses occur in the majority of patients, due to various induced genetic alterations, the diagnosis of which could be developed to novel predictive genetic markers.

Cutaneous Melanomas: A Single Center Experience on the Usage of Immunohistochemistry Applied for the Diagnosis.

Cutaneous melanoma (cM) is the deadliest of all primary skin cancers. Its prognosis is strongly influenced by the stage at diagnosis, with early stages having a good prognosis and being potentially treatable with surgery alone; advanced stages display a much worse prognosis, with a high rate of recurrence and metastasis. For this reason, the accurate and early diagnosis of cM is crucial-misdiagnosis may have extremely dangerous consequences for the patient and drastically reduce their chances of survival. Although the histological exam remains the "gold standard" for the diagnosis of cM, a continuously increasing number of immunohistochemical markers that could help in diagnosis, prognostic characterization, and appropriate therapeutical choices are identified every day, with some of them becoming part of routine practice. This review aims to discuss and summarize all the data related to the immunohistochemical analyses that are potentially useful for the diagnosis of cM, thus rendering it easier to appropriately applicate to routine practice. We will discuss these topics, as well as the role of these molecules in the biology of cM and potential impact on diagnosis and treatment, integrating the literature data with the experience of our surgical pathology department.

Distinct genomic features across cytolytic subgroups in skin melanoma.

BACKGROUND: Skin melanoma is a highly immunogenic cancer. The intratumoral immune cytolytic activity (CYT) reflects the ability of cytotoxic T and NK cells to eliminate cancer cells, and is associated with improved patient survival. Despite the enthusiastic clinical results seen in advanced-stage metastatic melanoma patients treated with immune checkpoint inhibitors, a subgroup of them will later relapse and develop acquired resistance. We questioned whether CYT associates with different genomic profiles and thus, patient outcome, in skin melanoma. METHODS: We explored the TCGA-SKCM dataset and stratified patients to distinct subgroups of cytolytic activity. The tumor immune contexture, somatic mutations and recurrent copy number aberrations were calculated using quanTIseq, MutSigCV and GISTIC2. Chromothriptic events were explored using CTLPScanner and cancer neoepitopes were predicted with antigen garnish. Each tumor's immunophenoscore was calculated using Immunophenogram. Mutational signatures and kataegis were explored using SigProfiler and compared to the known single or doublet base substitution signatures from COSMIC. RESULTS: Metastatic skin melanomas had significantly higher CYT levels compared to primary tumors. We assessed enrichment for immune-related gene sets within CYT-high tumors, whereas, CYT-low tumors were enriched for non-immune related gene sets. In addition, distinct mutational and neoantigen loads, primarily composed of C > T transitions, along with specific types of copy number aberrations, characterized each cytolytic subgroup. We found a broader pattern of chromothripsis across CYT-low tumors, where chromosomal regions harboring chromothriptic events, contained a higher number of cancer genes. SBS7a/b, SBS5 and SBS1 were the most prevalent mutational signatures across both cytolytic subgroups, but SBS1 differed significantly between them. SBS7a/b was mutually exclusive with SBS5 and SBS1 in both CYT subgroups. CYT-high patients had markedly higher immunophenoscore, suggesting that they should display a clinical benefit upon treatment with immune checkpoint inhibition therapy, compared to CYT-low patients. CONCLUSIONS: Overall, our data highlight the existence of distinct genomic features across cytolytic subgroups in skin melanoma, which might affect the patients' relapse rate or their acquisition of resistance to immune checkpoint inhibition therapies.

Centipedegrass extract enhances radiosensitivity in melanoma cells by inducing G2/M cell cycle phase arrest.

Melanoma is aggressive, highly metastatic, and potentially fatal. In the case of patients with advanced melanoma, it is difficult to expect a good prognosis, since this cancer has low sensitivity to chemotherapy and radiation therapy. The use of natural ingredients may enhance existing therapies. Centipedegrass extract (CGE) which contains phenolic structures and C-glycosyl flavones, has been shown to have anti-inflammatory effects and anti-cancer effects. The purpose of this study was to evaluate the radio sensitizing effects of CGE in combination with ionizing radiation (IR). Two melanoma cell lines were exposed to IR after treatment with CGE at concentrations that were not toxic alone. The effects of CGE + IR on cell survival, cell cycle, and apoptotic cell death were examined using MTT and Muse® Cell Analyzer, and fluorescence microscopy. Molecular signaling mechanisms were explored by western blots. Our findings showed that co-treatment of CGE + IR reduced the survival of melanoma cells more than IR alone. Also, cell cycle arrest in CGE-treated cells was enhanced and these cells became more radiosensitive. CGE + IR increased apoptotic cell death more than IR alone. Western blot results showed that the effect of CGE + IR involved MAPKs (ERK1/2, p38, and JNK) pathway. Our study suggests that CGE + IR treatment enhanced radio-sensitization and cell death of melanoma cells via cell cycle arrest and the MAPKs pathway.

Late-onset hypophysitis after discontinuation of nivolumab treatment for advanced skin melanoma: a case report.

BACKGROUND: Nivolumab is an anti-programmed cell death protein 1 antibody, typically used as cancer immunotherapy agent. Despite multiple clinical benefits it might cause autoimmune-related side-effects, often involving the endocrine system. To our knowledge, this is the first case of nivolumab-induced hypophysitis manifesting several months after treatment discontinuation. CASE PRESENTATION: We, herein, report a 53-year-old patient with hypophysitis and isolated adrenocorticotropic hormone deficiency, who presented with recurring syncopal episodes and persistent mild hyponatremia. The performed challenged tests were consistent with secondary adrenal insufficiency, while responses of other anterior pituitary hormones were preserved. Magnetic resonance imaging revealed thickened pituitary stalk, consistent with hypophysitis. The patient's condition gradually improved after administration of hydrocortisone, with normalization of sodium and glucose-levels. The related literature is discussed. CONCLUSIONS: We conclude that even after discontinuation of nivolumab, isolated adrenal insufficiency can occur. Therefore, in case of administration of such agents, clinical assessment, and routine monitoring of blood pressure, sodium-, glucose-levels, pituitary hormones as well as magnetic resonance imaging are needed to identify such conditions and prevent an adrenal crisis.

Aetiology and Pathogenesis of Cutaneous Melanoma: Current Concepts and Advances.

Melanoma develops from malignant transformations of the pigment-producing melanocytes. If located in the basal layer of the skin epidermis, melanoma is referred to as cutaneous, which is more frequent. However, as melanocytes are be found in the eyes, ears, gastrointestinal tract, genitalia, urinary system, and meninges, cases of mucosal melanoma or other types (e.g., ocular) may occur. The incidence and morbidity of cutaneous melanoma (cM) are constantly increasing worldwide. Australia and New Zealand are world leaders in this regard with a morbidity rate of 54/100,000 and a mortality rate of 5.6/100,000 for 2015. The aim of this review is to consolidate and present the data related to the aetiology and pathogenesis of cutaneous melanoma, thus rendering them easier to understand. In this article we will discuss these problems and the possible impacts on treatment for this disease.

Outcomes of retreatment with anti-PD-1 monotherapy after response to first course in patients with cutaneous melanoma.

Aim: To determine outcomes of retreatment with anti-PD-1 monotherapy for melanoma. Materials & methods: This retrospective study included adults with unresectable cutaneous melanoma who achieved stable disease (SD) or better after anti-PD-1 monotherapy and were retreated with anti-PD-1 monotherapy after ≥90-day gap. We determined overall survival and real-world tumor response. Results: For 21 eligible patients, from retreatment initiation, median follow-up was 14.4 months (range, 2.6-34.5); median overall survival was 30.0 months (95% CI: 14.4-not reached); 1-year survival was 100% (95% CI: 100-100%); 2-year survival was 83% (48-96%). Of 16 patients with recorded best real-world tumor response, ten (63%) responded (complete/partial response); three achieved SD; three had progressive disease. Conclusion: Patients with advanced melanoma achieving SD/better after first-course anti-PD-1 monotherapy may benefit from retreatment.

Cutaneous malignant melanoma in children and adolescents treated in pediatric oncology units.

OBJECTIVES: Recent progress in the understanding of tumor biology and new targeted therapies has led to improved survival in adults with malignant melanoma (MM). MM is rare in children, especially before puberty. We report here our experience with pediatric patients with MM, describe the clinical presentation, treatment and evolution, and compare prepubescent and postpubescent disease. METHODS: A retrospective, descriptive, national multicenter study was undertaken of 52 cases of MM in children and adolescents. Demographic, histopathology, treatment evolution data, and survival distributions are described. RESULTS: Median age was 15 years (5-18). The tumors were often amelanotic (45%) and raised (83%), and Breslow thickness was greater than 4 mm in 35% of cases. Histological examination showed superficial spreading (n = 16) or spitzoid (n = 16) or nodular (n = 9) pattern. Twelve children (23%) were less than 10 years of age. The spitzoid histotype was more frequent in prepubescent children (seven of 12). Seventeen patients relapsed, of whom four had skin lesions initially diagnosed as benign. Ten patients died after relapse. Five-year event-free survival and overall survival were 62.7% (95% confidence interval [CI]: 45.3-76) and 75.5% (95% CI: 56.8-87.1), respectively. CONCLUSIONS: MM appears to be different in prepubescent children, of whom most had a spitzoid histotype. Diagnosis can be difficult, leading to delay in treatment. New biological tools to identify targets for treatment in MM and to differentiate spitzoid melanomas from Spitz nevi now exist. As effective targeted therapies are now available, we recommend requesting biological examination of all melanocyte-derived skin lesions in children that could be malignant.

Antimelanoma effect of Salmonella Typhimurium integration host factor mutant in murine model.

AIM: This study aimed to evaluate an attenuated Salmonella ihfA-null mutant strain as therapeutic agent to control tumor growth. MATERIALS & METHODS: After bacterial toxicity evaluation, C57BL/6JUnib mice were inoculated with B16F10 cells and treated with two Salmonella strains (LGBM 1.1 and LGBM 1.41). RESULTS: LGBM 1.1 can reduce tumor mass, but it exerts some toxic effects. Although LGBM 1.41 is less toxic than LGBM 1.1, it does not reduce tumor mass significantly. Indeed, animals treated with LGBM 1.41 present only slightly initial delay in tumor progression and increased survival rate as compared with the control. CONCLUSION: The null-mutants of ihfA gene of Salmonella Typhimurium could be a promising candidate for melanoma treatment.

The role of physical therapists in the early detection of skin melanoma: insights from an anonymous survey.

Introduction: Skin melanoma is the most severe form of skin cancer. Recent years have seen an increase in melanoma incidence. Melanomas often appear on the back, a hidden area, leading to late diagnoses. Physical therapists, who frequently treat patients with lower back pain, could play a crucial role in early melanoma detection. Methods: An anonymous online survey was conducted among 254 Israeli physical therapists to assess their perspectives on melanoma detection, their knowledge in identifying suspicious lesions, and their referral patterns. The survey included sections on demographics, professional perspectives, melanoma knowledge, personal or family experiences with melanoma, and referral frequency for dermatological evaluation. Results: The survey revealed that 75.2% of physical therapists viewed melanoma detection as part of their professional duties, yet 59.1% reported insufficient knowledge in identifying suspicious lesions. Despite this, 94.1% expressed a desire to improve their knowledge. However, only 44.1% actively referred patients with suspicious lesions to dermatologists. There was a significant positive correlation between professional experience and referral rates (p-value < 0.001), indicating that more experienced therapists were more likely to refer patients. Discussion: The study highlights the critical need for incorporating melanoma detection training into physical therapy education and professional development. Enhancing physical therapists' knowledge and skills in this area could improve early detection and patient outcomes. Despite the potential role of physical therapists in melanoma detection, current training programs lack emphasis on this aspect, underscoring the importance of revising educational curricula to include skin cancer detection techniques. Conclusion: The findings suggest that while physical therapists recognize their role in melanoma detection, there is a significant knowledge gap. Addressing this through targeted education and training could enhance early detection efforts and improve patient care.

The Long-Term Results of Electrochemotherapy in the Treatment of Patients with Locoregionally Advanced, Unresectable Melanoma.

Background/Objectives: Despite observing progress in recent years in the treatment of patients with advanced melanoma, the optimal management of locoregional recurrence has not been determined. Various methods are used to treat this group of patients. One of these methods is electrochemotherapy. The present study presents the distant results in treating patients with the locoregional recurrence of melanoma, using the technique of electrochemotherapy. Methods: This study includes a retrospective analysis of 88 patients' data with locoregional melanoma recurrence, treated with electrochemotherapy (ECT) between 2010 and 2023, in two reference centers. Results: Approximately 80% of patients responded to the ECT treatment, achieving partial or complete remission. In a multivariate analysis, statistically significant longer overall survival was found in the group of patients who achieved complete remission after ECT and were treated with immunotherapy. Discussion: The results may suggest the existence of synergy between ECT and immunotherapy. However, confirmation of this fact requires further prospective studies that will also establish the role of ECT in the combination treatment of patients with locoregional recurrence of melanoma.

Angiogenesis-elicited spectral responses of early invasive skin melanoma: Implications for the evaluation of lesion progression.

Early invasive skin melanoma (EISM) associated with partial tumor invasion to the thin and optically complex papillary dermis (PD) represents a critical stage before the onset of metastasis. EISM lesions may be accompanied by angiogenesis, which can alter the PD's blood and fibril contents. A comprehensive understanding about these interconnected processes is essential for enhancing the efficacy of EISM optical evaluation methodologies. Employing a first-principles computational approach supported by measured data, we systematically assess the impact that angiogenesis can have on the EISM's spectral responses. Our findings indicate that these responses are discernibly affected by angiogenesis under distinct physiological conditions, with more substantial tissue alterations leading to accentuated spectral changes in the 550-600 nm region. Accordingly, we propose the use of a customized low-cost spectral index to monitor these processes. Furthermore, our investigation provides a high-fidelity in silico platform for interdisciplinary research on the photobiology of evolving skin melanomas.