Search Results (437)

Background: Patients diagnosed with melanoma are at increased risk of developing multiple primary melanomas (MPMs). Identifying clinical and genetic factors associated with MPM is critical for implementing personalized surveillance strategies. This study aims to describe the clinical, histopathological, and genetic characteristics of patients with MPM managed in a tertiary hospital and to contextualize findings within the current literature. Methods: We conducted a retrospective review of patients diagnosed with two or more primary melanomas between 2010 and 2023 at a tertiary dermatology unit. Demographic data, personal and family cancer history, phototype, melanoma characteristics, genetic testing, staging, treatments, and outcomes were collected. These data were compared with findings from the recent literature. Results: Thirteen patients (ten males, three females; median age: 59 years) were found to have a total of 33 melanomas. Most patients had Fitzpatrick phototype II and no immunosuppression. The number of melanomas per patient ranged from two to five. Synchronous lesions were observed in two patients. Common locations included the trunk and extremities. Histologically, 57% were in situ melanomas, and subsequent melanomas were generally thinner than the index lesion. Two patients showed progression to advanced disease. One patient was positive for MC1R mutation; the rest were negative or inconclusive. Additional phenotypic and environmental risk factors were extracted from patient records and are summarized as follows: Ten patients (76.9%) had Fitzpatrick skin phototype II, and three (23.1%) had phototype III. Chronic occupational sun exposure was reported in four patients (30.8%), while five (38.5%) recalled having suffered multiple sunburns during childhood or adolescence. Eight patients (61.5%) presented with a total nevus count exceeding 50, and five (38.5%) exhibited clinically atypical nevi. None of the patients reported use of tanning beds. Conclusions: Our findings are consistent with the existing literature indicating that patients with MPM often present with thinner subsequent melanomas and require long-term dermatologic follow-up. The inclusion of genetic testing and phenotypic risk factors enables stratified surveillance and supports the application of personalized medicine in melanoma management. Full article

Background/Objectives: Melanoma is an aggressive type of skin cancer that poses serious health risks if not detected in its early stages. Although early diagnosis enables effective treatment, delays can result in life-threatening consequences. Traditional diagnostic processes predominantly rely on the subjective expertise of dermatologists, which can lead to variability and time inefficiencies. Consequently, there is an increasing demand for automated systems that can accurately classify melanoma lesions and retrieve visually similar cases to support clinical decision-making. Methods: This study proposes a transfer learning (TL)-based deep learning (DL) framework for the classification of melanoma images and the enhancement of content-based image retrieval (CBIR) systems. Pre-trained models including DenseNet121, InceptionV3, Vision Transformer (ViT), and Xception were employed to extract deep feature representations. These features were integrated using a weighted fusion strategy and classified through an Ensemble learning approach designed to capitalize on the complementary strengths of the individual models. The performance of the proposed system was evaluated using classification accuracy and mean Average Precision (mAP) metrics. Results: Experimental evaluations demonstrated that the proposed Ensemble model significantly outperformed each standalone model in both classification and retrieval tasks. The Ensemble approach achieved a classification accuracy of 95.25%. In the CBIR task, the system attained a mean Average Precision (mAP) score of 0.9538, indicating high retrieval effectiveness. The performance gains were attributed to the synergistic integration of features from diverse model architectures through the ensemble and fusion strategies. Conclusions: The findings underscore the effectiveness of TL-based DL models in automating melanoma image classification and enhancing CBIR systems. The integration of deep features from multiple pre-trained models using an Ensemble approach not only improved accuracy but also demonstrated robustness in feature generalization. This approach holds promise for integration into clinical workflows, offering improved diagnostic accuracy and efficiency in the early detection of melanoma. Full article

This narrative review examines the efficacy, cost-effectiveness, and aesthetic outcomes of Mohs micrographic surgery (MMS) compared to standard excision for treating non-melanoma skin cancers (NMSCs). A comprehensive literature search was conducted across multiple databases, including PubMed, Scopus, and Cochrane Library, covering studies published from 2000 to 2024. Key terms such as “Mohs Micrographic Surgery,” “non-melanoma skin cancer,” “recurrence rates,” “cost-effectiveness,” and “aesthetic outcomes” were utilized. Inclusion criteria encompassed peer-reviewed articles, clinical trials, and observational studies focusing on MMS and standard excision outcomes. Exclusion criteria included studies with inadequate data or those not published in English. The review highlights the superior oncologic outcomes of MMS, its cost-effectiveness over the long term, and comparable aesthetic results to standard excision principally. Methods: This narrative review was conducted following established guidelines for reporting narrative reviews. A systematic search strategy was employed across selected databases, with the last search conducted in May 2025. The search terms used were “Mohs Micrographic Surgery,” “non-melanoma skin cancer,” “recurrence rates,” “cost-effectiveness,” and “aesthetic outcomes.” Studies included were published between 2000 and 2024, in English, and provided data on the specified outcomes. Results: The majority of studies indicated that MMS offers superior recurrence-free survival rates compared to standard excision. Regarding cost-effectiveness, MMS was found to be more economical over the long term due to reduced recurrence rates and the need for fewer re-excisions. Aesthetic outcomes were comparable between MMS and standard excision, with both methods yielding satisfactory results. Discussion: The findings of this review support the use of MMS as a preferred treatment for high-risk NMSCs, particularly in cosmetically sensitive areas. While MMS may involve higher initial costs, its long-term cost-effectiveness and superior oncologic outcomes justify its use. The aesthetic outcomes associated with MMS are comparable to those of standard excision, making it a viable option for patients concerned with cosmetic results. Limitations: This review acknowledges several limitations, including the heterogeneity of study designs and potential selection biases inherent in the included studies. Additionally, the absence of randomized controlled trials comparing MMS and standard excision directly limits the strength of the conclusions drawn. Conclusions: This narrative review underscores the advantages of MMS in treating high-risk NMSCs, particularly in terms of recurrence rates and long-term cost-effectiveness. While both MMS and standard excision offer comparable aesthetic outcomes, the superior oncologic results of MMS make it a preferable option in certain clinical scenarios. Full article

Introduction: The interface between T cells and the tumor microenvironment, termed the ‘immunological synapse’, consists of multiple checkpoint protein pairs co-expressed on both sides of the synapse. mir-16, a microRNA from a widely known tumor-suppressor family of miRNAs, was previously shown by us to be downregulated in melanoma. As other miRNAs from this family have been shown to directly target checkpoint proteins, here we investigated whether miR-16 influences the expression patterns of checkpoint proteins in melanoma. Methods: Single-cell gene expression data from the melanoma microenvironment were retrieved from a public database. Melanoma cell lines were established from metastatic lesions and transiently transfected with an hsa-miR-16-5p-mimic RNA or a mir-16-expressing plasmid. The mRNA expression profiles were analyzed using an Affymetrix microarray. Direct targets of miR-16 were identified by luciferase reporter assays. Protein levels were assessed by Western blotting. Results: Bioinformatic analysis revealed that the expression levels of eight checkpoint mRNAs, known to be present on the melanoma side of the immunological synapse, were highly correlated. Four of these mRNAs contained putative binding sites for the miR-15/16 family. miR-16 expression was significantly reduced in melanoma cells, compared to normal melanocytes. Luciferase reporter assays demonstrated that miR-16 directly targets the 3′ untranslated regions (3′UTRs) of CD40, CD80. The mRNAs downregulated following miR-16 overexpression were highly enriched for genes involved in autophagy, vesicle-mediated transport, and the regulation of protein membrane localization. Among these, VTI1B and SMPD1 were confirmed to be direct targets of miR-16. Transient overexpression of miR-16 resulted in a significant reduction in SMPD1 and VTI1B levels in melanoma cell lines. Conclusions: Our findings suggest that miR-16 potentially modulates melanoma tumorigenesis, metastasis and immunogenicity by altering the composition of checkpoint proteins at the immunological synapse and by regulating cellular pathways associated with intracellular trafficking and transmembrane protein presentation. Full article

Cutaneous manifestations can serve as early and sometimes the first clinical indicators in various hereditary cancer predisposition syndromes. This review provides a comprehensive overview of the dermatological signs associated with these syndromes, aiming to facilitate their recognition in clinical practice. Hereditary Breast and Ovarian Cancer syndrome is notably linked to an increased risk of melanoma. BAP1 tumor predisposition syndrome is characterized by BAP1-inactivated melanocytic tumors. Muir–Torre syndrome, a variant of Lynch syndrome, presents with distinctive cutaneous neoplasms such as sebaceous carcinomas, sebaceous adenomas, and keratoacanthomas. PTEN hamartoma tumor syndrome commonly features hamartomatous growths, trichilemmomas, acral keratoses, oral papillomas, and genital lentiginosis. Gorlin syndrome is marked by basal cell carcinomas and palmoplantar pits, while Peutz–Jeghers syndrome is identified by mucocutaneous pigmentation. In familial adenomatous polyposis, the cutaneous findings include epidermoid cysts, fibromas, desmoid tumors, and lipomas. Additionally, we examined monogenic disorders associated with cancer risk and skin involvement, such as xeroderma pigmentosum, neurofibromatosis type 1, familial atypical multiple-mole melanoma syndrome, and Fanconi anemia. The early recognition of these dermatologic features is essential for a timely diagnosis and the implementation of appropriate surveillance strategies in individuals with hereditary cancer syndromes. Full article

Small molecule inhibitors that target the E3 ligase activity of MDM2-MDM4 have been explored to inhibit the oncogenic activity of MDM2-MDM4 complex. MMRi62 is a small molecule that was identified using an MDM2-MDM4 E3 ligase-based high throughput screen and a cell-death-based secondary screen. Our previous studies showed that MMRi62 promotes MDM4 degradation in cells and induces p53-independent apoptosis in cancer cells. However, MMRi62 activity in solid tumor cells such as melanoma cells, especially in BRAF inhibitor resistant melanoma cells, have not been explored. Although its promotion of MDM4 degradation is clear, the direct MMRi62 targets in cells are unknown. In this report, we show that MMRi62 is a much more potent p53-independent apoptosis inducer than conventional MDM2 inhibitors in melanoma cells. A brief structure-activity study led to development of SC-62-1 with improved activity. SC-62-1 potently inhibits and eliminates clonogenic growth of melanoma cells that acquired resistance to BRAF inhibitors. We developed a pair of active and inactive SC-62-1 probes and profiled the cellular targets of SC-62-1 using a chemical biology approach coupled with IonStar/nano-LC/MS analysis. We found that SC-62-1 covalently binds to more than 15 hundred proteins in cells. Pathways analysis showed that SC-62-1 significantly altered several pathways including carbon metabolism, RNA metabolism, amino acid metabolism, translation and cellular response to stress. This study provides mechanistic insights into the mechanisms of action for MMRi62-like quinolinols. This study also suggests multi-targeting compounds like SC-62-1 might be useful for overcoming resistance to BRAF inhibitors for improved melanoma treatment. Full article

Background/Objectives: Non-melanoma skin cancer (NMSC) is among the most common cancers in the United States, with solar ultraviolet (UV) radiation being a primary etiological factor. T-LAK cell-originated protein kinase (TOPK), a serine/threonine kinase activated by solar UV, has been implicated in skin carcinogenesis. This study aimed to investigate the mechanistic role of TOPK in solar UV-induced skin damage and tumor development. Methods: RNA sequencing (RNA-seq) was performed on skin tissues from wild-type (WT) and TOPK knockout (KO) mice, with or without solar UV exposure, to identify TOPK-regulated genes and pathways. Follow-up experiments using Western blotting, immunofluorescence, and luciferase assays were conducted in vitro and in vivo. Functional assays included 3D spheroid and Transwell co-culture systems involving cutaneous squamous cell carcinoma (cSCC) and fibroblast cells. Results: TOPK deletion altered gene expression profiles and inhibited solar UV-induced activation of multiple signaling pathways, including cytokine–cytokine receptor interaction, PI3K/AKT, MAPKs, PKG, cAMP, and calcium signaling. RNA-seq and protein analyses identified interleukin-19 (IL19) as a key downstream effector suppressed by TOPK deletion. In cSCC and fibroblast cells, TOPK knockdown reduced IL19 expression and secretion. IL19 promoted cSCC growth and activated PI3K/AKT, ERK, and TOPK pathways. Additionally, chronic TGFβ exposure increased IL19 expression and activated fibroblasts, as indicated by elevated αSMA and FAPα levels. Conclusions: These findings establish TOPK as a central regulator of solar UV-induced skin carcinogenesis, partially via modulation of IL19 signaling and fibroblast activation. Targeting TOPK may offer a novel strategy for the prevention and treatment of NMSC. Full article

Background/Objectives: In many cases, the detection of a single lesion could revolutionise patient clinical management; not all localisations, especially those with a low uptake and, consequently, a low Tumour-to-Background Ratio (TBR), are readily detectable using [¹⁸F]F-FDG PET/CT. LAFOV-PET offers a potential enhancement in lesion detection, but the proportion of patients who would benefit from its use has yet to be determined. With the present analysis, we aimed to assess which clinical contexts the enhancement in lesion detection could affect the most. Methods: This retrospective study included 764 patients who underwent [¹⁸F]F-FDG PET/CT between January and April 2024. Data were obtained through a review of PET/CT reports. Inclusion criteria comprised patients who attended our centre for cancer pathologies or masses of undetermined nature (MUNs) in a staging setting, excluding patients who had undergone a prior [¹⁸F]F-FDG PET/CT scan or who had received therapy for any cancer pathology. This analysis focused on the total number of lesions identified, as well as the SUVmax of the lesion with the highest uptake. We analysed the proportion of patients who were within the range of number of lesions between 1 and 2, as well as who had an SUVmax of the lesion with the highest uptake between 2 and 5, either in the whole patient population or in the pathologies with a larger numerosity in the present study. Results: Among the 862 scans analysed, 289 (34%) were found to be negative, while 573 (66%) presented at least one localisation. In total, 4.5% of patients presented both a lesion number of between 1 and 2 and an SUVmax of the lesion with the highest uptake between 2 and 5. Among the malignancies that were the most common in the analysed population, a higher-than-average proportion of patients meeting these criteria were found in melanoma (6.2%), breast cancer (5.9%), and multiple myeloma (4.8%) patients. Conversely, the conditions that presented a lower proportion of patients in this range were suffering from MUNs (4.0%), lung cancer (2.1%), head–neck cancer (2.1%), suspected lymphoma (2.0%), and colon cancer (0.0%). Conclusions: Our analysis shows that almost 1 in 20 patients evaluated at oncological staging with [¹⁸F]F-FDG PET/CT could benefit from the increased diagnostic sensitivity offered by LAFOV-PET scanners. These data, although preliminary, support the need for future prospective controlled studies to confirm the actual clinical impact of implementing LAFOV-PET in current practice. Full article

The etiology of melanoma is multifactorial and arises from the interplay of genetic, phenotypic, and environmental factors. The genetic predisposition to melanoma is influenced by a complex interaction among genes exhibiting varying levels of penetrance (high, moderate, and low), each contributing differently to the susceptibility of the disease. Furthermore, penetrance may vary based on the incidence of melanoma across diverse populations and geographical regions. Advances in genetic sequencing technologies have facilitated the identification of novel genes potentially associated with melanoma, as well as the characterization of relevant germline variants. While the most extensively researched variant is CDKN2A, recent studies have highlighted other variants unrelated to CDKN2A as significant areas of investigation. Among them, high-penetrance genes encompass CDK4, BAP1, POT1, TERT, ACD, and TERF2IP. In contrast, moderate-penetrance genes include MC1R, MITF, and SLC45A2, while low-penetrance genes consist of OCA2, TYRP1, and TYR. In addition to elevating the risk of melanoma, these genetic alterations may also predispose individuals to internal neoplasms. This review aims to provide a comprehensive overview of the definitions of sporadic, multiple primary, familial, and hereditary melanoma, with a particular emphasis on non-CDKN2A germline variants and their dermoscopic and phenotypic features. Full article

Background/Objectives: Cowden syndrome (or PTEN hamartoma tumor syndrome) (CS/PHTS) belongs to a group of inherited disorders associated with the development of multiple hamartomas. The clinical presentation of patients may include dysmorphic facial features, macrocephaly, developmental delay, and multiple benign and malignant tumors of various localizations. At the same time, only thyroid cancer is thought to have an increased risk in childhood. Skin lesions in CS/PHTS occur in 90–100% of patients and include multiple tricholemmoma, papilloma, acral keratosis, pigmentation changes, as well as rarer forms like vascular malformations, fibromas, neuromas, melanoma, and basal cell carcinoma. Methods: Next-generation sequencing and Sanger sequencing were used to search for PTEN genetic variants. A histological and immunohistochemical examination of tumor biopsies and skin lesions was performed. Results: A total of 13 patients from six families with CS/PHTS, including 10 children, were described. Seven pediatric patients belonged to families with paternal transmission of the PTEN pathogenic variants, while three others were de novo cases. Atypical manifestations in CS/PHTS were diffuse large B-cell lymphoma in one adult, a renal cell carcinoma, three germ cell tumors, and a linear epidermal nevus in pediatric patients. A literature review of the identified pathogenic variants in the PTEN gene was performed, assessing their clinical significance and analyzing the traditional and modified diagnostic criteria as applied to the pediatric population. Conclusions: Taking into account the low incidence of CS/PHTS, the data presented significantly expand our current understanding of this disease and guide physicians to consider a wider range of possible malignant neoplasms in pediatric patients with CS/PHTS. Full article

Heart failure (HF) remains a major global health challenge, driven by multifactorial pathophysiological processes, such as systemic congestion, endothelial dysfunction, and inflammation. While natriuretic peptides are well-established biomarkers for diagnosing and monitoring HF, they do not fully capture the complexity of vascular involvement. CD146, also known as melanoma cell adhesion molecule (MCAM), is a transmembrane glycoprotein primarily expressed on endothelial cells and involved in cell adhesion, vascular permeability, and angiogenesis. Its soluble form (sCD146), released in response to multiple pathophysiological stimuli, including venous and arterial endothelial stretch, oxidative stress, and inflammatory cytokine activation, has emerged as a promising biomarker reflecting both hemodynamic congestion and systemic endothelial stress. This review synthesizes current knowledge on the structure, regulation, and release mechanisms of CD146 and explores its clinical utility in HF. Elevated sCD146 levels have been associated with echocardiographic and radiological indicators of congestion, as well as with adverse outcomes. While promising, its application is limited by variability, lack of standardization, and confounding elevations in non-cardiac conditions, including malignancy. Full article

Human cutaneous malignant melanoma is a skin cancer that develops from melanocytes, the cells specialised in the production of eu- and pheomelanin. A growing body of evidence suggests that pheomelanin in particular is involved in melanoma development. The aim of this study was to develop a new method enabling the determination of the pheomelanin in formalin-fixed paraffin-embedded (FFPE) tissue specimens of human nodular (NM) and superficial spreading (SSM) melanomas. The pheomelanin level was evaluated in a small amount of material obtained from FFPE melanoma samples (less than 1 mg), using a multi-step procedure of paraffin removal, tissue rehydration, and homogenisation, omitting the melanin isolation step. The obtained product was studied for pheomelanin content using the Py-GC/MS/MS method operating in a multiple reaction monitoring (MRM) mode. The results of our research confirmed the presence of all the pheomelanin markers in the FFPE human melanoma specimens and showed that the tissues analysed contained different amounts of pheomelanin isomers (5-S-cysteinylDOPA and 2-S-cysteinylDOPA). The developed Py-GC/MS/MS procedure enables sensitive quantification of pheomelanin in FFPE human melanoma samples, facilitating broader studies on its role in melanoma development and progression. This method opens new avenues for investigating pheomelanin’s involvement in melanoma malignancy. Full article

Background: Studies on somatic mutations in cancer typically report single-nucleotide variants in coding regions, while mutations in short tandem repeats (STRs) are usually overlooked. Homopolymeric regions, a subset of STRs, are stretches of DNA where only a single nucleotide is repeated multiple times (e.g., AAAAA or TTTTT). Only recently have mutations in such STR regions been seen in colorectal cancer, where microsatellite instability (MSI) is common. In non-melanoma skin cancer (NMSC), MSI is rare. In this study, we focus on somatic mutations in such homopolymeric regions in NMSC and their functional implications. Methods: We performed targeted DNA sequencing (paired tissue and blood from the same individual), using more than 400 cancer-related genes from 32 NMSC patients as cases and non-lesional skin tissue from 16 independent individuals as controls. Results: We identified NMSC-associated STR somatic mutations. These are associated with the dysregulation of DNA damage and repair mechanisms. In artificial intelligence (AI) predictive modeling, these markers could successfully differentiate basal cell carcinoma (BCC) and non-lesional skin tissue. To our knowledge, we present the first study focusing on STR somatic mutations in multiple cancer-related genes in NMSC found only in tumor tissue and not in non-lesional skin tissue. Some of them (APC, BRAF) are associated with more pronounced dysregulation of relevant gene pathways (hedgehog, Notch signaling, and Wnt signaling). Conclusions: Our findings suggest that this STR somatic mutation status might potentially be used to select BCC patients who could benefit from certain precision therapy including hedgehog inhibitors, gamma-secretase inhibitors, anti-Vasuclar endothelial growth factor (VEGF), proteasome inhibitors, and immune check-point inhibitors. Full article

The extraction of adherent cells, such as B16 murine melanoma cells, from Petri dish cultures is critical in biomedical applications, including cell reprogramming, transplantation, and regenerative medicine. Traditional detachment methods—enzymatic, mechanical, or chemical—often compromise cell viability by altering membrane integrity and disrupting adhesion proteins. To address these challenges, this study investigated sensor-based detection of the pre-detachment phase in a MPWM (Microfluidic Pulse Width Modulation) extraction system. Our approach integrates a micromechatronic system with a microfluidic suction circuit, real-time CCD imaging, and computational analysis to detect and characterize the pre-detachment moment before full extraction. A precisely controlled hydrodynamic force field progressively disrupts adhesion in multiple stages, reducing mechanical stress and preserving cell integrity. Real-time video analysis enables continuous monitoring of positional dynamics and oscillatory responses. Image processing and deep learning algorithms determine object center coordinates, allowing the MPWM system to dynamically adjust suction parameters. This optimizes detachment while minimizing liquid absorption and reflux volume, ensuring efficient extraction. By combining microfluidics, sensor detection, and AI-driven image processing, this study established a non-invasive method for optimizing adherent cell detachment. These findings have significant implications for single-cell research, regenerative medicine, and high-throughput biotechnology, ensuring maximal viability and minimal perturbation. Full article

Melanoma, known for its aggressive nature and propensity for developing drug resistance, remains a significant clinical challenge. The emergence of resistance to both targeted therapies (like BRAF/MEK inhibitors) and immunotherapies is a major obstacle to achieving durable responses and improving patient survival. HDACs, a class of epigenetic enzymes, modulate gene expression and chromatin structure by removing acetyl groups from histone and non-histone proteins. In melanoma, aberrant HDAC activity contributes to resistance through multiple mechanisms. HDACs influence key oncogenic signaling pathways frequently dysregulated in melanoma, such as the MAPK, PI3K/AKT, and WNT/β-catenin cascades. By altering the activity of these pathways, HDACs promote the survival and proliferation of melanoma cells even in the presence of therapy. Beyond their direct effects on tumor cells, HDACs also play a crucial role in shaping the tumor microenvironment. They can suppress anti-tumor immune responses by reducing immune cell infiltration, modulating cytokine production, and fostering an immunosuppressive milieu. This further contributes to resistance to immunotherapies. Given the central role of HDACs in these resistance mechanisms, HDAC inhibitors (HDACis) have emerged as potential therapeutic agents to restore drug sensitivity. HDACis can induce cell death, inhibit proliferation, and enhance immune responses in melanoma cells. Preclinical and clinical studies have explored the combination of HDACis with existing therapies to overcome resistance. While promising, the clinical application of HDACis is accompanied by challenges, including toxicity, the need for biomarkers to predict response, and the optimization of combination strategies. Ongoing research is dedicated to developing more selective and potent HDACis and to better understand how to effectively incorporate them into melanoma treatment regimens. This review provides a comprehensive overview of the multifaceted ways in which HDACs contribute to melanoma drug resistance and discusses the potential of HDAC-targeted therapies to improve patient outcomes. Full article