Search Results (80)

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: 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

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

Immune checkpoint inhibitors (ICIs) have transformed melanoma treatment; however, predicting patient responses remains a significant challenge. This study reviews the potential of artificial intelligence (AI) to optimize ICI therapy in melanoma by integrating various diagnostic tools. Through a comprehensive literature review, we analyzed studies on AI applications in melanoma immunotherapy, focusing on predictive modeling, biomarker identification, and treatment response prediction. Key findings highlight the efficacy of AI in improving ICI outcomes. Machine learning models successfully identified prognostic cytokine signatures linked to nivolumab clearance. The combination of AI with RNAseq analysis had the potential for the development of personalized treatment with ICIs. A machine learning-based approach was able to assess the risk-benefit ratio for the prediction of immune-related adverse events (irAEs) using the electronic health record (EHR) data. Deep learning algorithms demonstrated high accuracy in tumor microenvironment analysis, including tumor region identification and lymphocyte detection. AI-assisted quantification of tumor-infiltrating lymphocytes (TILs) proved prognostically valuable in primary melanoma and predictive of anti-PD-1 therapy response in metastatic cases. Integrating multiple diagnostic modalities, such as CT imaging and laboratory data, modestly enhanced predictive performance for 1-year survival in advanced cancers treated with immunotherapy. These findings underscore the potential of AI-driven approaches to refine biomarker identification, treatment prediction, and patient stratification in melanoma immunotherapy. While promising, clinical validation and implementation challenges remain. Full article

Background/Objectives: The revolution for the treatment of melanoma came with the approval of checkpoint blockade antibodies. However, a substantial proportion of patients show primary or secondary resistance to this type of immunotherapy, indicating the need for alternative therapeutic strategies. Dendritic cells (DCs) of the skin are prime targets for vaccination approaches due to their potential to prime naïve T cells and their accessibility. This study aimed to develop and evaluate novel vaccines targeting the C-type lectin receptor DEC-205 to deliver melanoma-associated antigenic peptides to skin DCs. Methods: We cloned MHC-I-restricted peptides from the glycoprotein (gp)100_25–33 and Tyrosinase-related protein (trp)2_180–188 into the DEC-205 antibody sequence with modified peptide cutting sites from the OVA_257–264 SIINFEKL peptide. We tested their potential to induce CD8⁺ T cell responses in both in vitro and in vivo settings. Tumor growth inhibition was evaluated in the transplantable B16.OVA melanoma murine model using a multi-epitope DC-based vaccine combining both peptides. Results: The cross-presentation of both gp100 and trp2 peptides was confirmed in vivo when peptide sequences were flanked by the OVA_257–264 peptide cutting sites. Moreover, the combination of both antigenic peptides into a multi-epitope DC vaccine was required to inhibit B16.OVA melanoma growth. Conclusions: Our findings suggest that a DC-targeted vaccination approach using multiple epitopes deriving from melanoma antigens could represent a promising strategy for melanoma therapy. Full article

Background: Uveal melanoma is the most common primary intraocular cancer in adults; however, it remains rare. Despite its rarity, metastatic uveal melanoma poses significant treatment challenges. Tebentafusp, a T-cell receptor–bispecific molecule targeting glycoprotein 100 and CD3, has shown substantial survival benefits for HLA-A*02:01 positive patients. A notable complication associated with tebentafusp and similar immunotherapies is cytokine release syndrome (CRS), occurring in nearly 90% of tebentafusp-treated patients. Although typically mild, severe CRS (grade 3) affects around 1% of patients. The unpredictable nature of CRS complicates patient management during treatment. Methods: Monitoring cytokine levels, as key indicators of inflammation, may therefore be crucial for understanding and managing CRS. Advanced proteomic technologies enable the simultaneous measurement of multiple cytokines, providing a comprehensive view of inflammatory responses. Results: In this case, a patient with metastatic uveal melanoma developed CRS after tebentafusp treatment. A proteomic analysis tracked the cytokine changes from baseline to post-treatment, revealing significant elevations in inflammatory markers. Conclusions: These findings suggest potential strategies for more personalized CRS management in similar therapies. Full article

Drug repurposing is a cost-effective and innovative strategy for identifying new therapeutic applications for existing drugs, thereby shortening development timelines and accelerating the availability of treatments. Applying this approach to the development of cosmeceutical ingredients enables the creation of functional compounds with proven safety and efficacy, adding significant value to the cosmetic industry. This study evaluated the potential of rifampicin, a drug widely used for the treatment of tuberculosis and leprosy, as a cosmeceutical agent. The anti-melanogenic effects of rifampicin were assessed in B16F10 melanoma cells, showing no cytotoxicity at concentrations up to 40 µM and a significant reduction in intracellular tyrosinase activity and melanin content. Mechanistically, rifampicin reduced the expression of melanogenic enzymes, including tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2, via a protein kinase A (PKA)-dependent pathway, leading to the suppression of microphthalmia-associated transcription factor (MITF), which is a key regulator of melanogenesis. Additionally, rifampicin inhibited the p38 signaling pathway but was independent of the PI3K/protein kinase B (Akt) pathway. Furthermore, it decreased Ser9 phosphorylation, enhancing glycogen synthase kinase-3β (GSK-3β) activity, promoted β-catenin phosphorylation, and facilitated β-catenin degradation, collectively contributing to the inhibition of melanin synthesis. To evaluate the topical applicability of rifampicin, primary human skin irritation tests were conducted, and no adverse effects were observed at concentrations of 20 µM and 40 µM. These findings demonstrate that rifampicin inhibits melanogenesis through multiple signaling pathways, including PKA, MAPKs, and GSK-3β/β-catenin. This study highlights the potential of rifampicin to be repurposed as a topical agent for managing hyperpigmentation disorders, offering valuable insights into novel therapeutic strategies for pigmentation-related conditions. Full article

Background/Objectives: Voglibose, an α-glucosidase inhibitor commonly prescribed to manage postprandial hyperglycemia in diabetes mellitus, demonstrates potential for repurposing as an anti-melanogenic agent. This study aims to explore the inhibitory effects of voglibose on melanogenesis and elucidate its molecular mechanisms, highlighting its possible applications in treating hyperpigmentation disorders. Methods: The anti-melanogenic effects of voglibose were investigated using B16F10 melanoma cells. Cell viability, melanin content, and tyrosinase activity were assessed following voglibose treatment. Western blot analysis was performed to examine changes in melanogenic proteins and transcription factors. The role of signaling pathways, including PKA/CREB, MAPK, PI3K/AKT, and GSK3β/β-Catenin, was analyzed. Primary human skin irritation tests were conducted to evaluate the topical safety of voglibose. Results: Voglibose significantly reduced melanin synthesis and tyrosinase activity in B16F10 cells in a dose-dependent manner. Western blot analysis revealed decreased expression of MITF, TRP-1, and TRP-2, indicating the inhibition of melanogenesis. Voglibose modulated key signaling pathways, including the suppression of PKA/CREB, MAPK, and AKT activation, while restoring GSK3β activity to inhibit β-catenin stabilization. Human skin irritation tests confirmed voglibose’s safety for topical application, showing no adverse reactions at 50 and 100 μM concentrations. Conclusions: Voglibose demonstrates anti-melanogenic properties through the modulation of multiple signaling pathways and the inhibition of melanin biosynthesis. Its safety profile and efficacy suggest its potential as a repurposed drug for managing hyperpigmentation and advancing cosmeceutical applications. Full article

Background/Objectives: Melanoma is an aggressive cutaneous malignancy with a rising incidence. While most cases are sporadic, 5–10% are hereditary, especially in patients with multiple or familial melanomas. The aim of this study is to explore the epidemiological, clinical, histological, and genetic features of this class of patients to identify risk factors for better management and surveillance. Methods: Between 2021 and 2024, patients with multiple melanomas or a familial history of melanoma were recruited. Collected data included demographic, clinic-pathologic features, and genetic analyses. Results: Patients >60 years had a higher prevalence of multiple melanomas (>50%, p = 0.0002), while familial melanoma was more common in those <40 years (54.3%). UV exposure increased with age, while sunscreen use decreased (p = 0.0004). Younger patients showed the highest nevi counts (mean: 139.6) and density (p < 0.0001). Dermatologists more frequently detected subsequent melanomas in older patients (>60 years) (p = 0.001). Genetic testing and melanoma subtypes showed no significant age-related differences. Conclusions: melanoma can develop at any age, and early detection through regular screening is crucial. Older patients (>60 years) have a higher prevalence of multiple melanomas, influenced by UV exposure and genetics. Indeed, in our cohort, a history of sun exposure, sunburns, and tanning bed use emerged as key risk factors, particularly among older individuals. Genetic testing showed a 4.3% rate of pathogenic/likely pathogenic variants, mainly in CDKN2A. Family history and nevus burden are significant risk factors, highlighting the need for targeted surveillance in high-risk populations. Full article

Background: Diagnosis of nevoid melanoma (NeM) is often difficult because NeM closely resembles a common nevus clinically and histologically. Methods: A retrospective study was conducted on 110 patients diagnosed with and/or treated for primary nevoid melanoma at the Veneto Institute of Oncology and at the University Hospital of Padua from August 1999. Results: Mean Breslow thickness was of 1.4 mm. Sentinel lymph node biopsy was conducted in nearly half of the patients, and positivity was detected in 16.7% of them. Twenty-four clinical and 23 dermoscopic pictures were collected. Papular and macular lesions prevailed over nodular and plaque-type lesions. Different hues of brown, pink, and red color were most represented. Twenty nevus-like NeMs and four multicomponent-pattern NeMs were observed. The Most frequent dermoscopic patterns for nevus-like NeM were atypical pigmented reticulum, irregular globules and dots, and hyperpigmented blotches. Atypical vessels, asymmetric peripheric striae, blue-white veil, and areas of regression were less frequent and prevailed in multicomponent pattern NeM. A structureless pattern was also featured. Many patients in the series had multiple melanomas. However, none of them had numerous multiple nevoid melanomas. Conclusions: NeM should not be regarded as a separate biological entity from classical melanoma, and the same histological and clinical prognostic factors apply to NeM. Clinically and dermoscopically, it often resembles benign nevi, although some clues such as evolution and some dermoscopic patterns could suggest malignancy. Clinical suspicion might prove crucial to further pathological analysis and recognition. Full article

Recent genome-wide association studies (GWASs) have identified many single nucleotide polymorphisms (SNPs) that alone weakly affect melanoma risk, but their combined effect on a polygenic risk score (PRS) can have a far bigger impact on estimating risk. However, the PRS is not yet at the stage of being utilized in clinical practice, and further evidence is needed. In this study, 270 melanoma patients fulfilling the criteria for a suspected genetic predisposition but with a negative genetic test for high/medium-penetrance genes were genotyped for 57 SNPs selected in previous GWASs to construct a PRS model. We found a significantly higher mean PRS₅₇ in all melanoma cases than in controls (0.58 vs. 0.00, p < 0.001), and the mean PRS₅₇ in multiple primary melanoma cases was twice that in single melanoma cases (0.689 vs. 0.362, p = 0.025). Interestingly, our results confirm the association of the PRS₅₇ not only with other melanoma risk factors but also with a younger age at diagnosis. This evidence supports the potentially powerful discriminative role of PRS in the selection of high-risk patients who should undergo stricter surveillance protocols. Full article

Background and Objectives: Multiple primary malignant tumors represent a small percentage of the total number of oncological cases and can involve either metachronous or synchronous development and represent challenges in diagnosis, staging, and treatment planning. Our purpose is to present a rare case of bladder adenocarcinoma in a female patient with multiple primary malignant tumors and to provide systematic review of the available literature. Materials and Methods: A 67-year-old female patient was admitted with altered general condition and anuria. The past medical history of the patient included malignant melanoma (2014), cervical cancer (2017), colon cancer (2021), obstructive anuria (2023), and liver metastasectomy (2023). Transurethral resection of bladder tumor was performed for bladder tumors. Results: Contrast CT highlighted multiple pulmonary metastases, a poly nodular liver conglomerate, retroperitoneal lymph node, II/III grade left ureterohydronephrosis, and no digestive tract tumor masses. The pathological result of the bladder resection showed an infiltrative adenocarcinoma. Conclusions: The difference between primary bladder adenocarcinoma tumor and metastatic colorectal adenocarcinoma is the key for the future therapeutic strategy. Identification and assessment of risk factors such as viral infection, radiotherapy, chemotherapy, smoking, and genetics are pivotal in understanding and managing multiple primary malignant tumors. Personalized prevention strategies and screening programs may facilitate the early detection of these tumors, whether synchronous or metachronous. The use of multicancer early detection (MCED) blood tests for early diagnosis appears promising. However, additional research is needed to standardize these techniques for cancer detection. Full article

The purpose of this article is to provide a literature review of the epigenetic understanding of conjunctival melanoma (CM), with a primary focus on current gaps in knowledge and future directions in research. CM is a rare aggressive cancer that predominantly affects older adults. Local recurrences and distant metastases commonly occur in CM patients; however, their prediction and management remain challenging. Hence, there is currently an unmet need for useful biomarkers and more effective treatments to improve the clinical outcomes of these patients. Like other cancers, CM occurrence and prognosis are believed to be influenced by multiple genetic and epigenetic factors that contribute to tumor development/progression/recurrence/spread, immune evasion, and primary/acquired resistance to therapies. Epigenetic alterations may involve changes in chromatin conformation/accessibility, post-translational histone modifications or the use of histone variants, changes in DNA methylation, alterations in levels/functions of short (small) or long non-coding RNAs (ncRNAs), or RNA modifications. While recent years have witnessed a rapid increase in available epigenetic technologies and epigenetic modulation-based treatment options, which has enabled the development/implementation of various epi-drugs in the cancer field, the epigenetic understanding of CM remains limited due to a relatively small number of epigenetic studies published to date. These studies primarily investigated DNA methylation, ncRNA (e.g., miRNA or circRNA) expression, or RNA methylation. While these initial epigenetic investigations have revealed some potential biomarkers and/or therapeutic targets, they had various limitations, and their findings warrant replication in independent and larger studies/samples. In summary, an in-depth understanding of CM epigenetics remains largely incomplete but essential for advancing our molecular knowledge and improving clinical management/outcomes of this aggressive disease. Full article

Background: Traditional treatment methods for non-melanoma skin cancer (NMSC) include surgical excision with histological evaluation, yet advancements such as reflectance confocal microscopy (RCM) and superficial radiation therapy (SRT) offer non-invasive management alternatives. This study aims to evaluate the use of RCM for the evaluation of treatment outcomes after SRT in managing localized NMSC. Methods: A prospective interventional case series study was conducted on patients treated for NMSC with SRT between March 2020 and December 2023. Suspected NMSC lesions were initially evaluated with a handheld dermoscope and then imaged at multiple depths using a VivaScope 1500 RCM. Two dermatologists trained in RCM reviewed the images. Confirmed NMSC lesions were biopsied and treated with SRT, followed by RCM imaging at six months post-treatment to assess cancer clearance, scarring, and inflammation. Results: Of the 38 lesions (composed of SCC (24) and BCC (14)) treated affecting the 29 patients, all lesions showed no residual tumor activity upon conducting follow-up RCM (100% clearance). Scarring and mild erythema were noted clinically. Six lesions demonstrated moderate to severe inflammation at a 6-month follow-up. Conclusions: This study demonstrates successful non-invasive management of localized NMSC using RCM and SRT. RCM was able to non-invasively demonstrate complete tumor clearance achieved by SRT with minimal adverse effects. These findings support considering the use of RCM and SRT as primary diagnostic, monitoring, and treatment options for NMSC without the need for biopsies, especially for elderly patients or those unsuitable for surgery due to medical conditions. Full article

A major reason for the failure of the immune system to detect tumor antigens (TAs) is the insufficient uptake, processing, and presentation of TAs by antigen-presenting cells (APCs). The immunogenicity of TAs in the individual patient can be markedly increased by the in situ targeting of tumor cells for robust uptake by APCs, without the need to identify and characterize the TAs. This is feasible by the intra-tumoral injection of α-gal micelles comprised of glycolipids presenting the carbohydrate-antigen “α-gal epitope” (Galα1-3Galβ1-4GlcNAc-R). Humans produce a natural antibody called “anti-Gal” (constituting ~1% of immunoglobulins), which binds to α-gal epitopes. Tumor-injected α-gal micelles spontaneously insert into tumor cell membranes, so that multiple α-gal epitopes are presented on tumor cells. Anti-Gal binding to these epitopes activates the complement system, resulting in the killing of tumor cells, and the recruitment of multiple APCs (dendritic cells and macrophages) into treated tumors by the chemotactic complement cleavage peptides C5a and C3a. In this process of converting the treated tumor into a personalized TA vaccine, the recruited APC phagocytose anti-Gal opsonized tumor cells and cell membranes, process the internalized TAs and transport them to regional lymph-nodes. TA peptides presented on APCs activate TA-specific T cells to proliferate and destroy the metastatic tumor cells presenting the TAs. Studies in anti-Gal-producing mice demonstrated the induction of effective protection against distant metastases of the highly tumorigenic B16 melanoma following injection of natural and synthetic α-gal micelles into primary tumors. This treatment was further found to synergize with checkpoint inhibitor therapy by the anti-PD1 antibody. Phase-1 clinical trials indicated that α-gal micelle immunotherapy is safe and can induce the infiltration of CD4+ and CD8+ T cells into untreated distant metastases. It is suggested that, in addition to converting treated metastases into an autologous TA vaccine, this treatment should be considered as a neoadjuvant therapy, administering α-gal micelles into primary tumors immediately following their detection. Such an immunotherapy will convert tumors into a personalized anti-TA vaccine for the period prior to their resection. Full article