Search Results (332)

Conventional melanoma is exceedingly rare in the pediatric population, particularly among prepubescent children, and its diagnosis and management necessitate a multidisciplinary approach. The objective of this present report is to delineate the diagnostic pathway and therapeutic management of a 4-year-old girl with conventional melanoma, with particular focus on the molecular context. A pigmented lesion located on the auricle was surgically excised, and subsequent histopathological and immunohistochemical analyses confirmed the diagnosis of malignant melanoma (pT3b). Radiologic investigations revealed no evidence of metastatic disease, and comprehensive genetic testing utilizing next-generation sequencing (NGS) identified no pathogenic variants in the germline genes examined, nor in the BRAF, NRAS, KRAS, and TP53 genes within the excised lesion. The patient remains in good general health. This case report adds to the limited body of literature on melanoma in pediatric patients and underscores the importance of thorough diagnostic evaluation in this age group. Full article

Background: Metastatic melanoma is a highly aggressive malignancy with poor prognoses and frequent resistance to conventional chemotherapy. Approximately 40% of melanoma cases carry the BRAF^V600E mutation, for which vemurafenib, a selective BRAF^V600E inhibitor, is approved. Despite initial clinical benefits, vemurafenib often leads to drug resistance and relapse, highlighting the need for improved therapeutic strategies. Objectives, methods: In this study, we designed, synthesized, and characterized five novel vemurafenib analogs—RF-86A, RF-87A, RF-94A, RF-94B, and RF-96B—with the aim of enhancing anti-proliferative and anti-metastatic effects against human melanoma cells. Results: All compounds induced apoptosis in BRAF^V600E-mutated A375 cells, with RF-86A displaying the lowest IC₅₀ value among the series, comparable to that of vemurafenib. Moreover, RF-86A exhibited the highest selectivity index, as determined using HEK293T cells as a non-tumorigenic control. Additionally, migration assays and gelatin zymography demonstrated that the analogs, unlike vemurafenib, significantly inhibited matrix metalloproteinases MMP-2 and MMP-9, key enzymes involved in tumor invasion and metastasis. Conclusions: These findings suggest that structural modifications to the vemurafenib scaffold may improve therapeutic efficacy and offer a promising strategy to overcome acquired resistance. Full article

Malignant cutaneous melanoma is among the most aggressive forms of skin cancer, characterized by high metastatic potential and frequent resistance to standard therapies. Hydroxytyrosol, a phenolic compound derived from extra virgin olive oil, has shown promising anticancer properties in various models, yet its effects in 3D melanoma systems remain poorly understood. In this study, we used paired 3D spheroid models of non-tumorigenic (HEMa) and melanoma (C32) to assess the therapeutic potential of hydroxytyrosol. To evaluate the anti-tumoral effect of hydroxytyrosol, we performed cytotoxicity, metastasis, invasiveness, cell cycle arrest, apoptotic, and proteomic assays. Hydroxytyrosol treatment significantly impaired spheroid growth, reduced cell viability, and induced cell cycle arrest and apoptosis in C32 spheroids, with minimal cytotoxicity observed in HEMa models. Proteomic profiling further demonstrated that hydroxytyrosol selectively downregulated a network of oncogenic proteins, including ERBB2, ERBB3, ERBB4, VEGFR-2, and WIF-1, along with suppression of downstream PI3K-Akt and MAPK/ERK signaling pathways. In conclusion, compared to dabrafenib, hydroxytyrosol exerted a broader range of molecular effects and was more selective toward tumor cells. These findings support the use of hydroxytyrosol as a multi-targeted agent capable of attenuating melanoma progression through suppression of kinase signaling and tumor-stromal interactions. Full article

Uveal melanoma (UM), the most common primary intraocular malignancy in adults, poses a unique clinical challenge due to its high propensity for liver metastasis and poor responsiveness to conventional therapies. Despite the expanding landscape of immunotherapy in oncology, progress in managing metastatic uveal melanoma (mUM) remains limited, and no universally accepted standard of care has been established. In this review, we examine the current state and evolving strategies in immunotherapy for mUM, focusing on immune checkpoint inhibitors (ICIs), T cell receptor (TCR)-engineered therapies, and tumor-targeted vaccines. We also present a meta-analytical comparison of clinical outcomes between ICI monotherapy and combination regimens, alongside the recently FDA-approved T cell engager tebentafusp. Our analysis indicates that the triple combination of Ipilimumab, anti-PD-1 agents, and tebentafusp significantly enhances objective response rates, disease control rates, 1-year overall survival rates, and median overall survival (mOS) compared to ICI monotherapy alone. However, this enhanced efficacy is accompanied by increased toxicity due to broader immune activation. In contrast, tebentafusp offers superior tumor specificity and a more favorable safety profile in HLA-A*02:01-positive patients, positioning it as a preferred therapeutic option for this genetically defined subset of UM. Additionally, early-phase studies involving dendritic cell-based immunotherapies and peptide vaccines has shown encouraging signs of tumor-specific immune activation, along with improved tolerability. Collectively, this review underscores the urgent need for more precise and effective immunotherapeutic approaches tailored to the unique biology of mUM. Full article

Aldehyde dehydrogenase 2 (ALDH2) is a crucial detoxifying enzyme that eliminates toxic aldehydes. ALDH2 deficiency has been linked to various human diseases, including certain cancers. We have previously reported ALDH2 downregulation in human melanoma tissues. Here, we further investigated the biological significance of ALDH2 downregulation in this malignancy. Analysis of TCGA dataset revealed that low ALDH2 expression correlates with poorer survival in metastatic melanoma. Examination of human metastatic melanoma cell lines confirmed that most had ALDH2 downregulation (ALDH2-low) compared to primary melanocytes. In contrast, a small subset of metastatic melanoma cell lines exhibited normal ALDH2 levels (ALDH2-normal). CRISPR/Cas9-mediated ALDH2 knockout in ALDH2-normal A375 cells promoted tumor growth and MAPK/ERK activation. Given the pivotal role of MAPK/ERK signaling in melanoma and cellular response to acetaldehyde, we compared A375 with ALDH2-low SK-MEL-28 and 1205Lu cells. ALDH2-low cells were intrinsically resistant to BRAF and MEK inhibitors, whereas A375 cells were not. However, A375 cells acquired resistance upon ALDH2 knockout. Furthermore, melanoma cells with acquired resistance to these inhibitors displayed further ALDH2 downregulation. Our findings indicate that ALDH2 downregulation contributes to melanoma progression and therapy resistance in BRAF-mutated human metastatic melanoma cells, highlighting ALDH2 as a potential prognostic marker and therapeutic target in metastatic melanoma. Full article

Several new amino-substituted aza-acridine derivatives bearing one or two basic side chains have been designed and synthesized. Their anticancer activities were evaluated in vitro against two human cancer cell lines: T24 (urothelial bladder carcinoma, malignancy grade III) and WM266-4 (metastatic melanoma). Some of the synthesized compounds induced significant antiproliferative effects, with WM266-4 cells appearing more susceptible than T24 cells. This apparent cell-type selectivity may reflect differences in the mutational profiles and molecular target landscapes between the two cancer models. A stability study under hydrolytic conditions, based on a validated method, indicated that the most active compounds were stable under aqueous conditions. Computational analysis further supported the stability of these analogs, providing insights into the structure–stability relationships of the synthesized compounds. Full article

Gastrointestinal metastases of malignant melanoma are relatively common and pose significant challenges to clinical management due to their complex presentation and resistance to therapy. Early detection and a multidisciplinary treatment approach are critical to improve outcomes. This review highlights targeted treatment strategies for gastrointestinal melanoma metastases, focusing on current therapeutic options and the mechanisms underlying drug resistance. Advances in immune checkpoint inhibitors (ICIs) and targeted therapies, such as BRAF and MEK inhibitors, have revolutionized melanoma treatment, yet their efficacy is often limited by the emergence of resistance mechanisms, including genetic mutations, tumor microenvironment factors, and immune escape. Herein, we explore potential resistance biomarkers for resistance and emerging targeting treatments targeting these pathways. Understanding the molecular and cellular mechanisms driving drug resistance remains critical to overcoming therapeutic limitations, emphasizing the importance of collaborative efforts in research and clinical practice to refine therapeutic approaches and improve survival rates for patients with metastatic melanoma involving the gastrointestinal tract. Future directions include optimizing combination therapies and leveraging precision medicine to address resistance and disease progression. Full article

Background: Uveal melanoma (UM) is a relatively rare malignancy, yet it remains the most common primary intraocular cancer in adults. Several risk factors have been identified, including light iris color, fair skin tone, and cutaneous freckles. Methods: The aim of this article was an overview of the treatment methods for uveal melanoma, with a particular focus on emerging therapies such as tebentafusp and da-rovasertib. The research method was a review of the latest literature. Results: Genetic studies have uncovered key mutations in GNAQ and GNA11, which significantly contribute to UM pathogenesis. Treatment selection depends on tumor location and disease stage. In localized disease, radiotherapy—especially brachytherapy—is commonly used and generally effective. However, the prognosis worsens significantly once distant metastases, most often to the liver, develop, as no standard systemic therapy has demonstrated high efficacy in this setting. Recent years have seen the emergence of promising therapies, including tebentafusp, which stimulates immune responses against gp100-expressing melanoma cells, and darovasertib, a potent PKC inhibitor that targets MAPK pathway activation driven by GNAQ/GNA11 mutations. Both agents have shown encouraging tolerability; tebentafusp has demonstrated clinical benefit in Phase II and III trials, while darovasertib is still under investigation. Additionally, melphalan-based liver-directed therapy, particularly via hepatic arterial infusion (approved by the FDA), has shown potential in controlling liver-dominant disease in metastatic UM. This localized approach may provide significant benefit for patients with limited extrahepatic spread. Conclusions: Future research should focus on optimizing these novel strategies—tebentafusp, darovasertib, melphalan, and combination therapies—and on expanding our understanding of UM’s molecular drivers to enable the development of more effective, personalized treatments. Full article

Background/Objectives: Melanoma is an aggressive skin cancer with high metastatic potential and poor prognosis in advanced stages. Hesperidin, a natural flavonoid, has shown anticancer properties across various malignancies. This study aimed to evaluate the antiproliferative and pro-apoptotic effects of Hesperidin, alone and in combination with Cisplatin, on the human epidermoid carcinoma cell line A431. Materials and Methods: A431 cells were cultured under standard conditions and treated with different concentrations of Hesperidin and Cisplatin for 48 h. Cell viability was assessed using the MTT assay. Apoptosis was evaluated by Annexin V-FITC/PI staining and caspase-3/7 activity assays. Expression levels of Bax, caspase-3/7, and survivin were measured by RT-qPCR. Results: Hesperidin significantly reduced cell viability at both 24 and 48 h. Annexin V/PI staining revealed increased apoptosis, with the highest apoptotic ratio in the Hesperidin + Cisplatin group (p < 0.001). Caspase-3/7 activity was markedly elevated in Hesperidin-treated cells. RT-qPCR showed upregulation of Bax and caspase-3/7 and downregulation of survivin. Conclusions: Hesperidin demonstrated significant cytotoxic and pro-apoptotic effects in A431 cells. When combined with Cisplatin, a synergistic enhancement of apoptosis was observed. These findings support the potential of Hesperidin as a complementary agent in carcinoma therapy, pending further in vivo and clinical validation. Full article

Melanoma is an aggressive cutaneous malignancy with increasing global incidence and high metastatic potential. While ultraviolet (UV) radiation remains the primary environmental risk factor, emerging evidence suggests that dietary factors may influence melanoma risk, progression, and treatment outcomes. This comprehensive review examines the impact of dietary components, including fats, vitamins, minerals, antioxidants, bioactive compounds, and the gut microbiome, on melanoma pathogenesis. The current literature indicates that diets rich in polyunsaturated fatty acids (PUFAs), antioxidants, and plant-based bioactive compounds may confer protective effects against melanoma by modulating oxidative stress, inflammation, and immune response. Additionally, the gut microbiome plays a critical role in melanoma progression and immunotherapy response, with dietary patterns influencing microbial composition and, consequently, host immunity. Despite these promising associations, research remains limited, and findings across studies are inconsistent, preventing the establishment of definitive dietary guidelines for melanoma prevention and management. Future research should focus on large-scale prospective studies to elucidate the mechanisms underlying the dietary influences on melanoma and determine evidence-based nutritional strategies. Understanding the interplay between diet, immune modulation, and gut microbiome composition represents a promising avenue for advancing melanoma prevention and treatment strategies. Full article

Background and clinical significance: Cutaneous melanomas sometimes display unusual histopathological features, reminiscent of various other malignancies, either primary or metastatic. However, due to the highly aggressive nature of cutaneous melanomas, an accurate and timely diagnosis is mandatory. This requires extensive histopathological and immunohistochemical analyses and molecular tests, if needed. Case presentation: In this respect, we present two cases of primary cutaneous melanomas exhibiting rhabdoid features and genuine divergent rhabdomyosarcomatous differentiation confirmed by immunoreactivity for myogenin and loss of positivity for some melanocytic markers. We discuss the diagnosis approach for these particularly rare entities, highlighting the most useful immunohistochemical panel. Additionally, we also provide an extensive review of all the previously reported similar lesions, focusing on the epidemiological, histopathological, immunohistochemical and molecular features, as well as discussing the prognostic and treatment options for rhabdomyosarcomatous cutaneous melanomas. Conclusions: These rare cases of primary cutaneous melanomas with rhabdomyosarcomatous differentiation underscore the diagnostic challenges posed by such unusual histopathological variants. In order to establish the correct diagnosis a comprehensive immunohistochemical workup, including both melanocytic and myogenic markers, is required. These findings are supported by a detailed review of the literature, emphasizing the importance of recognising these rare melanoma subtypes for providing the appropriate prognostic assessment, and therapeutic management. Full article

Objective: Early diagnosis and treatment of metastatic pericardial disease are crucial to prevent the life-threatening complication of cardiac tamponade. Thin Layer Cytology (TLC), a widely adopted technique in cytology, has gained significant acceptance for most specimens. Our study aimed to assess the utility of TLC in diagnosing metastatic neoplasms and their origins in pericardial effusions, as well as monitoring response to chemotherapy. Methods: We examined 184 pericardial fluids collected by pericardiocentesis and processed using the ThinPrep liquid-based technique. Various immunocytochemical markers were used to determine the site of metastatic neoplasms. We also evaluated the response to therapy in 53 patients with lung and breast cancer. Results: Out of 184 specimens, 113 pericardial fluids were diagnosed as positive for malignancy, while 71 were negative. Twenty-three cases of unknown primary site were included in the total positive cases. Ninety cases positive for malignancy had a known primary site of origin, including 31 lung carcinomas, 22 breast carcinomas, 10 ovarian carcinomas, 6 T-cell lymphomas, 3 urinary bladder carcinomas, 4 renal carcinomas, 5 adenocarcinomas of the colon, 5 prostate carcinomas, 2 parotid adenocarcinomas, and 2 melanomas. Regarding the 53 cases with chemotherapy treatment, the cytologic examination of pericardial fluid showed a remarkable reduction in neoplastic burden after the third dose of cisplatin or thiotepa instilled into the pericardial cavity. ThinPrep provided excellent preservation of cytomorphological features, high cellularity per slide, and a clear background. This comprehensive analysis provides crucial information about the types and distribution of cancerous cells present in the samples. Conclusions: Thin Layer Cytology (TLC) is a valuable diagnostic tool for detecting metastatic pericardial malignancy. It allows the examination of exfoliated cells from the pericardial fluid, providing crucial information for diagnosis, management, and monitoring the acute responsiveness to intrapericardial chemotherapy. Immunocytochemistry (IHC) can identify specific markers for various types of cancer, enabling a more accurate diagnosis and guiding further treatment decisions. Full article

Melanoma, a malignant skin tumor, is the third skin tumor and the third cause of brain metastases. The development and introduction of systemic therapies, such as Braf inhibitors and checkpoint inhibitors, have guaranteed an increase in overall survival. The appearance of brain metastases, which determines a median survival of less than 5 months, represents a sign of systemic disease progression and tumor instability. In this view, in addition to systemic therapy, the therapeutic options can be surgery, stereotactic surgery, and whole-brain radiation therapy. However, it has been observed that the response to systemic therapies of brain metastatic lesions, compared to extracerebral ones, does not guarantee complete local tumor control, thus increasing the mortality and morbidity of patients. This phenomenon, tumor escape, makes systemic therapy partly ineffective. How melanoma cells migrate, cross the blood–brain barrier, and invade brain tissue is still being studied. The melanocytic metastatic brain tumor microenvironment and its assay seem to have a key role in the response and therefore in the progression of metastatic lesions. Through this work, the intent is to underline the importance of the brain tumor microenvironment and how it can influence tumor growth, its response to therapy, and the patient’s overall survival. Full article

Metastatic melanoma is an aggressive skin cancer with a five-year survival rate of only 35%. Despite recent advances in immunotherapy, there is still an urgent need for the development of innovative therapeutic approaches to improve clinical outcomes of patients with metastatic melanoma. Prior research from our laboratory revealed that loss of the I-branching enzyme β1,6 N-acetylglucosaminyltransferase 2 (GCNT2), with consequent substitution of melanoma surface I-branched poly-N-acetyllactosamines (poly-LacNAcs) with i-linear poly-LacNAcs, is implicated in driving melanoma metastasis. In the current study, we explored the role of galectin-3 (Gal-3), a lectin that avidly binds surface poly-LacNAcs, in dictating melanoma aggressive behavior. Our results show that Gal-3 favors binding to i-linear poly-LacNAcs, while enforced GCNT2/I-branching disrupts this interaction, thereby suppressing Gal-3-dependent malignant characteristics, including extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway activation, BCL2 expression, cell proliferation, and migration. This report establishes the crucial role of extracellular Gal-3 interactions with i-linear glycans in promoting melanoma cell aggressiveness, placing GCNT2 as a tumor suppressor protein and suggesting both extracellular Gal-3 and i-linear glycans as potential therapeutic targets for metastatic melanoma. Full article

The dissemination of malignant cells to the brain is a late-stage complication of cancer, leading to significant morbidity and mortality. Brain metastases (BM) affect 20–30% of cancer patients, primarily originating from lung cancer, breast cancer, and melanoma. Despite advances in molecular-targeted therapies, brain metastatic disease remains incurable, with a poor median survival of ≤12 months if left untreated. The lack of therapeutic efficacy is mainly attributed to the presence of the blood–brain barrier (BBB) and genetic differences between BM and their primary tumors. Previously published data have identified potential driver mutations of BM. However, the mechanisms underlying brain cancer dissemination remain unknown. Recent studies emphasize the pivotal role of metabolic adaptations in supporting the metastatic process, particularly in the nutrient-poor microenvironment characteristic of the brain. Understanding the interplay between metabolism and genetic alterations associated with brain metastatic disease could unveil novel therapeutic targets that are more effective in treating patients. This review focuses on relevant metabolic pathways in cancer, particularly brain cancer dissemination, while also presenting information on current preclinical models of BM, relevant clinical trials, and preclinical studies targeting metabolic reprogramming, providing an overview for advancing therapeutic strategies in BM. Full article