Search Results (5,718)

Desmoplastic melanoma (DM) is an uncommon subtype of cutaneous melanoma that presents distinct diagnostic and treatment challenges. This review aims to explore the role of adjuvant radiation therapy (RT) in managing DM. To evaluate this question, we reviewed relevant published reports on DM and its treatment and synthesized these findings. It was found that the clinical behavior of DM varies significantly based on its classification as either “pure” DM (pDM, >90% desmoplastic features) or mixed DM (mDM, <90% desmoplastic features). Patients with pDM have a uniquely high risk of local recurrence but a relatively lower likelihood of nodal disease. Recent studies question the necessity of sentinel lymph node biopsy for pDM patients while illustrating impressive response rates to immune checkpoint inhibition. Most data supporting adjuvant RT predate these changes in surgical management and systemic therapy, yet consistently demonstrate that adjuvant RT reduces the absolute risk of local recurrence by >50%, without significant long-term toxicity. Thus, the existing literature continues to support the conclusion that adjuvant RT effectively reduces the likelihood of local recurrence in pDM patients. Although evolving surgical and systemic therapies are reshaping treatment approaches, adjuvant RT should remain a standard of care. Full article

The migratory and invasive capabilities of melanoma cells contribute to metastasis. Therefore, targeting the genes driving these processes can support melanoma therapy. Rab27A and Rab27B contribute to tumor formation progression in many types of cancer through various mechanisms, including the secretion of small extracellular vesicles (sEVs). We explored the role of these GTPases in melanoma cell functioning in three RAB27A knockout (KO) cell lines (A375, DMBC12, and SkMel28) and a double RAB27A/B KO A375 cell line. The loss of RAB27A impaired the migration and invasion of DMBC12 and SkMel28 cells; however, the behavior of highly aggressive A375 cells was unaffected. The RAB27A/B double knockout moderately decreased the migratory capacity of A375 cells without disturbing their invasiveness. Additionally, the silencing of RAB27A did not affect the number and mean size of the sEVs, despite some alterations in the protein content of the vesicles. Both Rab27 isoforms can, at least partially, act independently. The potential role of Rab27A in the functioning of melanoma cells depends on the individual character of the cell line, but not on its basal expression, and seems to be unrelated to the secretion of sEVs. Full article

Non-melanoma skin cancers (NMSCs), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are highly prevalent and a significant cause of morbidity. Image-guided superficial radiation therapy (IGSRT) uses integrated high-resolution dermal ultrasound to improve lesion visualization, but it is unknown whether efficacy varies by histology. This large retrospective cohort study was conducted to determine the effect of tumor histology on freedom from recurrence in 20,069 biopsy-proven NMSC lesions treated with IGSRT, including 9928 BCCs (49.5%), 5294 SCCs (26.4%), 4648 SCCIS cases (23.2%), and 199 lesions with ≥2 NMSCs (1.0%). Freedom from recurrence at 2, 4, and 6 years was 99.60%, 99.45%, and 99.45% in BCC; 99.58%, 99.49%, and 99.49% in SCC; and 99.96%, 99.80%, and 99.80% in SCCIS. Freedom from recurrence at 2, 4, and 6 years following IGSRT did not differ significantly comparing BCC vs. non-BCC or SCC vs. non-SCC but were slightly lower among SCCIS vs. non-SCCIS (p = 0.002). There were no significant differences in freedom from recurrence when stratifying lesions by histologic subtype. This study demonstrates that there is no significant effect of histology on freedom from recurrence in IGSRT-treated NMSC except in SCCIS. These findings support IGSRT as a first-line therapeutic option for NMSC regardless of histology. Full article

Melanoma is a malignant, highly metastatic neoplasm showing increasing morbidity and mortality. Tumor invasion and angiogenesis are based on remodeling of the extracellular matrix (ECM). Selective inhibition of functional components of cell–ECM interaction, such as hyaluronic acid (HA), matrix metalloproteinases (MMPs), and integrins, may inhibit tumor progression and enhance the efficacy of combination treatment with immune checkpoint inhibitors (ICIs), chemotherapy, or immunotherapy. In this review, we combine the results of different approaches targeting extracellular matrix elements in melanoma in preclinical and clinical studies. The identified limitations of many approaches, including side effects, low selectivity, and toxicity, indicate the need for further studies to optimize therapy. Nevertheless, significant progress in expanding our understanding of tumor biology and the development of targeted therapies holds great promise for the early approaches developed several decades ago to inhibit metastasis through ECM targeting. Full article

Vitiligo is a skin condition characterized by the loss of pigment, resulting in white patches on various parts of the body. It occurs when melanocytes, the cells that are responsible for producing skin pigment, are destroyed or stop functioning. This study aimed to investigate the melanogenic potential of various 4-methylcoumarin (4MC) derivatives, including 6-methoxy-4-methylcoumarin (6M-4MC), 7-methoxy-4-methylcoumarin (7M-4MC), 7-amino-4-methylcoumarin (7A-4MC), 6,7-dihydroxy-4-methylcoumarin (6,7DH-4MC), 7,8-dihydroxy-4-methylcoumarin (7,8DH-4MC), and 6,7-dimethoxy-4-methylcoumarin (6,7DM-4MC), in B16F10 melanoma cells. Our findings revealed that, while 4MC, 7A-4MC, 6,7DH-4MC, and 7,8DH-4MC did not exhibit any effect on melanin production, significant stimulation of melanogenesis was observed with 6M-4MC, 7M-4MC, and 6,7DM-4MC, with 6M-4MC demonstrating the most pronounced effect. 6M-4MC significantly stimulated melanin production and tyrosinase activity in a concentration-dependent manner in B16F10 cells. A Western blot analysis revealed that 6M-4MC increased the expression levels of microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2). Further mechanistic studies showed that 6M-4MC inhibited extracellular signal-regulated kinase (ERK) and protein kinase B (AKT), which led to the upregulation of MITF and TRP proteins and subsequent activation of melanin synthesis. Additionally, 6M-4MC activated GSK3β phosphorylation, reduced β-catenin phosphorylation, and stimulated melanogenesis via the GSK3β/β-catenin pathway. Moreover, a primary skin irritation test was conducted on the upper backs of 32 healthy female volunteers to assess the potential irritation or sensitization from 6M-4MC when applied topically at concentrations of 50 µM and 100 µM. The test results showed no adverse effects on the skin. Collectively, these findings suggest that 6M-4MC may be a promising pigmentation stimulator for use in cosmetics and in the medical treatment of hypopigmentation disorders, particularly in the treatment of skin conditions such as vitiligo. Full article

This study compares dosimetric outcomes of high-dose-rate (HDR) interventional radiotherapy (IRT) using Iridium-192, Volumetric Modulated Arc Therapy (VMAT), and electron beam therapy for non-melanoma skin cancer (NMSC). A retrospective analysis of 25 patients showed that IRT provided a significantly higher mean dose to the clinical target volume (CTV) compared to VMAT and electron beam therapy. IRT and VMAT had comparable V95%CTV coverage, whilst electron therapy was less feasible for large CTVs. IRT delivered higher surface doses while minimizing deep tissue exposure compared to partial arc VMAT. Our findings support IRT for personalized and effective NMSC treatment. Full article

Little is known about the impacts of fatigue after cancer treatment, including whether cancer-related fatigue impacts people’s use of healthcare. This study sought to examine how cancer-related fatigue impacts healthcare use after completing cancer treatment. A population-based survey was administered in Nova Scotia, Canada, to examine survivors’ experiences and needs after completing cancer treatment. Respondents included survivors of breast, melanoma, colorectal, prostate, hematologic, and young adult cancers who were 1–3 years post-treatment. Survey responses were linked to cancer registry, physicians’ claims, hospitalization, and ambulatory care data. Data were analyzed descriptively and using regression models. The final study cohort included 823 respondents. Younger respondents reported higher levels of cancer-related fatigue compared to older respondents. More females than males reported cancer-related fatigue. Upon adjusted analyses, those with cancer-related fatigue had lower odds of being discharged to primary care for their cancer-related follow-up (odds ratio = 0.71, p = 0.029). Moreover, those with cancer-related fatigue had 19% higher primary care use (incidence rate ratio = 1.19, p < 0.0001) and 37% higher oncology use (incidence rate ratio = 1.37, p < 0.016) during the follow-up period compared to those without cancer-related fatigue. Providers (oncology and primary care) may require additional support to identify clinically relevant fatigue and refer patients to appropriate resources and services. Full article

Vincristine, a vinca alkaloid, is used in chemotherapy protocols for cancers such as acute leukemia, Hodgkin’s disease, neuroblastoma, cervical carcinoma, lymphomas, breast cancer, and melanoma. Among the common adverse effects of vincristine is peripheral neuropathy, with most patients receiving a cumulative dose over 4 mg/m² who develop varying degrees of sensory neuropathy. The onset of vincristine-induced peripheral neuropathy can greatly affect patients’ quality of life, often requiring dose adjustments or the discontinuation of treatment. Moreover, managing vincristine-induced peripheral neuropathy is challenging, with few effective therapeutic strategies available. In the past decade, preclinical studies have explored diverse substances aimed at preventing or alleviating VIPN. Our review consolidates these findings, focusing on the analgesic efficacy and potential mechanisms of various agents, including pharmaceutical drugs, natural compounds, and antioxidants, that show promise in reducing neuropathic pain and protecting neural integrity in preclinical models. Key novel therapeutic options, such as metabolic agents (liraglutide), enzyme inhibitors (ulinastatin), antipsychotics (aripiprazole), interleukin-1 receptor antagonists (anakinra), hormones (oxytocin), and antioxidants (thioctic acid), are highlighted for their neuroprotective, anti-inflammatory, and antioxidant effects. Through this synthesis, we aim to enhance the current understanding of VIPN management by identifying pharmacological strategies that target critical molecular pathways, laying the groundwork for future clinical studies. By clarifying these novel pharmacological approaches and elucidating their mechanisms of action, this review provides a foundation for developing more effective VIPN treatment strategies to ultimately improve patient outcomes. Full article

Recent years have brought new, highly effective systemic treatments to clinical practice, which can be used to treat patients with locally advanced or metastatic skin cancers. Using these regimens in neoadjuvant strategy influences surgical treatment by facilitating surgical resection, avoiding extensive resections with complex reconstructions and even omitting surgery in some cases. Integrating systemic therapy with surgery is ongoing and requires novel quality measures of surgical treatment to capture the clinical benefits of multidisciplinary strategies better. The Textbook Outcome (TO) is a novel measure of surgical quality, which captures the short-term outcomes of surgery and reflects long-term survival. Textbook Outcomes match a particular type of surgery, are intuitive to interpret, and may be widely applied in surgical oncology and general surgery. Therefore, this review aims to describe recent findings on neoadjuvant skin cancer treatment and their implications for surgical proceedings in the context of Textbook Outcomes. Full article

Immunotherapy, particularly immune checkpoint inhibitors like PD-1, PD-L1, and CTLA-4, has revolutionized cancer treatment. However, the role of the innate immune system, especially pattern recognition receptors, in cancer development and immunity is gaining more and more attention. Dectin-1, a C-type lectin receptor primarily involved in antifungal immunity, has emerged as a significant player in cancer biology, exhibiting both pro-tumor and anti-tumor roles. This dual function largely depends on the tumor type and microenvironment. Dectin-1 can promote immune responses against tumors like melanoma and breast cancer by enhancing both innate and adaptive immunity. However, in tumors like pancreatic ductal adenocarcinoma and colorectal cancer, Dectin-1 activation suppresses T cell immunity, facilitating tumor progression. This review explores the complex mechanisms by which Dectin-1 modulates the tumor microenvironment and discusses its potential as a therapeutic target for cancer treatment. Full article

This study aimed to verify whether germline single nucleotide variants (SNV) in CTLA-4 gene, c.-1765C>T, c.-1661A>G, c.-1577G>A, and c.-1478G>A, influence the risk, clinicopathological aspects, and survival of patients with CM, as well as its functional consequences. A total of 432 patients with CM and 504 controls were evaluated. CTLA-4 genotypes were identified by real-time polymerase chain reaction (RT-PCR) and expression of CTLA-4 by quantitative PCR (qPCR) and luciferase assay. Cell cycle, proliferation, apoptosis/necrosis, and migration analyses were performed in SK-MEL-28 and A-375 cell lines modified to present homozygous ancestral or variant genotypes by CRISPR technique. Individuals with the CTLA-4 c.-1577 AA genotype and the combined CTLA-4 c.-1577 and c.-1478 AA + AA genotypes were at 1.60- and 3.12-fold higher risk of developing CM, respectively. The CTLA-4 c.-1577 AA genotype was seen as an independent predictor of worse event-free survival and was also associated with higher gene expression, higher cell proliferation, lower cell apoptosis, and higher cell migration. Our data present, for the first time, evidence that CTLA-4 c.-1577G>A alters the risk and clinical aspects of CM treated with conventional procedures and may be used for selecting individuals for tumor prevention and patients for distinct treatment. Full article

Melanoma represents a formidable challenge in dermatological oncology due to its resistance to conventional treatments. The Celandine Alkali Injection Formula (CAIF) offers benefits on clinical internal medicine treatments, within which chelidonine and tetrandrine are recognized as potential quality markers. However, their synergistic mechanisms facilitating their anti-melanoma action remain unveiled. This study embarked on an exploration of CAIF’s therapeutic potential through a multifaceted research design, integrating system pharmacological predictions with empirical molecular biological evaluations. The dual application of chelidonine and tetrandrine within CAIF exhibited a pronounced inhibitory effect on the proliferation of B16F10 cells, surpassing the effectiveness of individual compound administration. Computational predictions identified the top 50 targets, involved in key signaling pathways including cell cycle regulation, and melanogenesis. RNA sequencing further elucidated that the combinatory treatment modulated a broader spectrum of differentially expressed genes, implicating crucial biological processes including cell differentiation, and tyrosinase metabolism. The combination markedly enhanced melanogenesis and apoptotic indices, arrested cell cycle progression, and fostered cellular differentiation. Notably, chelidonine additionally curtailed the migratory capacity of B16F10 cells. Our findings underscore the therapeutic potential of chelidonine and tetrandrine, key components of CAIF, in effectively combating melanoma by targeting cell proliferation, migration, differentiation, and melanogenesis. Full article

Background/Objectives: Facial pigmented skin lesions are extremely common, starting from the fourth to fifth decades, especially in South-European countries, often located in the periorbital region. These include malignant forms, Lentigo maligna (LM) and lentigo maligna melanoma (LMM), characterized by growing incidence, and a series of benign simulators, including solar lentigo (SL), pigmented actinic keratosis (PAK), seborrheic keratosis (SK) and lichen planus-like keratosis (LPK). The clinical differential diagnosis of atypical pigmented skin lesions (aPFLs) can be difficult, even for dermatologists, leading to inappropriate skin biopsies with consequent aesthetic impacts. Dermoscopy of the facial area is a specific dermoscopic field that requires dedicated training and proved to increase diagnostic accuracy in dermatologists. Since these lesions are often seen by ophthalmologists at first, we aimed to evaluate the effect of a focused dermoscopy training course on a group of ophthalmologists naïve to the use of a dermatoscope. Methods: A set of 80 periorbital pigmented skin lesions with both clinical and dermoscopic images was selected and evaluated by six ophthalmologists before and after a one-day intensive dermoscopic training course. They were required to evaluate 80 periorbital lesions one month before and after a one-day intensive dermoscopic training course, illustrating second-level diagnostic options such as reflectance confocal microscopy (RCM), obtaining a total of 480 evaluations. Specifically, they had to provide, for each case, a punctual diagnosis and a management option among dermoscopic follow-up/skin biopsy/RCM/LC-OCT. Descriptive statistics were carried out, and the accuracy (ACC), sensitivity (SE), and specificity (SP), with their 95% confidence interval (95% CI), were estimated. Results: In the pre-course test, ophthalmologists achieved 84.0% SP, 33.3% SE and 63.7% ACC, while after the course, SE increased by +9% (i.e., 41.7%), SP decreased by 4%, and ACC remained comparable, i.e., 64.6%. In the management study, the percentage of benign lesions for which a close dermoscopic follow-up was suggested significantly decreased (51.6% versus 22.2%), in parallel with an increase in the number of lesions referred for RCM. As for malignant cases, the reduction in responses “close dermoscopic follow-up” decreased from 37.0% to 9.9%, (−27%), in favor of RCM (+15%) and skin biopsy (+12%). Conclusions: The ophthalmologists proved to be very receptive in quickly metabolizing and putting into practice the concepts learned during the one-day intensive dermoscopy training course. Indeed, after only a one-day lesson, they were able to increase their SE by 9% and to improve their management strategy. The present findings highlight the importance of providing training ophthalmologists in dermoscopy during residency programs, in terms of benefits for the correct patient care. Full article

The balance between apoptosis and autophagy plays a key role in cancer biology and treatment strategies. The aim of this study was to assess the effect of the mTOR kinase inhibitor everolimus and chloroquine on the regulation of proliferation, caspase-3 activation, and apoptosis in melanoma cells. We studied the activity of caspase-3 and the levels of caspase-3 and -9 using the Western blot technique. Cellular apoptosis was examined using a DNA fragmentation assay, and changes in the cell nucleus and cytoskeleton were examined using fluorescence microscopy DAPI, OA/IP. We also studied the rearrangement of lipid structures using fluorescent dyes: Nile Red and Nile Blue. A low nanomolar concentration of the mTOR kinase inhibitor everolimus in combination with chloroquine activated the apoptosis process and decreased cell proliferation. These changes were accompanied by an obvious change in cell morphology and rearrangement of lipid structures. Alterations in lipid redistribution accompanying the process of apoptosis and autophagy are among the first to occur in the cell and can be easily monitored in in vitro studies. The combination of mTOR inhibitors and chloroquine represents a promising area of research in cancer therapy. It has the potential to enhance treatment efficacy through complementary mechanisms. Full article

Objective: To evaluate whether primary tumor treatment provides a survival benefit in uveal melanoma by comparing patients who declined treatment (Natural History Study, NHS) with those who received treatment in the Collaborative Ocular Melanoma Study (COMS) for medium-sized choroidal melanomas. Methods: Individual-level survival data were reverse-engineered from cumulative all-cause mortality curves in the original COMS and NHS publications. Censoring patterns were estimated from numbers at risk and descriptive statistics. A Bonferroni-corrected significance level of 0.017 was applied. Additionally, to ensure a conservative approach, NHS cohort data were iteratively adjusted by reducing the 8-year cumulative mortality by one percentage point if the Cox regression hazard ratio for all-cause mortality, the unadjusted risk ratio for death, and the 95% confidence intervals (CIs) of the Kaplan–Meier curves did not show a smaller survival difference than originally reported. Results: Kaplan–Meier analysis revealed significantly higher cumulative mortality in the NHS cohort compared to the COMS cohort (log–rank p = 0.012). When restricting the analysis to the first 8 years to account for unclear censoring patterns beyond this period, the NHS cohort still demonstrated worse survival (p = 0.008). A sensitivity analysis, varying censoring times by ±25% over 1000 iterations, confirmed worse survival in the NHS cohort in 100% of cases. Conclusions: In this re-evaluation, patients who declined treatment for medium-sized choroidal melanomas had significantly worse survival, suggesting a potential survival benefit of primary tumor treatment. Full article