Ocular melanoma, the most common primary ocular malignancy in adults, is a rare subtype of melanoma characterized by high malignancy and poor prognosis. The aim of this study is to investigate the tumor cells and microenvironmental heterogeneity in two ocular melanoma subtypes at the single-cell level. We performed single-cell analysis across 28 ocular melanoma samples, including 14 uveal melanoma and 14 conjunctival melanoma (CoM) samples. Tumor cells and immune cells were analyzed to investigate the heterogeneous cellular composition in the tumor microenvironment. We compared the transcriptome profile of uveal melanoma and CoM to uncover subtype-specific biological signatures and molecular programs. Compared with uveal melanoma, CoM exhibited significantly higher immune cell infiltration. Tumor cells from the two subtypes displayed distinct transcriptional states and functional pathway activities. CoM was enriched for melanoma subpopulations characterized by epithelial-mesenchymal transition-related and stemness-associated transcriptional programs, together with relatively higher copy number variation scores, suggesting transcriptional and genomic features previously associated with more aggressive tumor behavior. While uveal melanoma was characterized by CD8+ T cells with relatively higher cytotoxicity- and terminal exhaustion-associated activities, CoM exhibited comparatively lower cytotoxicity and terminal exhaustion signatures but higher progenitor-like and exhausted-like effector features. CoM also showed increased infiltration of monocytes and CXCL3+ tumor-associated macrophages with elevated M2-associated signature activity. Our study provides a comprehensive comparison between two ocular melanoma subtypes at the single-cell level, revealing distinct cellular compositions, transcriptional state distributions, and molecular programs of tumor cells, as well as immune microenvironmental features.
Melanoma is the most aggressive form of skin cancer, characterized by high metastatic potential and frequent resistance to targeted therapies. Traditional 2D cultures and animal models often fail to accurately mimic the complexity of the human tumor microenvironment (TME). To improve the recapitulation of the cellular and mechanical microenvironmental cues, we bioengineered a melanoma-skin-on-a-chip platform using an edgeless 3D skin reconstruction strategy, which allows for creating mechanically relevant skin microenvironments. The platform integrates a dermis compartment made of primary dermal fibroblasts, human umbilical vein endothelial cells (HUVECs), and melanoma spheroids (generated using MeWo and A375 cell lines), and an epidermis compartment made of differentiated layers of primary keratinocytes. Melanoma spheroids consist of a mixture of melanoma cells, fibroblasts and endothelial cells in collagen droplets, and when incorporated into the engineered dermis, form morphologically heterogeneous structures that mimicked in vivo tumor masses and late vertical progression phase of melanoma. The model successfully recapitulated key aspects of the tumor microenvironment, including increased peritumoral cancer-associated fibroblast (CAF) marker expression and extracellular matrix (ECM) remodeling. To evaluate the therapeutic relevance of the model, we evaluated the effects of MEK and BRF inhibitors on tumor cell proliferation and apoptosis. By day 7 post-tumor integration, vascular organization differed between melanoma backgrounds, with the MeWo construct showing 2.3-fold higher vessel area fraction and 3.65-fold higher vascular length density than the A375 construct, indicating enhanced vascular coverage and network density. This vascularized melanoma-skin-on-a-chip provides a human-relevant platform for studying melanoma invasion, response to therapeutics, and tumor-microenvironment dynamics. It holds strong potential for preclinical drug screening and offers a foundation for developing personalized therapeutic strategies.
Melanoma outcomes vary by subgroups. Identify institutional/systemic factors contributing to outcome differences. Retrospective cohort study of melanoma patients seen 1/1987-5/2023 at a VA center and nearby tertiary care center sharing providers. Outcomes include melanoma-specific survival (MSS) and mortality (MSM). Compared to the tertiary center (n=9,682, 5,564 males), VA patients (n=638, 612 males) were older and had a greater proportion of melanoma in situ (p<0.0001). When comparing VA males to males treated at the tertiary center, MSS was increased for localized melanoma (p=0.003), but decreased for regional (p=0.0002) and distant disease (p=0.02). When comparing VA males to VA-insured males at the tertiary center, MSS remained increased for localized disease (p<0.0001), but differences for regional or distant disease were no longer significant. Within the tertiary center, publicly insured patients had increased MSM compared to privately insured (Medicare, hazard ratio [95%CI] 1.46 [1.22,1.75]; Medicaid, 1.67 [1.28,2.18]; Military/VA 1.92 [1.15,3.20]). Smaller number of VA-insured patients. Differences in preventative screening and selective referrals may contribute to increased survival at the VA for early-stage melanoma. Insurance type within and between institutions is associated with differential mortality outcomes for advanced melanoma stages, indicating a need for additional care standardization.
To develop and deploy a publicly accessible online risk estimation tool for cutaneous melanoma that prioritizes high recall to minimize missed diagnoses, using real-world clinical photographs rather than dermoscopic images, and to bridge the gap between artificial intelligence research and clinical implementation. A 'segmentation-first, then-classification' strategy was adopted. Lesions were segmented using MFSNet pretrained on dermoscopic images. The classification model was customized from EfficientFormerV2-L by integrating dual attention, multi-scale pooling, and feature fusion modules. A balanced dataset of 934 clinical images (467 melanoma, 467 nevus) from PAD-UFES-20, Seven-Point Check, Med-node, and other sources was used. Weighted BCEWithLogitsLoss (positive weight up to 6) was applied to increase the penalty for false negatives. External validation was performed on 32 smartphone-captured images (16 melanoma, 16 nevus). The model was deployed online with an automated image quality check. The customized model (trained from scratch, positive weight 6) achieved a recall of 0.95, precision of 0.75, and F1 score of 0.84 on cross-validation, outperforming the base EfficientFormerV2-L (recall 0.88). Dermoscopic pretraining unexpectedly degraded classification performance on clinical images. External validation showed significantly higher malignant potential scores for melanoma versus nevus cases (P < 0.0001). The online tool is freely available at http://www.make-a-difference.top/mmscreen. This study provides a practical, high-recall online melanoma screening tool for real-world clinical images. Its free public access and emphasis on minimizing false negatives address critical gaps in early melanoma detection, particularly in primary care settings.
Malignant melanoma has a strong propensity for early metastatic dissemination, yet conventional clinicopathological predictors such as Breslow thickness do not fully capture individual metastatic risk. The endothelial protein C receptor (EPCR) exerts context-dependent functions across malignancies, but its clinical significance in melanoma remains unclear. We retrospectively analyzed primary tumor specimens from 62 patients with invasive melanoma; 61 with complete outcome data formed the analytic cohort for metastasis analyses. EPCR expression in melanoma cells was evaluated by immunohistochemistry using semi-quantitative intensity and extent scores (0-3). Tumor-infiltrating lymphocytes were graded according to the Melanoma Institute Australia scoring system. Higher EPCR expression was associated with lower odds of documented lymph-node and distant metastatic involvement. In prespecified parsimonious multivariable logistic regression models adjusted for tumor thickness and ulceration, higher EPCR extent remained independently associated with reduced lymph-node involvement (adjusted odds ratio: 0.36, 95% confidence interval:, 0.17-0.70). EPCR expression showed a positive association with CD8+ tumor-infiltrating lymphocyte scores. Higher EPCR expression in primary melanoma was independently associated with reduced lymph-node involvement and with a CD8+-inflamed tumor microenvironment, suggesting EPCR may complement conventional pathological predictors of metastatic risk.
Sugar sweetened beverages (SSBs), artificially sweetened beverages (ASBs), and fruit and vegetable juices are consumed worldwide, yet their associations with cancer remain unclear. Within World Cancer Research Fund International's Global Cancer Update Programme (CUP Global), we conducted a systematic review by searching PubMed and Embase until September 2024 for cohort studies of SSBs, ASBs, and juices and cancer risk. Meta-analyses were conducted to calculate the relative risks (RRs) and 95% CIs per 1 serving/day (355 mL for SSBs/ASBs; 177 mL for juices). Evidence was graded by the CUP Global Expert Panel. The CUP Global standard protocol was registered at: https://osf.io/7utbm/ . We identified 158 publications from 51 cohorts. There was evidence of a probable causal positive association for SSBs, including carbonated SSBs, with pancreatic cancer incidence (RR 1.09 [95% CI 1.01-1.16]; I 2 =8%, n=18 studies), and for SSBs with colorectal cancer incidence (RR 1.07 [95% CI 1.00-1.14]; I 2 =41%, n=13). Limited suggestive evidence supported positive associations of SSBs with ovarian (RR 1.61 [95%CI 1.03-2.53]; I 2 =0%, n=2), endometrial (RR 1.21 [95%CI 1.03-1.42]; I 2 =0%, n=3), and postmenopausal breast cancer incidence (RR 1.05 [95%CI 1.00-1.10] ; I 2 =0%, n=6), and of carbonated ASBs with leukaemia incidence (RR 1.29 [95%CI 1.01-1.64]; I 2 =0%, n=2). There was evidence of a probable causal positive association for orange juice with different types of skin cancer including melanoma (RR 1.21 [95%CI 1.08-1.34]; I 2 =0%, n=4), and basal (RR 1.12 [95%CI 1.06-1.17]; I 2 =46%, n=2) and squamous cell carcinoma (RR 1.13 [95%CI 1.04-1.24]; I 2 =0%, n=2). An interactive evidence platform is available at: https://teacup.cc.ic.ac.uk/soft-drinks-cancer.html . This review provides evidence supporting probable causal associations of SSBs with pancreatic and colorectal cancers, and of orange juice with skin cancers, with additional suggestive evidence for SSBs with other obesity-related cancers, extending concerns about sugary drink consumption beyond cardiometabolic health to cancer risk. World Cancer Research Fund network of charities (American Institute for Cancer Research; World Cancer Research Fund; Wereld Kanker Onderzoek Fonds).
Patients who receive a rare cancer diagnosis begin a diagnostic and treatment journey which is complicated by personal fear of the unknown and the reality of a scientific and clinical research community which may not have many insights, options, and definitive answers to enable long-term survival. Patients and families may initially struggle to find clinicians well-informed in the rare cancer and clinical trials of emerging therapies. Patient advocacy groups focused on specific rare cancers have established an important role and point of contact for connecting patients who share the same diagnosis, for sharing experience and perspective along the clinical journey. In this article, a patient diagnosed with uveal melanoma (UM) relates the elements of his unfolding clinical journey and the influence of a unique patient advocacy group impacting his care, decisions, personal advocacy for optimizing his own care, and quest for new and meaningful therapeutic opportunities. This journey is accompanied by a rapid evolution of prognostic analytical and clinical therapeutic research overlapping the same time frame. Key insights along the patient journey identify opportunities for clinicians to more closely observe and resolve acute and late sequelae which significantly impact quality of life after the initial diagnosis and treatment. In this article, a patient with a diagnosis of uveal melanoma recounts their diagnostic and treatment experience over 6 years. The author's insights on clinical interactions and miscues may help inform those involved in cancer research on revolutionary advances in prognostic genomics in a rare disease.
Melanoma is one of the most aggressive forms of cancer in human due to its ability to invade tissues and metastasize. The aim of this work is to examine the effect of our patented compound Prunus spinosa Trigno + Nutraceutical Activator Complex (PsT + NAC®) on primary (WM115), metastatic (WM266-4), and malignant (A375) human melanoma cell lines. The data show that PsT + NAC® induced a dose- and time-dependent reduction in cell viability in all melanoma cell lines, particularly in the metastatic WM266-4. Persistent morphological changes indicative of cell death were observed, which remained irreversible even after the cells recovered from treatment. The treatment with PsT + NAC® altered cell migration and motility by remodeling of actin cytoskeleton. Cell cycle analysis revealed a G2/M phase arrest in the primary WM115 cells, and a G1 phase arrest-at lower concentrations-in the metastatic WM266-4 cells, and in the malignant A375 cells. As the treatment concentration increased, all melanoma cell lines showed an increase in the sub-G1 population, associated with apoptosis. Western blotting analysis revealed that lower concentrations of PsT + NAC® induced a protective autophagic response, while higher concentrations triggered caspase-dependent apoptosis. These results demonstrate the efficacy of PsT + NAC® in inhibiting the growth of BRAF-mutant melanoma cells.
The use of targeted therapies, such as BRAF/MEK inhibitors, has led to a considerable increase in melanoma-specific survival rates; however, prolonged responses remain uneven and uncertain. Moreover, there is a lack of reliable biomarkers that can predict the type and duration of the response. This study aimed to determine whether pTERT mutations affect progression-free survival and overall survival in melanoma patients treated with BRAF/MEK inhibitors. This study employed a retrospective observational design. We included 77 patients with metastatic BRAF (V600) mutated melanoma treated with BRAF/MEK inhibitors. The data analysis included only patients with known pTERT mutation status (WT, -124C>T, -146C>T, and -138_139 CC>TT) and clinical variables collected at two different centers. Progression-free survival and overall survival were determined using Kaplan-Meier curves and Cox regression models. A multivariate analysis with 56-month follow-up suggested a decreased melanoma overall survival with BRAF (V600K) mutation (hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.2-4.0; p = 0.016), the Stage M1c/M1d (HR 3.3; 95% CI 1.7-6.5; p = 0.001), ECOG ≥ 1 (HR 3.6; 95% CI 1.9-6.7; p = 0.001) and not having the -138_139 CC>TT pTERT mutation (HR 3.2; 95% CI 1.0-10.5; p = 0.052). These findings suggest that the tandem -138_139 CC>TT, a less frequent pTERT mutation subtype, may be associated with a trend toward improved prognosis in patients with metastatic melanoma treated with BRAF/MEK inhibitors. However, due to the limited sample size, this study is essentially an exploratory investigation. It requires independent validation with a larger sample to determine the effect of TERT promoter mutations, together with other clinical parameters, on treatment response to BRAF/MEK inhibitors.
Sentinel lymph node (SLN) involvement remains one of the strongest prognostic markers in cutaneous melanoma; however, the SLN is not merely a staging specimen. It is the first organized immune-stromal site exposed to lymph-borne melanoma-derived extracellular vesicles (EVs), soluble mediators, proteins, lipids, and non-coding RNAs (ncRNAs) before and during metastatic seeding. Current evidence supports a model in which melanoma-derived EVs traffic through lymphatic vessels, enter draining nodes, interact with lymphatic endothelial cells, medullary macrophages, dendritic cells, and T cells, and remodel lymphovascular, stromal, and immune compartments. Key vesicle-associated mechanisms include NGFR/p75NTR-positive small extracellular vesicles (sEVs) that drive lymphangiogenesis and nodal metastasis, PD-L1-positive vesicles that suppress T-cell activation, CD36-linked pathways that reshape myeloid lipid metabolism, and uPAR-associated vesicles that promote endothelial and matrix remodeling. EV-associated miRNAs, lncRNAs, and circRNAs may further regulate fibroblast activation, macrophage behavior, MAPK/ERK signaling, PTEN-related stromal restraint, glycolysis, autophagy, and tumor-suppressive pathways. This review integrates clinical SLN biology, lymphatic vesicle trafficking, cargo-specific protein and ncRNA pathways, immune tolerance, stromal remodeling, multi-omic profiling, and therapeutic interception. Comparative evidence from cutaneous squamous cell carcinoma and Merkel cell carcinoma broadens the field, but direct evidence linking lymphatic EVs to SLN remodeling remains strongest in melanoma.
Melanoma treatment has evolved substantially over recent decades, incorporating targeted therapies and immunotherapy alongside conventional approaches such as surgery, chemotherapy, and radiotherapy. Despite these advances, achieving high tumor specificity while minimizing off-target toxicity remains a major clinical challenge. In this context, Cancer-Testis Antigens (CTAs) have emerged as highly promising immunotherapeutic targets due to their predominant expression in malignant cells, strong immunogenicity, and functional involvement in tumor progression and survival. Therefore, this review aims to critically analyze the immunogenic and oncogenic potential of CTAs, synthesize current preclinical and clinical evidence across distinct CTA subfamilies, and highlight innovative CTA-based immunotherapeutic strategies for the treatment of melanoma. Increasing evidence indicates that CTAs play critical roles in maintaining tumor cell viability, genomic stability, and immune evasion, thereby offering unique opportunities for the development of highly specific anticancer therapies. Preclinical and clinical studies evaluating vaccines based on single or multiple CTAs, in combination with chemotherapeutic agents, adoptive T-cell therapies, and immune checkpoint inhibitors have demonstrated encouraging outcomes, particularly involving MAGE (melanoma-associated antigen), New York esophageal squamous cell carcinoma 1 (NY-ESO-1), and preferentially expressed antigen in melanoma (PRAME). Nevertheless, several biological and translational challenges remain. In this scenario, the future success of CTA-based therapies will depend on a deeper understanding of their molecular mechanisms, intratumoral expression heterogeneity, and immunological interactions, as well as on the rational design of combinatorial and personalized therapeutic approaches.
Despite substantial clinical benefit from immune checkpoint inhibitors (ICI), advanced melanoma remains challenging due to frequent treatment resistance. Resistance may be intrinsic (primary) or emerge over time (secondary). Biomarkers predicting distinct resistance phenotypes before therapy are lacking. As key mediators of cellular communication, extracellular vesicles (EVs) represent promising biomarkers. This study aimed to identify baseline EV proteome-derived pathways and biomarkers associated with overall, primary, and secondary resistance to ICI in advanced melanoma and to derive biomarker signatures predictive of progression-free survival (PFS). EVs were isolated from pretreatment plasma samples of 46 patients with advanced melanoma using size exclusion chromatography and ultracentrifugation. Proteomic profiling was performed by liquid chromatography-mass spectrometry using DIA-NN. Pathway enrichment and network analyses were conducted using Reactome, Metascape, Cytoscape, and DAVID. Resistance-associated proteins were integrated into composite biomarker signatures and evaluated for association with PFS. Overall resistance was characterized by enrichment of platelet- and complement-associated pathways. Primary resistance was associated with enhanced Fc gamma receptor (FCGR) signaling and downregulation of KSRP-associated post-transcriptional regulatory processes. In contrast, secondary resistance was preceded by distinct baseline EV proteomic patterns involving complement activation and reduced hemostasis- and platelet-related pathways. EV-derived biomarker signatures for overall, primary, and secondary resistance independently discriminated patients according to PFS. Baseline plasma EV proteomics reveals distinct systemic biological programs associated with different resistance phenotypes to ICI in advanced melanoma. EV-derived biomarker signatures enable stratification by PFS and warrant validation in larger, multicentric cohorts.
Non-Melanoma Skin Cancer (NMSC) arises from oxidative stress induced by ultraviolet (UV) radiation, ongoing inflammation, and genetic mutations that promote cell growth. Mainstream treatment often faces challenges of recurrence and toxicity, highlighting the necessity for more targeted therapies. Incorporation of multiple drugs with advanced nanotechnology appears to emerge as a promising therapeutic approach. This review analyses the effectiveness of multifactorial interventions for NMSC, addresses limitations with traditional treatments, highlighting how advanced technologies can overcome these challenges. The literature search was conducted through trusted databases to identify the included studies for systematically categorization, mechanistic understanding, formulation innovations and traditional relevance. This article examines the progress in nanogel-based systems for NMSC treatment over decades, emphasizing their adaptable design, stimulus responsiveness, and targeted drug delivery. These features enhance treatment effectiveness while reducing overall toxicity. It discusses a delivery system incorporating combinations of synthetic drugs and plant-derived compounds by means of nanogel as a carrier, demonstrating synergistic anti-tumor effects and improved safety profiles, making the treatment more potent, effective, and comprehensive. Despite positive outcomes in preclinical studies, significant translational challenges persist in formulation development and manufacturing, including drug-excipient compatibility, stability, reproducibility, scalability of nanogels and meeting regulatory standards. Non-Melanoma Skin Cancer (NMSC) is the most common type of cancer worldwide, typically caused by sun damage, long-term skin inflammation, and genetic mutations. While standard treatments exist, they often come with harsh side effects and a high risk of the cancer returning, which has led scientist to develop a smarter approach using ‘nanogels.’ These are microscopic, flexible smart carriers that carry cancer medication directly to a tumor, releasing the medicine only when they detect specific environmental triggers in the cancer cells, like change in temperature. By delivering the drugs in combination, precisely where they are needed, nanogels can safely combine standard medical treatments with natural, plant derived compounds to aggressively fight the cancer while shielding the rest of the body from the toxic side effects. While this holistic approach has shown incredible promise in laboratory testing, researchers are still working through the engineering hurdles of manufacturing and regulatory of these nanogels safety, consistency, and on a large scale before they can be used in every medical clinic.
Uveal melanoma (UM) is a biologically distinct melanoma subtype in which excellent local tumor control contrasts sharply with a high risk of delayed metastases. The frequent occurrence of distant relapse months to years after index local therapy suggests systemic dissemination early in the disease course. Inadvertently, many patients harbor minimal residual disease (MRD), comprising microscopic tumor cell populations that persist after primary tumor treatment and are undetectable by conventional imaging techniques. Historically, UM management has focused on local tumor eradication followed by surveillance, however, better understanding of the clinical trajectory of UM coupled with advances in systemic therapeutics have generated increasing interest in perioperative systemic approaches. Neoadjuvant therapy provides the opportunity to downsize the primary tumor, eliminate occult micrometastatic disease, dynamically evaluate disease biology, and inform further therapeutic decision-making. Adjuvant approaches aim to suppress or eradicate MRD following local control in patients at elevated risk of relapse. Although current evidence remains investigational or early-phase, perioperative systemic therapy represents an important research frontier in UM that holds the potential to reshape its therapeutic paradigm. Herein, we comprehensively synthesize the biological rationale, the latest data, and the ongoing clinical trials supporting perioperative systemic therapy, and discuss the emerging role of circulating tumor DNA (ctDNA) in the management of UM.
Germline genetic testing is increasingly incorporated into the care of patients with uveal melanoma, yet optimal testing strategies remain unclear. This study aimed to evaluate the outcome of germline clinical genetic testing in uveal melanoma (UM) patients who met the National Comprehensive Cancer Network (NCCN) guidelines for genetic testing. A retrospective chart review was conducted on UM patients seen in The Ohio State University Cancer Genetics Clinic between 5/1/2021 and 9/19/2025. Seventy individuals underwent clinical genetic testing, primarily via large multigene panels. Ten UM patients, including two related individuals, had pathogenic or likely pathogenic (P/LP) variants in known cancer genes (BAP1, BRCA1, BRCA2, MBD4, MUTYH, POT1, XRCC2). Among unrelated individuals, the positive rate was 13% (8/69). Excluding carrier genes, the rate was 10.1% (7/69). Eight patients would have been missed if only tested for BAP1 per American Society of Clinical Oncology (ASCO) 2024 recommendations. There was no association between tumor size, stage, and germline P/LP variants. In summary, NCCN guidelines are useful in the prioritization of UM patients for genetic testing. Additionally, these findings support genetic counseling for multigene panel testing in high-risk uveal melanoma patients. Further studies of the impact of germline variants on UM disease outcome are warranted.
Immune checkpoint inhibitors have transformed melanoma management; however, immune-related adverse events (irAEs) remain a major source of morbidity. Soluble immunomodulatory proteins are established biomarkers of autoimmune reactivity but have not been validated as predictors of irAEs. Evaluating their associations with irAEs may help identify patients at elevated risk and inform optimization of adjuvant checkpoint inhibitor therapy. Baseline serum samples from patients with resectable melanoma receiving adjuvant anti-programmed-death-1 therapy were obtained from the University of Pittsburgh Melanoma Center biospecimen repository (n = 43). Soluble immunomodulatory proteins were quantified using Milliplex technology. Mean pretreatment protein levels were compared between patients with and without irAEs using two-sample t-tests. Siglec-7 and Siglec-9 were elevated in patients who developed any irAE. Dermatitis was associated with elevated B7-H3 and major histocompatibility complex class I polypeptides. Thyroiditis was associated with elevated Nectin-4 and CXCL13 and reduced LAG3. Colitis was associated with elevated arginase. Hepatitis was associated with increased Galectin-3 and decreased Galectin-1, CD40L, CD226, and Nectin-4. Nectin-4 remained significant after false discovery rate adjustment in both thyroiditis and hepatitis, and CD226 remained significant in hepatitis. Potential biomarkers of recurrence-free survival (perforin, CD25, and ICOSL) and overall survival (FGL1) were also identified. Baseline soluble immunomodulatory proteins may predict the development of specific irAEs and survival outcomes from adjuvant anti-programmed-death-1 treatment. Notably, Nectin-4 may serve as a biomarker for both thyroiditis and hepatitis. Prospective studies are warranted to validate these findings.
By comparing conventional ultrasonography (US) and contrast-enhanced ultrasonography (CEUS) features of liver metastases of melanoma (LMM) with those of other common liver metastases from non-melanoma malignancies (non-LMM), a differential diagnosis nomogram was developed and internally validated to explore its clinical application value. This single-center, retrospective, case-control study enrolled 108 patients with LMM (109 lesions) and 95 patients with non-LMM (109 lesions) at our institution from January 2017 to April 2025. All cases were confirmed by pathological diagnosis. Univariate analysis was performed to compare clinical characteristics and US/CEUS features between groups. Variables with P < 0.05 were entered into a stepwise bidirectional regression model (based on the Akaike information criterion (AIC)) to identify independent risk factors and assess collinearity (using variance inflation factor (VIF)). A nomogram was developed using logistic regression and generalized estimating equations (GEE) and evaluated by the area under the receiver operating characteristic curve (AUC-ROC), bootstrapping (1000 resamples), calibration curves, and decision curve analysis (DCA). The independent risk factors included in the nomogram model were morphology, posterior acoustic enhancement, number, enhancement pattern and wash-out time. The model demonstrated an AUC of 0.892 (95% CI: 0.849-0.935) and a bias-corrected AUC of 0.873 (95% CI: 0.805-0.933) by bootstrapping. Both calibration curves and DCA demonstrated the nomogram's favorable calibration and clinical utility (Hosmer-Lemeshow test, P > 0.05). The LMM differential diagnosis nomogram based on US/CEUS features complements clinical screening and facilitates precise diagnosis while aiding in subsequent treatment evaluation and follow-up.
Ectopic adrenal tissue is usually found in well-described locations, mainly along the embryological pathway of the adrenal glands. In some cases, fragments of this tissue are found in non-physiological anatomical locations. This discovery, often made by chance, raises questions about these abnormal locations and prompts discussion of etiopathological hypotheses, considering the literature. A 71-year-old man presented with an unclassifiable acral invasive melanoma, according to Clark's staging system, located in the third interdigital space of the right foot. The patient underwent surgical excision consisting of amputation of the fourth toe with 2 cm margins, followed by the removal of right inguinal sentinel lymph nodes for histological and immunohistochemical evaluation. During this evaluation, ectopic adrenal tissue was identified in the periganglionic fat. This case reports the rare discovery of ectopic adrenal tissue during a sentinel lymph node procedure. Although such findings are uncommon, they emphasize the importance of considering embryological migration anomalies in differential diagnoses. Recognizing these benign adrenal rests is crucial to avoid misinterpretation, particularly in oncologic settings such as melanoma. Awareness of ectopic adrenal tissue is essential to prevent diagnostic errors and unnecessary concern about metastasis during oncologic surgical procedures.
Cutaneous malignant melanoma is a highly aggressive skin cancer with poor prognosis. Although microRNA (miRNA)-based gene therapy shows promise, its clinical translation is limited by rapid degradation in serum and the barrier function of the stratum corneum. Herein, we engineer a programmable, targeted, and non-invasive nanoplatform, termed MARS (MUC1-Aptamer-functionalized, tetrahedral framework nucleic acid-based miRNA delivery system for gene Silencing). The therapeutic miR-30a-5p is encapsulated within a self-assembled DNA tetrahedron, an architecture that confers exceptional structural stability. The framework is specifically functionalized with an MUC1 aptamer to act as a navigator for active tumor targeting while simultaneously carrying the gene-silencing payload. In vitro assays demonstrate that MARS successfully delivers miR-30a-5p into A375 cells, effectively silencing the transcription factor E2F7 and subsequently triggering the intrinsic apoptotic pathway. Importantly, in vivo studies using a xenograft mouse model reveal that topically applied MARS can penetrate the skin barrier and accumulate in tumor tissues, achieving a tumor growth inhibition rate of 66.86%, comparable to intravenous anti-PD-L1 immunotherapy but with superior safety, compliance, and cost-effectiveness. This study presents MARS as a robust strategy that integrates stability, programmable dual-functionality (targeting and gene silencing), and non-invasive transdermal capabilities, providing a promising strategy for localized melanoma treatment.
Neoadjuvant immune checkpoint inhibition (ICI) has demonstrated high pathological response rates in resectable stage III melanoma and is increasingly used for selected patients with low-volume stage IV disease. However, the surgical and perioperative implications remain incompletely defined. A systematic review and meta-analysis were performed to evaluate oncologic, surgical, and immune-related outcomes following neoadjuvant ICI and curative-intent surgery. MEDLINE, EMBASE, and the Cochrane Library, were systemically searched for both prospective and retrospective studies including adults with resectable stage III or oligometastatic stage IV melanoma treated with neoadjuvant ICI followed by planned surgery. Outcomes included pathological response, recurrence, failure or delay to surgery, perioperative complications, and treatment-related adverse events. Pooled estimates were calculated using random-effects meta-analyses. A total of 20 studies comprising 1384 patients were included. The pooled proportions of pathological complete response were 0.33 (CI 0.26-0.40), major pathological response 0.46 (CI 0.38-0.54), and overall pathological response 0.59 (CI 0.51-0.67). Pathological nonresponse occurred in 0.30 (CI 0.25-0.36). Failure or delay to surgery occurred in 0.09 (CI 0.07-0.12), with disease progression during neoadjuvant therapy reported in 0.06 (CI 0.04-0.10). Major perioperative complications (Clavien-Dindo ≥ III) occurred in 0.08 (CI 0.05-0.13), while major treatment-related toxicities (CTCAE grade ≥ III) occurred in 0.25 (CI 0.18-0.34). Comparative analyses demonstrated similar perioperative complication rates between neoadjuvant and adjuvant approaches, with lower recurrence risk favoring neoadjuvant therapy (p < 0.01). Neoadjuvant ICI produces substantial pathological responses while preserving surgical feasibility in resectable stage III and selected stage IV melanoma. Operative morbidity appears acceptable; however, systemic toxicity is common, and perioperative reporting remains heterogeneous.