Search Results (1,101)

Background/Objectives: Thymidylate synthase (TYMS) represents an important therapeutic target. Methods: In this study, TYMS expression was analyzed by immunohistochemistry on a tissue microarray containing 17,371 samples from 136 different tumor types. Results: TYMS staining was seen in 42.9% of 15,361 analyzable tumors, with weak staining in 35.4%, moderate in 5.7%, and strong in 1.8%. TYMS occurred in at least one case of 127 categories, of which 71 showed TYMS staining in at least 50% of cases, and 56 included at least one case with strong positivity. TYMS positivity occurred most commonly in lymphomas (81.3–96.5%), sarcomas and sarcomatoid carcinomas (33.3–100%), malignant melanoma (70.5–90.7%), cervical adenocarcinoma (78.3%), and squamous cell carcinomas of various sites (57.1–77.9%). High TYMS expression was linked to advanced pT (p = 0.0097), high grade (p < 0.0001), ER negativity (p < 0.0001), and PR negativity (p = 0.0002) in invasive breast cancer of no special type; high grade (p < 0.0050), high UICC stage (p = 0.0060), and nodal metastasis (p = 0.0120) in clear cell renal cell carcinoma (RCC); high grade (p < 0.05) and nodal metastasis (p = 0.0045) in papillary RCC; high Gleason grade (p < 0.0001) and advanced pT stage (p = 0.0149) in prostatic adenocarcinoma; high pT (p < 0.0001), nodal metastasis (p = 0.005), lymphatic (p = 0.0064) and venous invasion (p = 0.0005), left side location (p < 0.0001), and microsatellite instability (p < 0.0001) in colorectal adenocarcinoma; and high grade (p < 0.0001) in squamous cell carcinomas of different sites. Conclusions: TYMS is often overexpressed across different cancer entities and shows associations with several adverse histopathological parameters commonly used to describe tumor phenotypes. Full article

Background and Objectives: Systemic inflammation contributes to melanoma progression, yet the prognostic value of routinely available inflammatory ratios remains insufficiently characterized in real-world cohorts. We evaluated whether pre-treatment neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are independently associated with sentinel lymph node (SLN) positivity, histopathologic aggressiveness, and recurrence-free survival (RFS) in primary cutaneous melanoma. Methods: In this single-center, retrospective, exploratory, observational cohort, 87 adults with histologically confirmed primary cutaneous melanoma were stratified by pre-treatment NLR using a cut-off of 3.0 into low-NLR (n = 47) and high-NLR (n = 40) groups. Outcomes included Breslow thickness, ulceration, mitotic rate, AJCC stage, SLN status, and RFS over a median follow-up of 38.4 months. Discrimination was assessed by receiver operating characteristic (ROC) analysis, time-to-event endpoints by Kaplan–Meier and Cox proportional-hazards modelling, and SLN positivity by multivariable logistic regression. Results: High-NLR patients had thicker (median 2.1 vs. 0.8 mm, p < 0.001), more frequently ulcerated (42.5% vs. 12.8%, p = 0.003), and more advanced melanomas (early stage 27.5% vs. 68.1%, p < 0.001). SLN positivity among biopsied patients was 35.5% vs. 8.7% (p = 0.027). For RFS, NLR ≥ 3.0 carried a univariable hazard ratio (HR) of 4.32 (95% CI 1.60–11.67) and remained independently prognostic after multivariable adjustment (adjusted HR 2.87, 95% CI 1.04–7.92, p = 0.042). An NLR + PLR composite outperformed Breslow thickness for predicting SLN positivity (AUC 0.829 vs. 0.702, DeLong p = 0.041). Conclusions: In this exploratory, single-center retrospective cohort, pre-treatment NLR and PLR were inexpensive, widely available biomarkers that were associated with prognostically relevant melanoma features and outcomes. These hypothesis-generating findings suggest that inflammatory ratios could complement conventional histopathologic predictors, but they were derived and tested within a single small cohort without independent validation and require confirmation in larger, prospective, multi-center studies before any clinical application. Full article

Background/Objectives: Metastases from cutaneous malignancies to the female genital tract and pelvic lymph nodes are rare clinical entities that frequently masquerade as primary gynecologic tumors, leading to significant diagnostic challenges. The distinction between primary and metastatic disease is critical, yet complex, given the varying patterns of spread exhibited by different skin cancers. This study aims to provide a tumor-specific overview of these metastatic patterns to guide diagnosis and therapy. Methods: We conducted a narrative review informed by a systematic literature search of MEDLINE/PubMed, Embase, Scopus, and Web of Science for records regarding primary cutaneous melanoma, cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), Merkel cell carcinoma (MCC), and cutaneous lymphomas metastasizing to the female genital tract (FGT) or pelvic lymph nodes. Data were synthesized qualitatively to identify organotropic patterns, diagnostic pitfalls, and management outcomes across these distinct malignancies. Results: The analysis reveals distinct metastatic niches: cutaneous melanoma shows a predilection for the ovary, often mimicking epithelial ovarian carcinoma, whereas cSCC and MCC typically involve pelvic lymph nodes via contiguous spread from inguinal basins. Histologic evaluation with broad immunohistochemical panels is mandatory to confirm the diagnosis, as imaging alone lacks specificity. Crucially, the introduction of immune checkpoint inhibitors and targeted therapies has significantly improved survival in advanced melanoma, cSCC, and MCC, altering the role of pelvic surgery. Conclusions: Management of cutaneous malignancies metastatic to the pelvis is shifting from a focus on radical surgery to a systemic-first approach. Pelvic metastasectomy should be reserved for selected oligometastatic cases or symptom control within a multidisciplinary framework. Clinicians must maintain a high index of suspicion in patients with a history of skin cancer to avoid overtreatment and optimize quality of life. Full article

Background and Clinical Significance: Malignant melanoma with primary or metastatic intestinal involvement is a rare entity, often diagnosed late and associated with severe complications such as bowel obstruction and perforation. Differential diagnosis of primary intestinal lymphoma may be challenging in the absence of an identifiable primary lesion. Case Presentation: We report the case of a 35-year-old male with no significant medical history who was admitted for persistent abdominal symptoms. Contrast-enhanced abdominal CT revealed a giant circumferential jejunal mass (109/147/156 mm) causing marked luminal stenosis and mesenteric lymphadenopathy, initially raising suspicion of primary intestinal lymphoma. The patient subsequently developed upper intestinal obstruction and severe anemia (Hb 5.5 g/dL), requiring an emergency exploratory laparotomy. Intraoperatively, a voluminous unresectable tumor extending to the mesenteric root was identified, and a feeding jejunostomy was performed. The postoperative course was complicated by tumor perforation and generalized peritonitis, necessitating reoperation. Histopathological examination established the diagnosis of malignant melanoma, with no identifiable primary site, which is most consistent with metastatic melanoma (MUP). PET-CT staging demonstrated metastatic disease (mesenteric, retroperitoneal and supraclavicular lymph nodes, as well as subcutaneous nodules), consistent with a stage IV disease. Molecular analysis revealed a BRAF V600E mutation. Combined immunotherapy (Nivolumab + Ipilimumab) was initiated, resulting in a partial radiological response after three cycles. Conclusions: Intestinal involvement by malignant melanoma might mimic other gastrointestinal malignancies and be the cause of a delayed diagnosis and severe surgical complications. Multidisciplinary management is essential, and modern immunotherapy offers promising outcomes even in advanced-stage disease. Full article

In patients with advanced or metastatic melanoma; BRAF mutation assessment is routinely performed to identify patients who may benefit from BRAF-targeted therapy. This study aimed to assess the role of BRAF mutation status in relation to histopathological characteristics and survival of patients with stage II and III malignant melanoma. A prospective cohort of 108 patients with pT3 malignant melanoma who were treated in a comprehensive cancer center were included in the analysis. All patients were treated according to contemporary melanoma management guidelines between 2016 and 2024, with a minimum follow-up of 12 months extending to 2025. Overall survival (OS) and progression-free survival (PFS) analyses were performed in the study cohort. The study included 108 patients with stage II–III malignant melanoma, with a mean age of 56.73 ± 13.51 years. Superficial spreading melanoma was the most frequent histological subtype, followed by nodular and acral melanoma. Most tumors were classified as Clark level IV, with a median Breslow thickness of 3 mm, and ulceration was present in the majority of cases. Lymph node involvement was observed in over half of the patients, and BRAF mutations were identified in 56.48% of cases (the most common variant was V600E). Brisk tumor-infiltrating lymphocytes were significantly more frequent in BRAF wild-type tumors compared with BRAF-mutant tumors. When assessing associations with survival, BRAF mutation status was not found to be an independent predictor. In the multivariate Cox model, TIL status was associated with improved OS (HR 3.33, 95% CI 1.41–7.88, p = 0.006). In addition, in the multivariate analysis, TIL status was also associated with improved PFS (HR 5.23, 95% CI 2.22–12.3, p < 0.001). BRAF wild-type tumors were significantly more likely to exhibit a brisk infiltrate. BRAF mutation status was not found to be an independent predictor of survival. TIL status remained significantly associated with OS and PFS in multivariable analysis. Full article

Melanoma remains a major global health burden, though immunotherapy and targeted therapy have markedly improved survival. Obesity has paradoxically been associated with favorable outcomes in melanoma, yet body mass index (BMI) alone fails to capture its influence on treatment response. To address this gap, we conducted a multi-site cohort study within the Canadian Melanoma Research Network, including patients with advanced melanoma treated with immunotherapy or targeted therapy. Body composition was quantified using computerized tomography (CT) imaging to assess visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), skeletal muscle (SM) mass and intermuscular adipose tissue (IMAT), and associations with progression-free survival (PFS) and overall survival (OS) were evaluated. No overall association was seen for BMI, SAT, VAT, IMAT or SM with PFS or OS. In the targeted therapy subset, higher BMI, SAT, VAT and SM were associated with better OS (hazard ratios 0.56 to 0.65), while no effect was seen in the immunotherapy group. IMAT emerged as a novel prognostic marker, with elevated levels associated with lower OS in males and better OS in females. Our findings show that CT-based body composition is not associated with survival outcomes in patients with advanced melanoma receiving immunotherapy. Full article

Background: Melanoma incidence is rising rapidly worldwide and stands out due to its high lethality. Despite advances in clinical treatment and in understanding melanoma-sensitive genes and molecular pathogenesis, a specific area of ongoing research is the connection between stress-related β-adrenergic receptors (ARs), hypoxia, and neovascularization in melanoma tumor progression. This exploratory study aimed to investigate the expression of β3-AR, HIF-1α, and CD31 in several cellular subsets of atypical melanocytic lesions and their interplay in promoting melanoma malignancy. Methods: Twenty-seven patients with melanocytic lesions at different stages that were surgically removed were retrospectively selected; clinical-pathological and dermoscopic data were collected. Results: Immunohistochemical and digital evaluation revealed a significant upregulation of β3-AR in malignant melanoma melanocytes and in macrophages from invasive >pT1a melanomas compared to dysplastic nevi. Increased HIF-1α expression in malignant melanocytes and CD31 expression levels in >pT1a melanomas were observed. Ulcerated lesions exhibited a higher percentage of β3-AR, HIF-1α, and CD31 expression. Pearson correlation analysis revealed positive associations among these markers in human malignant melanoma, suggesting a potential relationship between adrenergic signaling, hypoxia, and tumor vascularization. Conclusions: These exploratory findings suggest that β3-AR, HIF-1α, and CD31 may represent interconnected components of the melanoma microenvironment. Unraveling these interactions in larger, independent cohorts and functional studies may provide additional insights into melanoma biology and help define their potential translational relevance. Full article

Background and Clinical Significance: Cutaneous squamous cell carcinoma (CSCC) is a common non-melanoma skin cancer, and while most cases are curable, a small proportion progresses to locally advanced or metastatic disease. As neoadjuvant immunotherapy with PD-1 inhibitors such as cemiplimab becomes more widely adopted, understanding real-world patterns of response remains essential. Case Presentation: We report a case of a man in his 50s with a large, locally advanced CSCC of the left hand in whom neoadjuvant cemiplimab was chosen to reduce tumor burden and preserve hand function when margin-negative resection was unlikely. The patient received four cycles of cemiplimab and demonstrated marked clinical improvement followed by complete pathological response at the primary site upon wide local excision. However, metastatic involvement of the epitrochlear and axillary lymph nodes was identified at surgery despite initial benign imaging. Postoperative PET/CT showed no additional disease, and the patient subsequently underwent axillary dissection and adjuvant cemiplimab with good functional recovery. Conclusions: This case highlights the potential for neoadjuvant cemiplimab to achieve substantial local tumor control and functional preservation while emphasizing the need for careful nodal assessment and ongoing surveillance in patients with very-high-risk CSCC. In cases where baseline cross-sectional staging is not performed, pre-existing occult nodal disease cannot be excluded. Full article

The rapid advancement of machine learning and artificial intelligence (AI) has created new opportunities to enhance diagnostic accuracy in dermatology, particularly within primary care settings. Computer-aided diagnosis (CAD) systems have demonstrated potential to support General Practitioners (GPs) by enabling earlier and more consistent identification of skin diseases. This review critically examines the literature on explainable artificial intelligence (XAI) for skin disease classification, with a specific focus on the evolution of explainability frameworks and the methodological implications of dataset selection. A comprehensive review of studies published between 2020 and 2025 was conducted across multiple academic databases, encompassing research on skin lesion detection, classification, and monitoring. The analysis reveals that deep learning architectures, particularly those leveraging transfer learning with models such as EfficientNet, ResNet, and Xception, frequently report high classification accuracies—often exceeding 90% when evaluated on single benchmark datasets. However, studies employing multiple datasets consistently demonstrate more stable and generalisable performance, albeit with modest reductions in reported accuracy, highlighting a critical trade-off between performance optimisation and real-world robustness. The review further identifies a clear temporal progression in the adoption of XAI techniques. Early studies relied on a broader range of post hoc explainability while later work increasingly consolidated around Grad-CAM, SHAP, and related attribution techniques, followed by gradual diversification into more specialised frameworks such as TCAVs (Testing with Concept Activation Vectors) and Prototype-based Networks. Despite these advances, the lack of clinically grounded explanations, limited integration of ethical considerations, and reliance on non-clinical imagery continue to constrain clinical applicability which we have explored using a GRADE-style narrative. Notably, evidence suggests that CAD systems can improve GP diagnostic accuracy for conditions such as melanoma and seborrhoeic keratosis; however, sustained clinical adoption remains contingent on transparent, reliable, and context-aware explainability mechanisms. Full article

Cutaneous Melanoma is a biologically heterogeneous malignancy. Although recent therapeutic advances have improved survival, durable remissions remain elusive for many patients. Surgical excision with stage-appropriate margins and selective nodal staging remains the cornerstone of curative-intent management. In contrast, conventional cytotoxic chemotherapy now plays a limited, largely palliative role given its modest efficacy and substantial toxicity. Targeted therapy with BRAF/MEK inhibitors has improved outcomes in patients with BRAF V600-mutant melanoma, resulting in rapid tumor regression and meaningful survival benefits. However, long-term disease control is frequently compromised by adaptive resistance, commonly driven by MAPK pathway reactivation or compensatory PI3K/AKT signaling. In parallel, immune checkpoint inhibitors targeting PD-1, CTLA-4, and emerging pathways have reshaped treatment across disease stages, enabling deep and sometimes durable responses. Despite this progress, primary and acquired resistance, as well as acute and chronic immune-related toxicities, continue to pose significant clinical challenges. Current therapeutic strategies focus on rational combinations of targeted therapy, checkpoint blockade, IL-2-based approaches, oncolytic viruses, and adoptive cell therapies such as tumor-infiltrating lymphocytes to enhance response depth and durability. However, these intensified regimens carry increased toxicity risks, highlighting the need for improved patient selection and monitoring. Overall, emerging evidence supports a paradigm shift toward optimized treatment sequencing, response-adapted surgical strategies, and biomarker-guided personalization to maximize clinical benefit while minimizing toxicity. Full article

Usnic acid (UA), a prominent lichen secondary metabolite, exhibits a unique dual therapeutic profile in dermatology, though its clinical translation is limited by systemic hepatotoxicity and poor solubility. This review comprehensively evaluates the topical efficacy, molecular mechanisms, and advanced formulation strategies of UA enantiomers and UA-rich extracts. A literature search across PubMed, Scopus, and Google Scholar identified 36 original publications focusing on anti-melanoma activity, photoprotection, and tissue regeneration. In vitro studies demonstrate that UA induces apoptosis in resistant melanoma cell lines (A375, HTB-140) via extrinsic/intrinsic pathways, with (−)-UA effectively overcoming doxorubicin resistance. Conversely, in non-cancerous models, low concentrations of UA accelerate wound and burn healing by upregulating vascular endothelial growth factor (VEGF), stimulating fibroblast proliferation, and optimizing extracellular matrix remodeling while preventing hypertrophic scarring. To mitigate skin sensitization and systemic risks, advanced drug delivery systems—including liposomes, nanoemulsions, chitosan nanogels, and electrospun scaffolds—have been developed, significantly enhancing skin permeability and localized dermal retention. Ultimately, the development of bio-functionalized smart dressings and targeted nano-formulations represents the most viable path toward unlocking the full clinical potential of UA in modern dermatological and oncological care. Full article

Immunotherapy has transformed cancer treatment; however, clinical benefit remains limited to a subset of patients, underscoring the need for robust biomarkers that capture tumor-immune interactions across cancer types. In this study, we performed a comprehensive pan-cancer, multi-omics characterization of the immune checkpoint–related molecules CD70, CD80, and TIGIT to evaluate their diagnostic, prognostic, and immunological relevance. Using integrative analyses of transcriptomic, epigenomic, genomic, pharmacogenomic, and single-cell RNA-sequencing data from The Cancer Genome Atlas and complementary resources, we assessed expression patterns, DNA methylation, somatic mutations, copy number alterations, immune infiltration, tumor stemness, and drug sensitivity. CD70, CD80, and TIGIT were broadly dysregulated across multiple malignancies, with coordinated overexpression particularly evident in kidney renal clear-cell carcinoma. Elevated expression of these immune checkpoints was associated with advanced tumor stage, aggressive molecular subtypes, and unfavorable survival outcomes in selected cancers, including uveal melanoma and renal malignancies. Functional analyses revealed significant associations between checkpoint expression and key oncogenic pathways, including epithelial–mesenchymal transition, apoptosis, and hormone receptor signaling, suggesting links with tumor progression and immune activation states. Immune deconvolution analyses indicated that TIGIT expression is associated with a T-cell–inflamed microenvironment and reduced neutrophil infiltration, while CD80 exhibited methylation-dependent associations with immune cell composition. Genomic and epigenetic alterations were found to correlate with checkpoint expression patterns and immune phenotypes across tumor types. Pharmacogenomic profiling identified associations between checkpoint expression and sensitivity to multiple anticancer agents; however, these findings are based on cell line datasets and should be considered predictive. Single-cell transcriptomic analyses further resolved cell-type–specific expression patterns, distinguishing tumor-intrinsic from immune-restricted expression profiles. Collectively, our findings establish CD70, CD80, and TIGIT as integrative biomarkers of tumor progression, immune contexture, and therapeutic response, providing a rationale for their clinical exploitation in precision immuno-oncology. Full article

Background/Objectives: Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer with a 40% recurrence rate. However, reliable biomarkers for early recurrence detection or treatment guidance are lacking, especially for virus-negative tumors. Circulating tumor DNA (ctDNA), a fragment of tumor-derived cell-free DNA in blood, has emerged across multiple cancers as a minimally invasive precision biomarker to detect minimal residual disease (MRD); predict recurrence; and monitor treatment response. This review’s objective was to summarize recent advances in ctDNA as a tool for therapeutic decision-making in MCC, contextualized by findings in other malignancies. Methods: A comprehensive literature review was performed, focusing on studies published between 2016 and 2026 that evaluate ctDNA in MCC and other cancers. Key prospective trials, observational studies, and case reports were identified through PubMed and relevant conference proceedings. Data on ctDNA assay methods (tumor-informed vs. tumor-agnostic), clinical sensitivity, lead time for recurrence detection, and predictive value for therapy response were extracted and synthesized. Results: Across cancers such as colorectal, lung, and melanoma, ctDNA positivity after curative treatment predicts relapse months in advance of imaging and can guide adjuvant therapy decisions. In MCC, recent studies demonstrate that ctDNA levels correlate with MCC tumor burden and exhibit high sensitivity and specificity for clinically evident disease. Stage I-III MCC patients who were ctDNA-positive within four months of treatment had a 7.4-fold higher recurrence risk within the subsequent 12–18 months of follow-up. Serial ctDNA monitoring may enable earlier intervention in otherwise asymptomatic ctDNA-positive MCC cases, helping distinguish responders from non-responders. Conclusions: ctDNA is an emerging precision biomarker that offers significant prognostic and surveillance utility in MCC. It enables earlier detection of recurrence, potentially allowing treatment to begin before clinical disease manifests. It also helps stratify patients by risk and treatment response, informing personalized surveillance intensity and therapeutic choices. Integrating ctDNA monitoring into MCC management could improve outcomes by guiding timely interventions, although prospective trials are needed to confirm that ctDNA-guided decisions translate to improved patient survival. Formal cost-effectiveness analyses have not yet been conducted and represent an important area for future investigation. Full article

Melanoma incidence rates have also been steadily increasing, emphasizing the need for improved prognostic and diagnostic tools with the goal of enhancing patients’ outcomes. Biomarkers in melanoma have emerged as an important component of melanoma management, offering insight into disease progression, tumor biology, and the potential for judging treatment responses. Traditionally, blood and immunohistochemical markers such as lactate dehydrogenase (LDH), S100 calcium-binding protein (S100B), human melanoma black-45 (HMB-45), and SRY-box transcription factor 10 (SOX10) have been widely used in melanoma diagnosis, staging, and monitoring. However, their clinical use has been limited because of their low specificity, especially in patients with early-stage disease. This has led to the development of molecular and genetic biomarkers, including BRAF, NRAS, and KIT mutations, which improved patients’ risk stratification and enabled targeted therapies, and gene expression signature assays such as DecisionDx (Castle Biosciences) and SkylineDx (Merlin) that are already used in clinics to help with surgical decisions and to assess patients’ prognosis. Other circulating biomarkers, including microRNAs, circulating tumor DNA and circulating tumor cells, have been developed to provide minimally invasive approaches to monitor tumor evolution and detect recurrence. However, none of these new approaches are used in clinics due to their low specificity and/or sensitivity. Additionally, nomograms or predictive models have been created using biomarkers and clinicopathologic data to assess patients’ outcomes and survival. While significant progress has been made, the integration of melanoma biomarkers into routine clinical practice remains limited. This review summarizes current advancements in melanoma biomarkers, including traditional serum and immunohistochemical markers, as well as developments in molecular, genetic, circulating, and predictive biomarker approaches. Full article

Cutaneous squamous cell carcinoma (cSCC) is one of the most common non-melanoma skin cancers worldwide. Although surgery and adjuvant therapies are often effective, the treatment of high-risk or advanced lesions remains challenging due to recurrence, resistance, toxicity, and limited long-term control. Natural compounds have, therefore, gained interest as multi-target agents for cancer prevention and treatment. This systematic review aimed to evaluate the antitumoral activity of natural compounds against cSCC. A systematic literature search was conducted following PRISMA 2020 guidelines. Sixty studies met the inclusion criteria and were analyzed using a conservative, mechanism-based classification framework. The included studies evaluated purified compounds, crude extracts, essential oils, formulations, and combination treatments. Despite chemical diversity, antitumoral activity converged on defined biological processes, including apoptosis, non-apoptotic regulated cell death, redox modulation, oncogenic signaling inhibition, cell-cycle arrest, epigenetic regulation, photodynamic ROS generation, and chemopreventive or immune-mediated mechanisms. Mechanistic specificity was higher among purified compounds, while complex extracts showed broader, context-dependent effects. Several agents demonstrated consistent in vitro and in vivo activity, which supports their translational relevance. Natural compounds target shared biological vulnerabilities in cSCC through mechanistically convergent pathways. The framework presented here supports mechanism-guided prioritization and may facilitate the translation of promising compounds into clinically relevant strategies. Full article