Search Results (7,084)

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

Aim: This study aimed to identify the clinical and pathological features of primary cutaneous melanomas in young patients, comparing them with those of older patients. Materials and Methods: We performed a retrospective study observing the differences with respect to clinical and pathological features in young patients versus older patients. We distributed the cases into two groups: patients < 40 years diagnosed with cutaneous melanoma and patients ≥ 40 years diagnosed with cutaneous melanoma. Results: From the total number of primary cutaneous melanomas diagnosed, 11% of cases were represented by young patients. The clinical and pathological features more frequently associated with cutaneous melanomas in AYAs (adolescents and young adults) were represented by the superficial spreading subtype (p = 0.0003), a brisk inflammatory infiltrate (p = 0.0061), a pT1–pT2 pathological stage (p = 0.0183), decreased mitotic activity (p = 0.0186), decreased Breslow index (p = 0.0301), and female sex (p = 0.022). Conclusions: The most important features of cutaneous melanomas diagnosed in AYA patients were represented by the superficial spreading subtype, the presence of a brisk inflammatory infiltrate, and a pT1–pT2 pathological stage. 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

Objectives: We aimed to descriptively evaluate the feasibility and clinical utility of TowardPi BO (4K ultra-HD microscope integrated with a 400 kHz swept-source intraoperative optical coherence tomography (SS-iOCT) system) in managing various ophthalmic surgical conditions in a real-world setting. Methods: We analyzed surgical videos and data from 123 consecutive cases that underwent elective surgery with the assistance of this SS-iOCT system at Beijing Tongren Hospital between 2 September 2025 and 10 February 2026. Cases were included when the iOCT provided critical, real-time information that directly influenced surgical decision-making or technique modification. Cases were excluded if iOCT served only routine confirmatory or educational purposes without altering the surgical plan. Results: A total of 72 surgical cases were included, comprising 7 intraocular lens implantations with ciliary sulcus fixation, 19 macular holes, 3 cases of macular hole retinal detachment (MHRD), 4 cases of macular schisis with or without foveal detachment (MSRD), 12 cases of submacular hemorrhage, 20 cases of rhegmatogenous retinal detachment (RRD), and 7 intraocular mass lesions. The 400 kHz SS-iOCT significantly aided in surgical visualization, guided real-time decision-making, and prompted modifications in surgical techniques. Conclusions: To our knowledge, this is the first real-world study to evaluate the application of a 400 kHz SS-iOCT system across a wide spectrum of ophthalmic conditions, including its novel use in intraocular tumors. From routine to complex surgical cases, SS-iOCT enhances surgical precision and facilitates real-time decision-making, ultimately contributing to improved surgical outcomes. Full article

Background: Immune checkpoint inhibitors have significantly improved survival in metastatic melanoma. Combination nivolumab plus ipilimumab demonstrated superior efficacy in randomized trials, including CheckMate 067, but data beyond the first-line setting remain limited. This study evaluated real-world outcomes and predictors of response across different lines of therapy, with an exploratory comparison between first- and second-line use. Methods: This retrospective single-center study included patients with metastatic melanoma treated with nivolumab plus ipilimumab as first- or second-line therapy at Moscow City Oncology Hospital No. 62 between September 2015 and October 2023. Eligible patients had histologically confirmed melanoma and received at least one cycle of dual immune checkpoint blockade. Clinical and demographic data were extracted from electronic medical records. The primary endpoints were progression-free survival (PFS) and overall survival (OS); secondary endpoints included objective response rate (ORR) and safety. Survival outcomes were estimated using the Kaplan–Meier method and compared using the log-rank test. Multivariable Cox proportional hazards models adjusted for clinically relevant covariates were applied to evaluate the association between treatment line and survival outcomes. Additional prognostic analyses were performed using backward stepwise multivariable Cox regression. Results: Median follow-up was 18.2 months (IQR, 6.7–30.4). Median PFS in the overall cohort was 7.9 months (95% CI, 4.2–11.5), and median OS was not reached (NR); 5-year OS: 50%. The ORR was 45.8%, including 15.1% complete responses. Median PFS was 9.0 months (95% CI, 5.0–12.9) in first-line and 6.1 months (95% CI, 3.4–8.8) in second-line patients. Median OS was NR in the first-line cohort and was 30.5 months (95% CI: NR) in the second-line cohort. In exploratory analyses, OS did not differ significantly between patients treated in the first-line (n = 141) versus second-line setting (n = 63) (p = 0.848). After adjustment for clinical and demographic characteristics, line of therapy was not associated with OS (HR 0.93; 95% CI, 0.58–1.50; p = 0.762). Immune-related adverse events were associated with longer PFS (HR 0.66; 95% CI, 0.46–0.93), although this may reflect time-dependent bias. Conclusions: Nivolumab plus ipilimumab demonstrated clinically meaningful activity in both first- and second-line settings. Outcomes were numerically lower than in clinical trials, consistent with broader real-world populations. In exploratory analyses, OS did not differ significantly between treatment lines after adjustment for clinical and demographic characteristics. These findings should be interpreted with caution given the retrospective design and potential sources of bias. 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, photodynamic agents, 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

Mohs micrographic surgery (MMS) is a highly specialized skin cancer procedure that combines complete microscopic margin assessment with maximal preservation of uninvolved tissue. The technique is based on staged excision of the tumor with systematic horizontal sectioning and real-time examination of the entire peripheral and deep surgical margins, allowing further tissue removal only in areas where residual tumor is identified. Its unique strength lies in the ability to detect subclinical tumor extensions that may be missed by conventional excision and standard vertical sectioning, thereby improving local control while minimizing unnecessary tissue sacrifice. Since its introduction in the 1930s by Frederic E. Mohs, the technique has evolved into a cornerstone of modern dermato-oncology, particularly for tumors arising in anatomically critical areas, recurrent neoplasms, and histologically aggressive malignancies. MMS is now widely regarded as the treatment of choice for high-risk basal cell carcinoma and cutaneous squamous cell carcinoma because of its superior cure rates and tissue-sparing approach. Beyond its oncologic advantages, MMS allows precise clinicopathologic correlation and immediate reconstruction tailored to the final defect, contributing to favorable functional and cosmetic outcomes. As experience with the technique has expanded, so too has interest in adjunctive tools for preoperative tumor delineation and margin control, further refining patient selection and surgical accuracy. Overall, MMS represents an essential advance over conventional excision for selected cutaneous malignancies, offering an optimal balance between radical tumor clearance and preservation of normal tissue. Full article

Background: Uveal melanoma is the most common intraocular malignancy in adults with a poor prognosis. Although local therapies are effective, treatment options for advanced disease remain limited. Combination strategies using chemotherapeutic agents and natural compounds, such as quercetin, are in focus for their potential to enhance antitumor efficiency and overcome resistance. Methods: The effects of doxorubicin, quercetin, and their combination were investigated in uveal melanoma cell lines. Cell viability was determined by an MTT assay, and apoptosis and cell cycle distribution by flow cytometry. Invasion assays were performed to evaluate metastatic potential, while modifications in signaling pathways were analyzed by Western blotting and qPCR. Results: Both doxorubicin and quercetin significantly reduced cell viability and induced apoptotic and necrotic cell death. The combination treatment demonstrated additional inhibitory effects in both cell lines, shown by increased SubG1 populations, reduced invasive capacity, and modulation of signaling pathways. Cell cycle analysis indicated treatment-induced growth inhibition. Notably, pathway modifications varied between cell lines, suggesting heterogeneous responses. Conclusions: Quercetin may potentiate certain antitumor effects of doxorubicin in uveal melanoma, particularly by reducing post-treatment invasiveness and modulating certain PI3K/AKT pathway-related proteins. These results support the possibility of quercetin-based combination therapies, although further molecular and in vivo studies are required. Full article

Melanoma has long represented a unique challenge in oncology. In its early stages, it can often be cured with surgery alone, resulting in excellent survival outcomes. Its biology is complex and heterogeneous, often including mutations such as BRAF and NRAS, which partly explain its high immunogenicity but also its capacity to relapse. For many decades, the standard approach in resectable stage III melanoma was surgery first, followed by adjuvant therapy. In the last decade, the development of immune checkpoint inhibitors created the opportunity to treat patients before surgery. The neoadjuvant approach is based on the hypothesis that treatment of the intact tumor may enhance antitumor immune priming and activation. The first prospective neoadjuvant studies, including OpACIN and OpACIN-neo, showed high pathological response rates with ipilimumab plus nivolumab and introduced pathological response as an early marker of long-term benefit. The PRADO study showed that treatment response could guide the extent of surgery required. The SWOG S1801 trial demonstrated better event-free survival with perioperative pembrolizumab compared to adjuvant therapy alone. Lastly, the phase III NADINA trial showed that neoadjuvant ipilimumab plus nivolumab followed by response-adapted adjuvant therapy significantly improves outcomes. Biomarkers such as PD-L1, IFN-γ signature, tumor mutational burden and imaging (PET scan) appear promising to predict response, but none have been sufficiently validated for routine clinical practice. Full article

Melanoma exhibits pronounced metabolic plasticity and mitochondrial dependency, contributing to therapeutic resistance and tumor progression. Targeting mitochondrial function therefore represents a promising anticancer strategy. 2-Aminoethyl dihydrogen phosphate (2-AEH₂P), a bioactive phosphomonoester, has demonstrated antiproliferative potential, while metformin, a clinically established antidiabetic drug, acts as a mitochondrial complex I inhibitor and metabolic modulator. This study investigated the cytotoxic and mechanistic effects of 2-AEH₂P and metformin hydrochloride, individually and in combination, in human (SK-MEL-28) and murine (B16-F10) melanoma models, using non-tumorigenic fibroblasts (FN1 and L929) as controls. Cell viability, proliferation dynamics, cell-cycle distribution, mitochondrial membrane potential (ΔΨm), and apoptosis-associated markers were evaluated by flow cytometry. 2-AEH₂P reduced melanoma cell viability and proliferation while inducing G2/M accumulation, DNA fragmentation, mitochondrial depolarization, increased cytochrome c release, caspase-3 and caspase-8 activation, upregulation of p53 and Bad, and downregulation of Bcl-2. Metformin alone exerted moderate cytotoxic and pro-apoptotic effects. Notably, combined treatment markedly potentiated mitochondrial depolarization and intrinsic apoptotic signaling in melanoma cells, significantly lowering IC₅₀ values and enhancing caspase activation and cytochrome c release. Bliss independence analysis demonstrated synergistic interaction in SK-MEL-28 and B16-F10 cells. Although interaction scores indicated synergy in one fibroblast model, absolute cytotoxicity remained lower than in melanoma cells. These findings demonstrate that metabolic co-targeting with metformin enhances mitochondrial dysfunction-associated apoptotic signaling in melanoma cells, supporting a drug repositioning strategy aimed at exploiting mitochondrial vulnerability in metabolically adaptable tumors. Full article

Background: Programmed death-1 (PD-1) inhibitors have significantly improved survival outcomes in melanoma; however, questions persist regarding comparative efficacy across regimens and the predictive value of PD-L1 expression as a biomarker. We therefore performed a meta-analysis evaluating outcomes according to PD-L1 expression status using the most recent follow-up data from each study. Methods: A systematic search was conducted in PubMed, Cochrane and ClinicalTrials.gov from 1 January 2010 to 1 April 2025 for phase II and III randomized clinical trials (RCTs) investigating PD-1 inhibitors as monotherapy or combined with other immune checkpoint inhibitors (ICIs) or targeted therapy in the adjuvant/metastatic setting. Pooled estimates were calculated with random-effects models, and risk of bias was assessed using the Cochrane RoB 2 tool. The present meta-analysis was performed following PRISMA guidelines and was registered in PROSPERO (ID: CRD420251090090). Results: Fifteen RCTs including 9979 patients were included. In the overall analysis, PD-1 inhibitors were associated with significantly improved overall survival (OS, HR = 0.75, 95% CI: 0.66–0.86) compared with control treatments. In the unresectable or metastatic setting, progression-free survival (PFS) was also significantly improved (HR = 0.61, 95% CI: 0.49–0.76). Survival benefits were observed in both PD-L1-positive and PD-L1-negative tumors, with improved PFS in PD-L1-positive (HR = 0.63, 95% CI: 0.48–0.83) and PD-L1-negative patients (HR = 0.58, 95% CI: 0.44–0.77), as well as improved OS in PD-L1-positive (HR = 0.69, 95% CI: 0.59–0.80) and PD-L1-negative patients (HR = 0.79, 95% CI: 0.67–0.93), without evidence of effect modification by PD-L1 expression. PD-1 inhibitor-based regimens were not associated with a statistically significant increase in grade 3–4 treatment-related adverse events (RR = 1.13, 95% CI: 0.71–1.79); however, heterogeneity was substantial (I² = 96.0%). Conclusions: PD-1 inhibitor-based therapies significantly improve survival outcomes in advanced melanoma across PD-L1 subgroups. No clear evidence of differential treatment benefit according to PD-L1 expression was observed, suggesting limited utility as a standalone predictive biomarker. Further studies integrating molecular and immune profiling are warranted to optimize individualized treatment selection. Full article

In this paper, we propose two novel defective survival models within the Gamma–G family: the defective Gamma–Gompertz and the defective Gamma–Dagum distributions. In contrast to the corresponding Gamma–G mixture cure formulation, in which the Gamma–G distributional parameters are combined with an explicit cure fraction mixing parameter, the proposed defective formulation induces the cure fraction through the limiting behavior of the survival function. Thus, within the same Gamma–G baseline structure, the model avoids introducing an additional cure fraction parameter. The motivation for these new models lies in the limited set of defective distributions currently available, despite the increasing demand for flexible cure rate models in biomedical applications. By extending the defective property to the Gamma–G construction, our approach fills this methodological gap while providing models that are both interpretable and computationally efficient. We show that the Gamma–G construction preserves defectiveness whenever the baseline distribution is defective, thus establishing a coherent theoretical foundation. Both models allow covariate effects through regression structures on shape, scale, and, in the case of the Gamma–Dagum distribution, on the cure fraction parameter, resulting in flexible and interpretable specifications. Parameters are estimated via maximum likelihood, and an extensive Monte Carlo study confirms estimator consistency and accurate coverage in finite samples. The practical relevance of the models is illustrated with two large clinical datasets on melanoma and cervical cancer from the São Paulo Cancer Registry. Results reveal that the proposed models provide competitive goodness-of-fit and offer useful insights into long-term survival compared to traditional cure rate approaches. Overall, this work introduces a unifying and flexible framework for defective survival models, extending their applicability and delivering practical improvements over existing cure models. Full article

Opioids are first-line therapy for cancer pain, yet up to 30% of patients fail to achieve adequate control at standard doses. Opioid response is partly genetically mediated, and understanding these factors may improve symptom management. This project aimed to assess the feasibility of using tumor bank DNA for pharmacogenetic analyses and to validate previously identified genetic variants associated with opioid response using existing genetic and clinical data. In this retrospective cohort study, clinical data (morphine equivalent daily dose, demographics) and genetic data (single-nucleotide polymorphisms) were analyzed across 31 candidate loci. Adult deceased patients with melanoma, colorectal, or lung cancer treated with opioids between 2016 and 2021 and with available tumor bank DNA were included. Patients without sufficient DNA or not deceased were excluded. Of 3503 potential samples, 502 met the inclusion criteria. The median morphine equivalent daily dose was 40 mg (range 1–2140 mg). Eleven loci across six genes may be associated with higher (OPRM1, TAOK3, NFKBIA, COMT, and RHBDF2) and lower (COMT and GCH1) opioid dose requirements (p < 0.05, not significant after Bonferroni correction). Ultimately, tumor bank DNA is a feasible resource for pharmacogenetic research. Identified loci may contribute to variability in opioid response and support future personalized pain management strategies. Full article

Objectives: To describe the scientific evidence regarding adjuvant treatment for stage III and IV cutaneous melanoma and the unresolved issues in this setting. Methods: This review examines the main studies on adjuvant medical therapies approved over the years by the Food and Drug Administration and European Medicines Agency together with the main evidence related to the treatments referred to in the National Comprehensive Cancer Network and European Society of Clinical Oncology guidelines at the time of submission (May 2026) for stage III and IV cutaneous melanoma. A particular focus on immunotherapy (interferon, ipilimumab, and anti-PD-1 antibodies, both as monotherapy and in combination) and targeted therapy with anti-BRAF agents, either as monotherapy or in combination with MEK inhibitors, is given. Besides that, this work also evaluates the role of radiation therapy and addresses some unresolved issues, such as adjuvant therapy in stage IIIA and treatment selection in BRAF-mutated melanoma. Results: Adjuvant therapy for stage III and IV cutaneous melanoma has evolved over the years, starting with interferon and progressing to the use of immunocheckpoint inhibitors and targeted therapy. However, not all treatments that have proven effective in metastatic disease have subsequently played a role in the adjuvant setting. Conclusions: Currently, adjuvant treatment for stage III and IV cutaneous melanoma involves the use of anti-PD-1 antibodies (nivolumab and pembrolizumab) and dabrafenib plus trametinib if the patient has a BRAF V600 mutation. It was not possible to identify the adjuvant therapy of choice for BRAF-mutated melanoma, and several factors must be considered when deciding between immunotherapy and targeted therapy. The role of radiation therapy remains controversial and could be discussed by the multidisciplinary team as part of the adjuvant strategy in selected patients. Likewise, adjuvant therapy for stage IIIA melanoma should be carefully evaluated in light of the risk–benefit ratio. Full article