The management of advanced bladder carcinoma involves a multidisciplinary approach, but the prognosis remains poor for many patients. The immune system plays a crucial role in this disease, influencing both tumor development and response to treatment, and exploiting the immune system against the tumor can be a valuable strategy to destroy neoplastic cells. This is the biological principle underlying Bacillus Calmette–Guérin (BCG) use and, more recently, immune checkpoint inhibitors (ICIs), like PD-1 (programmed death-1)/PD-L1 (programmed death-ligand 1) inhibitors. In fact, one of the best studied immune checkpoints is represented by the PD-1/PD-L1 axis, which is a well-known immune escape system adopted by neoplastic bladder cells. PD-L1 expression has been associated with a higher pathologic stage and has shown prognostic value in bladder carcinoma. Interestingly, high-grade bladder cancers tend to express higher levels of PD-1 and PD-L1, suggesting a potential role of such an axis in mediating disease progression. Immunotherapy with PD-1 and PD-L1 inhibitors has therefore emerged as a valuable treatment option and has shown efficacy in advanced bladder cancer patients, with high PD-L1 expression levels associated with better treatment responses. Our review aims to provide a comprehensive overview of the role of PD-L1 in advanced bladder cancer, focusing on its implications for treatment decisions and the prediction of treatment response. Overall, our work aims to contribute to the understanding of PD-L1 as a predictive biomarker and highlight its role in shaping therapeutic approaches for advanced bladder cancer.

Glioblastomas (GBMs), among the most aggressive and resilient brain tumors, characteristically exhibit high angiogenic potential, leading to the formation of a dense yet aberrant vasculature, both morphologically and functionally. With these premises, numerous expectations were initially placed on anti-angiogenic therapies, soon dashed by their limited efficacy in concretely improving patient outcomes. Neovascularization in GBM soon emerged as a complex, dynamic, and heterogeneous process, hard to manage with the classical standard of care. Growing evidence has revealed the existence of numerous non-canonical strategies of angiogenesis, variously exploited by GBM to meet its ever-increasing metabolic demand and differently involved in tumor progression, recurrence, and escape from treatments. In this review, we provide an accurate description of each neovascularization mode encountered in GBM tumors to date, highlighting the molecular players and signaling cascades primarily involved. We also detail the key architectural and functional aspects characteristic of the GBM vascular compartment because of an intricate crosstalk between the different angiogenic networks. Additionally, we explore the repertoire of emerging therapies against GBM that are currently under study, concluding with a question: faced with such a challenging scenario, could combined therapies, tailored to the patient’s genetic signatures, represent an effective game changer?

Upper tract urothelial carcinoma (UTUC) is a rare but aggressive malignancy with increasing incidence, often diagnosed at advanced stages due to the limitations of current diagnostic tools. Conventional methods such as urinary cytology, imaging, and ureteroscopy have important drawbacks, including low sensitivity, high costs, and procedural invasiveness. As a result, there is a growing need for non-invasive, highly accurate diagnostic approaches. Epigenetic biomarkers, particularly DNA methylation-based assays, have emerged as promising alternatives for UTUC detection and surveillance. Among these, Bladder EpiCheck® (BE) has shown remarkable sensitivity and specificity, particularly for high-grade tumors, making it a valuable adjunct to standard diagnostic techniques. By analyzing tumor-specific methylation patterns in urine samples, BE offers a practical and non-invasive solution that could improve early detection, reduce the need for ureteroscopy, and enhance risk stratification. Several studies have demonstrated its superior diagnostic accuracy, with sensitivity reaching 97.4 % and specificity up to 100 % for high-grade UTUC. Despite these advantages, challenges remain regarding the standardization of testing protocols, validation in larger patient cohorts, and evaluation of cost-effectiveness. Moreover, the role of DNA methylation biomarkers in guiding clinical decisions and predicting disease progression requires further investigation. This review explores the current state of UTUC diagnosis, compares BE with conventional and emerging biomarkers, and discusses its clinical applications, limitations, and future perspectives. The integration of molecular biomarkers like BE into clinical practice has the potential to revolutionize UTUC diagnosis, improving patient outcomes through more precise, non-invasive detection strategies.

Aseptic loosening (AL) represents the leading cause of long-term failure in total joint arthroplasty, often necessitating revision surgery. This review explores the complex mechanisms underlying AL, which involve a multifaceted interaction between the implanted biomaterials and the host immune response. We outline the key inflammatory mechanisms triggered by wear debris from polyethylene, polymethylmethacrylate, metal, and ceramic materials. We also examine emerging biomarkers for early detection and differentiation between stable and loosened implants, including proinflammatory cytokines, bone metabolism markers, extracellular matrix degradation products, microRNAs, and genetic polymorphisms. Lastly, we discuss current and future strategies for prevention and treatment, ranging from surgical optimization and biomaterial selection to pharmacological interventions. A comprehensive understanding of these mechanisms may help reduce the incidence of AL and improve long-term outcomes in arthroplasty patients.

Aseptic loosening (AL) represents the leading cause of long-term failure in total joint arthroplasty, often necessitating revision surgery. This review explores the complex mechanisms underlying AL, which involve a multifaceted interaction between the implanted biomaterials and the host immune response. We outline the key inflammatory mechanisms triggered by wear debris from polyethylene, polymethylmethacrylate, metal, and ceramic materials. We also examine emerging biomarkers for early detection and differentiation between stable and loosened implants, including pro-inflammatory cytokines, bone metabolism markers, extracellular matrix degradation products, microRNAs, and genetic polymorphisms. Lastly, we discuss current and future strategies for prevention and treatment, ranging from surgical optimization and biomaterial selection to pharmacological interventions. A comprehensive understanding of these mechanisms may help reduce the incidence of AL and improve long-term outcomes in arthroplasty patients.

Mutations in isocitrate dehydrogenase 1 or 2 ( IDH1/2 ) define a major subgroup of adult‐type diffuse gliomas and induce accumulation of D‐2‐hydroxyglutarate, resulting in extensive DNA and histone methylation changes. This epigenetic reprogramming underlies the glioma CpG island methylator phenotype (G‐CIMP) and contributes to tumour lineage, differentiation state and clinical behaviour. DNA methylation profiling has consequently evolved from a research tool into an important ancillary method for CNS tumour classification, molecular subclassification and copy‐number analysis. This narrative review examines the biological basis, analytical platforms and clinical applications of DNA methylation profiling in IDH‐mutant gliomas. Particular attention is given to the distinction between research‐defined G‐CIMP‐high and G‐CIMP‐low states and classifier‐defined lower‐grade and high‐grade methylation subclasses. High‐grade signatures, including A_IDH_HG and G‐CIMP‐low, are associated with adverse genomic features and outcome but should not be considered interchangeable or used in isolation to assign CNS WHO grade. Their interpretation requires integration with histology and established molecular criteria, including homozygous CDKN2A/B deletion. The review also discusses array‐based profiling, emerging Nanopore and long‐read approaches, computational quality control, and the integration of methylation data with genomic and transcriptomic alterations. Longitudinal studies indicate that a subset of IDH‐mutant astrocytomas undergoes methylation loss, copy‐number accumulation and altered cell‐state differentiation during progression, although these changes are not universal. The clinical relevance of MGMT promoter methylation is more context‐dependent than in IDH‐wildtype glioblastoma. Moreover, the INDIGO trial established the clinical activity of mutant IDH inhibition in selected Grade 2 gliomas but did not validate methylation class as a predictive biomarker or demonstrate complete epigenetic reversal. Emerging applications, including single‐cell and spatial epigenomics, tumour microenvironment deconvolution and CSF methylation profiling, remain investigational. Overall, DNA methylation profiling is most valuable when used as integrated diagnostic and risk‐stratification evidence within the complete histological, genomic and clinical context.