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?

The use of radioiodine therapy (RIT) is debated in intermediate-risk differentiated thyroid cancer (DTC) patients. The understanding of the molecular mechanisms involved in the pathogenesis of DTC can be useful to refine patient selection for RIT. We analyzed the mutational status of BRAF, RAS, TERT, PIK3 and RET, and the expression of PD-L1 (as a CPS score), the NIS and AXL genes and the tumor-infiltrating lymphocytes (TIL, as the CD4/CD8 ratio), in the tumor tissue in a cohort of forty-six ATA intermediate-risk patients, homogeneously treated with surgery and RIT. We found a significant correlation between BRAF mutations and a less than excellent (LER, according to 2015 ATA classification) response to RIT treatment (p = 0.001), higher expression of the AXL gene (p = 0.007), lower expression of NIS (p = 0.045) and higher expression of PD-L1 (p = 0.004). Moreover, the LER patient group had a significantly higher level of AXL (p = 0.0003), a lower level of NIS (p = 0.0004) and a higher PD-L1 level (p = 0.0001) in comparison to patients having an excellent response to RIT. We also found a significant direct correlation between the AXL level and PD-L1 expression (p < 0.0001) and a significant inverse correlation between AXL and NIS expression and TILs (p = 0.0009 and p = 0.028, respectively). These data suggest that BRAF mutations and AXL expression are involved in LER among DTC patients and in the higher expression of PD-L1 and CD8, becoming new possible biomarkers to personalize RIT in the ATA intermediate-risk group, as well as the use of higher radioiodine activity or other possible therapies.

Fusobacterium nucleatum (F. nucleatum), a Gram-negative anaerobe traditionally associated with periodontal disease, has recently emerged as a putative contributor to gastric carcinoma (GC) pathogenesis. Beyond its detection in gastric tissues, particularly in patients negative for Helicobacter pylori (H. pylori) or in advanced GC cases, F. nucleatum exerts diverse oncogenic effects. It promotes GC progression by modulating the tumor microenvironment through IL−17/NF-κB signaling, inducing tumor-associated neutrophils (TANs), upregulating PD-L1 expression, and enhancing immune evasion. Moreover, it increases tumor invasiveness via cytoskeletal reorganization, while extracellular vesicles (EVs) induced by the infection contribute to tumor cell proliferation, invasion, and migration. Clinically, its presence correlates with increased tumor mutational burden (TMB), venous thromboembolism, and poor prognosis. This review summarizes the current evidence regarding the emerging role of F. nucleatum in gastric tumorigenesis, examines its potential utility as a diagnostic and prognostic biomarker within the framework of precision oncology, and outlines the molecular methodologies presently employed for its detection in gastric tissue specimens.

In this retrospective observational multicenter study, we identified tumors and immune markers that are related to each other, which could help in selecting bladder primary urothelial carcinoma in situ (CIS) patients who respond better to Bacillus Calmette-Guérin (BCG) therapy. Seventy-three patients with primary bladder CIS who were homogeneously treated with BCG were studied. Tumor-infiltrating lymphocytes (TILs) measured as CD4/CD8 ratio, androgen receptor (AR), ADAR1, ADAR2, and PD-L1 expression were analyzed using immunohistochemistry, whereas miR-200a-3p and INF-γ were evaluated using qPCR on tissues before treatment. Results were correlated with clinicopathological features and Recurrence-Free Survival (RFS). High AR levels in CIS were significantly associated with higher ADAR1 expression, lower ADAR2 expression, higher PD-L1 TPS, higher CD4/CD8 ratio and multifocality of CIS (p<0.001). All patients with the above-mentioned characteristics had significantly worse RFS (p<0.0001). Multivariate and multiple regression analyses confirmed the predictive role of AR, ADAR2, and PD-L1, especially when all three parameters were combined. Additionally, we demonstrated that patients with lower AR and higher ADAR2 expressions had significantly higher levels of miR-200a-3p and INF-γ than those with higher AR and lower ADAR2 expression (p = 0.0011 and p = 0.0002, respectively). Our findings highlight the role of AR in the response to BCG therapy by modulating PD-L1 expression and TILs through the ADAR2, miR-200a-3p, and INF-γ pathways. Furthermore, our data provides valuable insights for optimizing BCG therapy in patients with CIS, paving the way for other possible combined treatment strategies.

Philadelphia‐negative myeloproliferative neoplasms (MPN), a spectrum of blood malignancies characterized by uncontrolled myeloid proliferation, persist as a key challenge in onco‐hematology due to their intricate molecular background, heterogeneous clinical phenotypes, and variable prognoses. Although generally accepted as indolent disorders, a considerable fraction of MPN patients exhibit progressive, and sometimes accelerated, bone marrow fibrosis, reflecting a critical shift toward a more debilitating condition marked by an increased symptom burden. As marrow scarring advances, hematopoietic capacity declines, severely compromising both patients' quality of life and survival. Increasing evidence highlights the crucial involvement of multiple players and mechanisms orchestrating marrow fibrotic transformation, thereby reflecting the multifaceted nature of this pathogenetic process. In this review, we untangle the pro‐fibrotic programs underlying fibrosis progression in MPN, critically analyzing the available scientific literature. We explore the potential impact of the mutational landscape on the fibrotic transformation risk and examine the role of dysfunctional megakaryocytes as principal catalysts of fibrotic remodeling. Additionally, we provide insight into the influence of the bone marrow microenvironment, examining the contribution of both soluble factors and direct cell‐cell communication in sustaining and exacerbating the fibrotic signature. The urgent need for earlier diagnoses, tailored prognoses, and more effective therapeutic strategies stresses the importance of investigating the pathological basis of fibrotic progression from a deeper perspective.