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BackgroundGlioblastoma (GBM) is an aggressive brain tumor with poor survival despite multimodal treatment. The impact of socioeconomic status (SES) and financial toxicity (FT) in GBM remains poorly defined.Patients and methodsThis prospective observational study involved 19 Italian centers and evaluated the association between SES, financial toxicity (FT), biological and clinical variables, and outcomes in newly diagnosed GBM patients within the Italian universal healthcare system. SES and FT data were collected at the start of radiochemotherapy and after 6 months using structured questionnaires, including the Patient Reported Outcome for Fighting FInancial Toxicity (PROFFIT) questionnaire for FT assessment.ResultsBetween March 2021 and September 2024, 405 patients were enrolled; 385 had evaluable baseline questionnaires and 374 histologically confirmed GBM were included in survival analyses. Mean (SD) PROFFIT score was 32.8 (24.2). Higher FT was associated with younger age (p <0.001), foreign birth (p <0.001), dependent family members (p=0.046), unemployment/work disability (p <0.001), work discontinuation (p=0.005), and lower income (p <0.001). FT was also strongly associated with worsening physical appearance and sexual activity (both p<0.001). Caregiver burden was substantial, with 52.2% reducing working hours and 11.6% leaving work due to the patient’s illness. PROFFIT score was not associated with PFS or OS.Conclusions The study showed that FT is a significant issue in GBM, particularly among vulnerable patients, even within a universal healthcare system. The high caregiver burden supports routine FT assessment and health policies aimed at reducing the economic and psychosocial impact of the disease.

Glioblastoma (GBM) is the most common malignant primary brain tumor in adult patients and has a poor prognosis despite current multimodal approaches that include surgery, radiation therapy, and chemotherapy. Local recurrence is almost inevitable, and treatment options for relapsed disease are limited. Poly-ADP-ribose polymerase inhibitors (PARPi) are standard of care in several advanced/metastatic solid malignancies including ovarian, breast, and prostate cancer. In GBM, PARPi could represent a novel promising class of therapeutic agents enhancing DNA repair defects present in specific GBM molecular subtypes. Indeed, these agents act by blocking DNA damage repair, amplifying the lethality of DNA-damaging therapies such as temozolomide (TMZ) and radiotherapy. Several PARPi have been investigated in combination with standard GBM therapy, without significant clinical improvement. However, their efficacy is strongly influenced by their ability to cross the blood-brain barrier and the presence of tumor resistance mechanisms. Clinical trials suggest that patient selection using molecular biomarkers and the timing of PARPi administration are crucial for maximizing therapeutic benefit. The choice of PARPi with optimal trapping and blood-brain barrier penetration capacity, together with molecular stratification based on genomic and expression profiles, appears crucial for the effective use of these agents in glioblastoma. This review investigates the biological mechanisms associated with PARPi within GBM tumor cells and assesses which patients could be the best candidates for PARPi treatment based on molecular profiling of the disease.

Primary central nervous system (CNS) tumors remain a major challenge in neuro-oncology due to their cellular heterogeneity, infiltrative growth, and the protective blood–brain barrier (BBB), which limits the effectiveness of systemic therapies. Despite aggressive multimodal treatments, patient survival remains poor, highlighting the urgent need for new therapeutic strategies. Ultrasound-based therapies, including focused ultrasound (FUS) and sonodynamic therapy (SDT), have emerged as promising approaches. FUS can transiently open the BBB and induce localized mechanical and thermal effects, enhancing drug delivery, while SDT activates tumor-specific sensitizers to generate reactive oxygen species that trigger cancer cell death. Preclinical and early clinical studies suggest that combining these modalities with chemotherapy, immunotherapy, or radiotherapy may improve treatment outcomes. Emerging tools such as AI-guided monitoring, theranostic platforms, and ultrasound-responsive nanoparticles could further enable personalized interventions. However, challenges remain, including protocol variability, tumor heterogeneity, and limited long-term safety data. Careful optimization and clinical validation are needed before these strategies can be widely adopted in the management of CNS tumors.

Purpose: Available prognostic scores for adult-type diffuse glioma with isocitrate dehydrogenase (IDH) mutant were validated before the evaluation of biomolecular features. The selection of patients who did not receive postoperative radiotherapy and chemotherapy would provide an ideal setting to describe the natural history of these tumors. Methods: We investigated the clinical outcomes of patients with adult-type diffuse glioma with isocitrate dehydrogenase IDH mutation approached with active surveillance after primary surgery. Results: We evaluated 61 patients consisting of 35 patients with IDH-mutant astrocytomas and 26 patients with IDH-mutant 1p19q oligodendrogliomas. The median follow-up was 13.1 years (95% CI 11.4–17.7). A total of 56 progression-free survival events were available at the time of analysis. The median age was 32.2 years, higher in IDH-mutant 1p19q oligodendrogliomas (39.5 years) compared to IDH-mutant astrocytomas (31.4 years; p = 0.003). Residual tumor [hazard ratio (HR) 2.63, 95% CI −1.23 to 5.58, p = 0.007], post-surgical diameter product (HR 1.11, 95% CI 1–1.22, p = 0.03), and midline crossing (HR 6.79, 95% CI 1.5–30.4, p = 0.005) were the only factors directly influencing progression-free survival in univariate analyses. No variables confirmed their predictive role in multivariate models. At the time of data analysis, we registered 22 overall survival (OS) events. In a multivariate Cox regression model, histo-molecular diagnosis (oligodendroglioma vs . astrocytoma; HR 0.28, 95% CI 0.10–0.8, p = 0.02) and initial tumor area assessed as continuous variables (HR 1.82, 95% CI 1.01–3.3, p = 0.05) independently affected the survival of patients (p = 0.01). Conclusions: In our series, the presence and dimension of residual tumors and midline crossing were the only independent variables predicting progression-free survival after primary surgery in grade 2 diffuse glioma.

Background: The androgen receptor (AR) is a ligand-dependent transcription factor of the nuclear steroid receptor superfamily, implicated in the pathogenesis of various solid tumors. The AR gene, located on chromosome Xq11–12, is accompanied by several X-linked genes that modulate AR expression and function, including FLNA, UXT, and members of the melanoma antigen gene (MAGE) family (MAGEA1, MAGEA11, MAGEC1, MAGEC2). While the AR has been investigated in multiple tumor types, its role in adult-type diffuse gliomas remains largely unexplored. Here, we characterized AR protein expression and the promoter methylation status of the AR and associated regulatory genes in adult-type diffuse gliomas. Methods: A retrospective analysis was conducted on 50 patients with adult-type diffuse gliomas, including IDH-mutant gliomas (grades 2–4) and IDH-wildtype glioblastomas (GBMs), classified according to the 2021 WHO criteria. AR nuclear expression was assessed by immunohistochemistry (IHC). Methylation-specific PCR and quantitative DNA methylation analyses were employed to evaluate promoter methylation of the AR and selected co-regulatory genes. Results: AR nuclear positivity correlated significantly with male sex (p = 0.04) and higher tumor grade, with the highest expression in IDH-wildtype GBMs (p = 0.04). In IDH-mutant gliomas, AR immunoreactivity was more prevalent in astrocytomas than in 1p/19q codeleted oligodendrogliomas (p = 0.02). AR expression was associated with unmethylated MGMT promoter status (p = 0.02). DNA methylation analysis revealed AR gene hypomethylation in tumors displaying nuclear AR positivity and in IDH-wildtype GBMs (Kruskal–Wallis p < 0.05). Additionally, methylation patterns of AR co-regulators located on the X chromosome suggest epigenetic regulation of AR signaling in gliomas. Conclusions: The findings reveal distinct AR pathway activation patterns in adult-type diffuse gliomas, particularly IDH-wildtype GBMs, suggesting that further exploration of antiandrogen therapies is warranted.

Drugs targeting mitochondrial energy metabolism are emerging as promising antitumor therapeutics. Glioma treatment is extremely challenging due to the high complexity of the tumor and the high cellular heterogeneity. From a metabolic perspective, glioma cancer cells can be classified into the oxidative metabolic phenotype (mainly depending on mitochondrial respiration for energy production) and glycolytic phenotype or “Warburg effect” (mainly depending on glycolysis). Herein, we reviewed the function of novel bio-active molecules targeting oxidative phosphorylation (OXPHOS), mitochondrial membrane potential and mitochondrial dynamics. These molecules exhibit intriguing preclinical and clinical results and have been proven to be promising candidates to be further developed for glioma therapy. However, despite these initial encouraging results, it is imperative to rigorously assess the side effects of these metabolic drugs, which have a non-negligible toxicity profile.

Background: Glioblastoma IDH-wildtype (GBM IDH-wt) is the most aggressive brain tumor in adults and is characterized by an immunosuppressive microenvironment. Different factors shaping its tumor microenvironment (TME) regulate tumor progression and treatment response. The aim of this study was to characterize the main immunosuppressive elements of the GBM IDH-wt TME. Methods: Immunohistochemistry for CD3, CD4, CD8, CD163, programmed death ligand 1 (PD-L1) and programmed death 1 (PD1) was performed on surgical tumor specimens from patients diagnosed with GBM IDH-wt, according to the CNS WHO 2021 criteria. The impact of categorical variables on time-dependent outcomes such as overall survival (OS) and progression-free survival (PFS) has been estimated through the Kaplan–Meier method. Results: We included 30 patients (19 males and 11 females), median age of 59.8 years (range 40.2–69.1 years). All patients underwent surgery followed by temozolomide concurrent with and adjuvant to radiotherapy. MGMT was methylated in 14 patients (47%) and unmethylated in 16 patients (53%). The overall absolute percentages of CD4+ lymphocytes, both intratumoral and perivascular, were significantly more represented than CD8+ lymphocytes in the TME (p = 0.02). A low density of CD4+ lymphocytes (≤10%) was found to be a favorable prognostic factor for GBM outcome (p = 0.02). Patients with MGMT methylated and unmethylated tumors exhibited a distinct TME composition, with a significant higher number of perivascular CD8+ lymphocytes (p = 0.002), intratumoral CD8+ lymphocytes (p = 0.0024) and perivascular CD4+ lymphocytes (p = 0.014) in MGMT unmethylated tumors. PD-L1 expression in tumor cell surface was observed in four tumors (13.3%), and PD1 expression in infiltrating T lymphocytes was observed in nine (30%) tumors, with predominantly perivascular distribution. Conclusions: MGMT methylated and unmethylated tumors exhibit different immune profiles, likely reflecting the different biology of these tumors. The expression of PD-L1 in GBM IDH-wt patients is confined to a small subpopulation. While we found a significant association between low CD4+ lymphocyte density (≤10%) and survival, given the small numbers of our cohort, the prognostic value of CD4+ lymphocyte density will need to be validated in large-scale studies.

Background: Human papilloma virus (HPV) infection is responsible for 4.5% of cancers worldwide, i.e., for around 630,000 new cases per year. Around 38,000 cases per year of HPV-related cancers arise in the head and neck region, of which 21,000 cases are oropharyngeal squamous cell carcinomas (OPSCCs), with an increasing frequency in high-income countries. In our work, we aimed to collect the available evidence about the awareness of the relation between HPV infection and head and neck cancer among patients and practitioners. Methods: This review was based on all available prospective and retrospective studies, case reports, and review articles published up to May 2024 in PubMed. The search keywords used included “human papilloma virus” plus “head and neck cancer”, “awareness”, “infection”, “vaccination”, “awareness in patients and practitioners”, “oropharyngeal squamous cell carcinoma”, “HPV16-18”, “HPV awareness”, “cervical cancer”. Results: In the U.S.A., with more than 150.00 participants interviewed through different studies, the identification of HPV infection as a risk factor for head and neck cancer (HNC) was made by only 12–39% of the participants. Similar conclusions were drawn from European studies in which only 10–52% of the participants recognized HPV as a risk factor for HNC. HPV-related HNC awareness in health care providers and medical/dental students showed a high variability among studies, being otolaryngology and dental sciences specialists the most conscious in comparison to general practitioners, who demonstrated a low level of awareness. Conclusions: There is a dangerous lack of awareness about HPV infection and its potential role in HNC among both general populations and health care practitioners. A great effort should be made to increase awareness in both practitioners and the general population on this topic, also aiming to increase the HPV vaccination coverage.