(1) Background/Objectives: Primary and secondary brain tumours often hold devastating prognoses and low survival rates despite the application of maximal neurosurgical resection, and state-of-the-art radiotherapy and chemotherapy. One limiting factor in their management is that several antineoplastic agents are unable to cross the blood–brain barrier (BBB) to reach the tumour microenvironment. Nanomedicine could hold the potential to become an effective means of drug delivery to overcome previous hurdles towards effective neuro-oncological treatments. (2) Methods: A scoping review following the PRISMA-ScR guidelines and checklist was conducted using key terms input into PubMed to find articles that reflect emerging trends in the utilisation of nanomedicine in drug delivery for primary and secondary brain tumours. (3) Results: The review highlights various strategies by which different nanoparticles can be exploited to bypass the BBB; we provide a synthesis of the literature on the ongoing contributions to therapeutic protocols based on chemotherapy, immunotherapy, focused ultrasound, radiotherapy/radiosurgery, and radio-immunotherapy. (4) Conclusions: The emerging trends summarised in this scoping review indicate encouraging advantageous properties of nanoparticles as potential effective drug delivery mechanisms; however, there are still nanotoxicity issues that largely remain to be addressed before the translation of these innovations from laboratory to clinical practice.

Background and Aim: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with poor prognosis despite maximal surgical resection, radiotherapy (RT), and temozolomide (TMZ) per the Stupp protocol. IDH-wild-type GBM, the predominant molecular subtype, frequently harbors EGFR amplification and is resistant to therapy, while MGMT promoter methylation predicts improved TMZ response. This study aimed to assess the prognostic impact of EGFR and MGMT status on survival and recurrence patterns in IDH-wild-type GBM. Materials and Methods: We retrospectively analyzed 218 patients with IDH-wild-type GBM treated at the Azienda Ospedaliero-Universitaria Senese (2016–2024). All patients underwent maximal safe surgical resection whenever feasible. The cohort includes patients who received gross total resection (GTR), subtotal resection (STR), or biopsy only, depending on tumor location and clinical condition, followed by intensity-modulated RT (59.4–60 Gy) with concurrent and adjuvant TMZ. EGFR amplification was assessed via FISH/NGS and immunohistochemistry; MGMT promoter methylation was determined using methylation-specific PCR. Progression-free survival (PFS), overall survival (OS), and recurrence patterns (in-field, marginal, out-field) were evaluated using Kaplan–Meier, Cox regression, and logistic regression analyses. Results: Among patients (64.7% male; mean age 61.8), 58.7% had EGFR amplification and 49.1% showed MGMT methylation. Median OS and PFS were 14 and 8 months, respectively. EGFR non-amplified/MGMT methylated tumors had the best outcomes (OS: 22.0 months, PFS: 10.5 months), while EGFR-amplified/MGMT unmethylated tumors fared worst (OS: 10.0 months, PFS: 5.0 months; p < 0.001). MGMT methylation was an independent positive prognostic factor (HR: 0.48, p < 0.001), while EGFR amplification predicted worse survival (HR: 1.57, p = 0.02) and higher marginal recurrence (OR: 2.42, p = 0.01). Conclusions: EGFR amplification and MGMT methylation significantly influence survival and recurrence dynamics in IDH-wild-type GBM. Incorporating these biomarkers into treatment planning may enable tailored therapeutic strategies, potentially improving outcomes in this challenging disease. Prospective studies are needed to validate biomolecularly guided management approaches.

Surgical resection remains a cornerstone in the multidisciplinary management of central nervous system (CNS) tumors, particularly diffuse gliomas. Traditionally, the role of surgery has been evaluated primarily through quantitative metrics such as extent of resection and its association with survival outcomes. However, despite maximal and radiologically complete resections, recurrence remains nearly universal in malignant CNS tumors, suggesting that surgical cytoreduction alone does not fully account for post-surgical disease dynamics. Emerging biological and molecular evidence indicates that surgery represents not merely a technical intervention, but a biologically active event that profoundly reshapes tumor evolution and treatment response. In this review, we propose a conceptual framework that redefines surgery as a key biological driver in CNS tumor progression. We synthesize evidence demonstrating that surgical trauma induces inflammation, hypoxia, vascular remodeling, immune modulation, and extracellular matrix reorganization, collectively reprogramming the residual tumor microenvironment. These changes create selective pressures that favor the survival and expansion of adaptive tumor cell subpopulations, including invasive and stem-like phenotypes. From an evolutionary perspective, surgical resection functions as an acute selective bottleneck acting on heterogeneous tumor ecosystems, contributing to clonal selection and molecular divergence at recurrence. We further examine the dissociation between surgical (anatomical) margins and molecular (biological) margins, highlighting how biologically active tumor cells infiltrate beyond radiologically defined boundaries. This discrepancy provides a biological explanation for marginal and distant recurrences and challenges anatomy-based paradigms of surgical completeness. Importantly, we discuss how surgery-induced biological changes influence postoperative radiotherapy and systemic therapies, affecting radiosensitivity, target delineation, and therapeutic vulnerability. Finally, we outline future directions toward surgery-integrated precision neuro-oncology, emphasizing the potential of spatial profiling, liquid biopsy, advanced imaging, and artificial intelligence to capture perioperative tumor evolution. By reframing surgery as a biological inflection point rather than a neutral prelude to adjuvant treatment, this review advocates for a dynamic, biology-driven continuum of care aimed at anticipating tumor adaptation and improving long-term disease control in CNS tumors.

Background: Clinical target volume (CTV) delineation in glioblastoma remains debated, particularly in the era of modern chemoradiation and image-guided radiotherapy. Whether reduced CTV margins can preserve oncological outcomes without increasing marginal or out-of-field failures remains uncertain. We evaluated the association of the gross tumor volume (GTV)-to-CTV margin with survival, patterns of failure, and its interaction with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Materials and Methods: We retrospectively analyzed a single-center cohort of patients with glioblastoma treated with conventionally fractionated chemoradiation (58–60 Gy in 29–33 fractions). Patients were categorized into two predefined margin groups: <1.5 cm and 1.5 cm. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and patterns of failure. Survival was assessed using Kaplan–Meier estimates and Cox regression, including an interaction term with MGMT status. Results: Among 102 eligible patients, 95 were included in the margin-based OS analysis. Reduced margins (<1.5 cm; applied range 1.0–1.4 cm) were not associated with worse OS, either overall or within MGMT subgroups. No significant differences were observed in PFS or recurrence patterns, with overlapping distributions and no increase in marginal or out-of-field recurrences. MGMT methylation and gross total resection were independently associated with improved survival, while no statistically significant interaction between margin and MGMT status was detected. Conclusions: In this retrospective exploratory cohort, reduced GTV-to-CTV margins were not associated with a clear signal of worse survival or less favorable recurrence patterns. These findings are consistent with the oncological adequacy of margins around 15 mm and justify cautious prospective evaluation of whether further reduction can be achieved safely, including formal assessment of toxicity, neurocognitive outcomes, and quality of life.

Surgical resection remains a cornerstone in the multidisciplinary management of central nervous system (CNS) tumors, particularly diffuse gliomas. Traditionally, the role of surgery has been evaluated primarily through quantitative metrics such as extent of resection and its association with survival outcomes. However, despite maximal and radiologically complete resections, recurrence remains nearly universal in malignant CNS tumors, suggesting that surgical cytoreduction alone does not fully account for post-surgical disease dynamics. Emerging biological and molecular evidence indicates that surgery represents not merely a technical intervention, but a biologically active event that profoundly reshapes tumor evolution and treatment response. In this review, we propose a conceptual framework that redefines surgery as a key biological driver in CNS tumor progression. We synthesize evidence demonstrating that surgical trauma induces inflammation, hypoxia, vascular remodeling, immune modulation, and extracellular matrix reorganization, collectively reprogramming the residual tumor microenvironment. These changes create selective pressures that favor the survival and expansion of adaptive tumor cell subpopulations, including invasive and stem-like phenotypes. From an evolutionary perspective, surgical resection functions as an acute selective bottleneck acting on heterogeneous tumor ecosystems, contributing to clonal selection and molecular divergence at recurrence. We further examine the dissociation between surgical (anatomical) margins and molecular (biological) margins, highlighting how biologically active tumor cells infiltrate beyond radiologically defined boundaries. This discrepancy provides a biological explanation for marginal and distant recurrences and challenges anatomy-based paradigms of surgical completeness. Importantly, we discuss how surgery-induced biological changes influence postoperative radiotherapy and systemic therapies, affecting radiosensitivity, target delineation, and therapeutic vulnerability. Finally, we outline future directions toward surgery-integrated precision neuro-oncology, emphasizing the potential of spatial profiling, liquid biopsy, advanced imaging, and artificial intelligence to capture perioperative tumor evolution. By reframing surgery as a biological inflection point rather than a neutral prelude to adjuvant treatment, this review advocates for a dynamic, biology-driven continuum of care aimed at anticipating tumor adaptation and improving long-term disease control in CNS tumors.

Radiotherapy for glioblastoma remains anchored to postoperative structural MRI and anatomy-based target definitions, despite marked spatial heterogeneity and dynamic biological change during chemoradiotherapy. Advanced MRI, amino-acid PET, radiomics, and habitat imaging can characterize tumor biology beyond conventional anatomy, yet their relevance to radiotherapy planning and their evidentiary maturity differ substantially. This narrative review examines the current evidence for biologically informed radiotherapy in glioblastoma and proposes an MRI-centered actionability framework that organizes imaging-derived findings into five levels of evidentiary maturity, from descriptive or associative signals to intervention-ready biomarkers, to guide literature interpretation, multidisciplinary discussion, and prospective protocol design. Standard MRI-based planning remains the clinical backbone, supported by contemporary guidelines and the absence of randomized evidence demonstrating benefit from routine biologically guided target modification. Advanced MRI is discussed as the most practical serial platform for treatment-course reassessment, amino-acid PET as a selective complementary tool for metabolic clarification and recurrence assessment, and radiomics and habitat imaging as promising but not yet intervention-ready research layers. Across modalities, prospective evidence supports feasibility more consistently than clinical benefit. The proposed framework is intended to separate biologically informative findings from those sufficiently validated to justify a defined radiotherapy consequence, and to structure the translational path toward intervention-grade evidence in glioblastoma radiotherapy.