Abbreviations: OS, overall survival; PFS, progression-free survival; EGFR, epidermal growth factor receptor; PTEN, phosphatase and tensin homolog; TP53, tumor protein 53; IDH1, isocitrate dehydrogenase 1; MGMT, O6-methylguanine-DNA methyltransferase; VEGF, vascular endothelial growth factor; PDGF, platelet-derived growth factor; CDK4, cyclin-dependent kinase 4. Lei et al. developed a model using transcriptome data from two cohorts of patients with GBM. They identified 341 metabolic genes that showed significant differences between normal brain and GBM tissues, among which, 56 genes were found to be correlated with the patients’ overall survival (OS). In the end, the model was constructed using a Lasso regression model with 18 genes and showed high accuracy in predicting the OS of the patients. In particular, the high-risk group of patients included in this model had a significantly shorter OS than the low-risk group in the training cohort (p < 0.0001) and in the independent external validation (p < 0.001). The study by Lei et al. showed that the prognosis of GBM is closely related to metabolic pathways and that, by using a model, it is possible to predict the prognosis of patients with GBM [41]. As is evident in contemporary neuro-oncology, searching for better diagnostic and therapeutic strategies for glioblastoma has led to a deep exploration of prognostic and predictive biomarkers. Increasingly, the evidence allows us to make a targeted choice regarding the type of treatment in relation to the molecular profile of the tumor. In fact, these biomarkers may now influence the choice of therapeutic approach. For example, the presence of the mutated IDH1 gene is associated with a better prognosis, and patients carrying this mutation may benefit from more aggressive surgical resection aimed at maximal tumor excision [42]. MGMT promoter methylation status is another crucial biomarker. Glioblastoma patients with MGMT promoter methylation tend to respond better to chemotherapy [43], and knowledge of this status may influence the decision on the extent of surgical resection and the subsequent use of adjuvant therapies. The expression of certain molecular markers, such as EGFR, may also impact the choice of treatment. Elevated EGFR expression may suggest a more aggressive tumor phenotype, influencing the decision for a more extensive surgical approach or the inclusion of targeted therapies [44]. Montano et al. observed significantly longer OS in GBM patients with high levels of EGFR treated with total resection and standard radiochemotherapy involving temozolomide [45]. An innovative approach to glioblastoma can be achieved not only through research on new biomarkers but also through new treatment technologies. Among the innovative avenues gaining traction is the study of PROteolysis TAgeting Chimeras (PROTACs) as potential game-changers in glioblastoma therapy [46]. PROTACs represent a paradigm shift in drug development, harnessing the cellular machinery to induce targeted protein degradation. In the context of glioblastoma, this approach holds the promise of selectively eliminating specific oncogenic proteins, thereby disrupting key pathways implicated in tumor progression. Yang et al. used a therapeutic nanosystem created by combining the BRD4-degrading PROTAC ARV-825 with a complex micelle. This micelle was able to penetrate the blood–brain barrier and target brain tumors. The drug released by this system shows antitumor effects by reducing cell proliferation, inducing apoptosis, and suppressing M2 macrophage polarization. These effects are achieved through the inhibition of IRF4 promoter transcription and the phosphorylation of STAT6, STAT3, and AKT [47]. To contextualize these advancements, a comprehensive understanding of the molecular landscape of glioblastoma subtypes is imperative. This molecular intricacy necessitates a tailored approach, recognizing that one-size-fits-all interventions may fall short in addressing the diverse manifestations of the disease. Neurosurgical approaches and treatment modalities are intrinsically linked to the molecular profile of the glioblastoma, and understanding these connections is pivotal in optimizing patient outcomes. The choice between maximal safe resection, adjuvant therapies, and targeted interventions hinges on a nuanced appreciation of the specific molecular signatures at play [48]. Given the complex interplay between biomarkers, neurosurgical strategies, and other therapeutic options, researchers approach a future in which personalized and precise interventions will redefine the trajectory of glioblastoma management.

3. Overview of Treatments for Gliomas

Surgery has been an important component of the management of gliomas since the late 19th century. The first surgical resection was performed in 1884 by Victor Horsley, who removed a frontal lobe glioma from a patient who had been experiencing seizures. On 25 November 1884, Mr. Rickman J. Godlee performed the first recognized resection of a primary brain tumor. The surgery was performed at the Hospital for Epilepsy and Paralysis in London, UK. The patient died postoperatively from apparent meningitis, but postmortem examination revealed no residuals of the excised glioma [49]. In the following decades, surgical techniques have continued to evolve, with the development of new tools and methods to access and remove brain tumors. In the early 20th century, Harvey Cushing became one of the most prominent neurosurgeons contributing significantly to glioma surgery. He is credited with developing the transsphenoidal approach, a minimally invasive method of accessing tumors located at the base of the skull. He also introduced the use of the operating microscope, which enabled more precise and controlled surgical resections [50]. In the mid-20th century, the use of neuroimaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) revolutionized the diagnosis and management of gliomas. These techniques enabled more accurate preoperative planning and intraoperative visualization of the tumor and surrounding brain tissue [51]. Many advances in glioma surgery have been made in recent decades, including the development of intraoperative neurophysiological monitoring, which enables the real-time monitoring of neurological function during surgery. This technique has helped to minimize the risk of neurological deficits associated with the surgical resection of gliomas [52]. In addition, image-guided navigation systems and endoscopic techniques have expanded the range of accessible tumors and increased the precision of surgical resection ^[53][54][53,54]. Despite these advances, surgical resection of gliomas remains a complex and challenging procedure, particularly for high-grade tumors located in critical or eloquent areas of the brain. Furthermore, for these cases, the development of new surgical tools, such as ultrasonic aspirators and lasers, has enabled more effective and efficient tumor removal. In recent years, interest has grown in the use of less invasive approaches, such as stereotactic radiosurgery and laser interstitial thermal therapy (LITT). These approaches may offer a less invasive alternative to surgical resection for certain types of tumors ^[55][56][55,56]. The primary goal of surgery is to safely remove as much of the glioma as possible while preserving neurological function. The extent of surgical resection is a major determinant of patient survival and functional outcomes [57]. Several factors should be considered when deciding on the optimal surgical approach to gliomas, including the location, size, and grade of the tumor, as well as the patient’s age and general health status [58]. In general, surgical resection is recommended for patients with low-grade gliomas and for those with high-grade gliomas who can tolerate the procedure [59]. The goal of surgery for high-grade gliomas is typically to achieve a safe maximal resection (SMR), which involves removing as much of the visible tumor as possible while preserving neurological function [60]. The extent of resection is typically assessed using MRI and is classified as gross total resection (GTR), subtotal resection (STR), or partial resection (PR) ^[61][62][61,62]. Several studies have demonstrated that achieving a GTR is associated with improved OS and progression-free survival (PFS) in patients with high-grade gliomas. A meta-analysis of 37 studies found that patients who underwent GTR probably increased the likelihood of 1-year survival compared with STR by about 61% and increased the likelihood of 2-year survival by about 19% (GTR compared with STR at 1 year: RR, 0.62; 95% CI, 0.56–0.69; p < 0.001) [63]. However, achieving a GTR is not always possible or safe. Indeed, in the case of tumors located in critical or eloquent areas of the brain case, the goal of surgery may be to obtain a biopsy or to remove the tumor to alleviate symptoms. Increasing evidence has shown that the use of fluorescence-guided surgery, which involves the administration of a fluorescent contrast agent that accumulates in tumor tissue, can improve the extent of glioma resection and increase PFS in patients with high-grade gliomas ^[64][65][64,65] These studies have demonstrated that patients undergoing fluorescence-guided surgery have a significantly higher rate of complete tumor resection than those undergoing conventional white-light surgery. Another recent study investigated the impact of intraoperative MRI (iMRI) on the extent of resection and patient outcomes in glioma surgery [60]. The study found that the use of iMRI can improve the extent of tumor resection and increase PFS in patients with high-grade gliomas. In addition, the use of iMRI is associated with a lower risk of postoperative neurological deficits. Advances in imaging technology have also led to the development of new tools for preoperative planning and intraoperative navigation. For example, diffusion tensor imaging (DTI) has been shown to provide valuable information on the location and orientation of white matter tracts in the brain, which can help surgeons avoid damaging these critical structures during tumor resection [66]. There has also been growing interest in the use of minimally invasive approaches for the treatment of gliomas, such as LITT and stereotactic radiosurgery (SRS). A recent study compared the effectiveness of LITT and SRS for the treatment of recurrent high-grade gliomas and found that both approaches were associated with similar rates of tumor control and survival [67]. The study suggested that LITT may be a less invasive alternative to SRS for certain types of recurrent gliomas. In summary, recent studies have focused on refining surgical techniques for glioma resection and identifying the most effective surgical strategies to improve patient outcomes. Advances in imaging technology and the development of new tools for operative navigation have also provided valuable insights into improving surgical precision and minimizing damage to surrounding brain tissue.

The Standard of Care for Gliomas

The standard of care for gliomas depends on various factors, including the grade of the tumor, the location and size of the tumor, and the patient’s health status. However, the current standard of care typically involves a combination of surgery, radiation therapy, and chemotherapy. Surgery is usually the first-line treatment and aims to remove as much of the tumor as possible while preserving critical brain functions. The extent of tumor resection is an important predictor of patient outcomes, and efforts to maximize resection while minimizing damage to the surrounding brain tissue have led to the development of various surgical techniques and technologies, such as intraoperative imaging and fluorescence-guided surgery [68]. Radiation therapy is typically used following surgery to kill any remaining tumor cells and prevent tumor regrowth. Various types of radiation therapy can be used for gliomas, including external beam radiation therapy, brachytherapy, and stereotactic radiosurgery [69]. The use of concurrent chemotherapy and radiation therapy has also been shown to improve outcomes in certain cases, such as for patients with high-grade gliomas [70]. Chemotherapy is usually reserved for cases where surgery and radiotherapy alone are not sufficient or in cases where the tumor recurs after initial treatment. Several chemotherapy agents can be used for gliomas, such as the DNA alkylating agents temozolomide (TMZ) and carmustine (BCNU) [71] TMZ is the most used drug in the treatment of high-risk gliomas after surgical resection. However, chemoresistance occurs in many patients, representing a substantial obstacle to successful therapy. A crucial role in chemoresistance is played by genes encoding for DNA repair proteins, such as DNA mismatch repair (MMR)-related proteins, O-6-methylguanine-DNA methyltransferase (MGMT), base excision repair (BER)-related proteins, AlkB homolog 2, alpha-ketoglutarate-dependent dioxygenase (ALKBH2), and proteins involved in homologous recombinational repair/non-homologous end joining (HRR/NHEJ), all of which correlate with TMZ efficacy [72]. Fortunately, today, it is possible to use a pharmacogenetically guided approach to predict the degree of sensitivity or resistance to a specific drug [73]. Although there are still barriers to overcome, pharmacogenetics, which studies responses to drug therapy based on a patient’s genetic background, is very useful in personalizing drug therapy in all medical areas ^[73][74][73,74]. Regarding TMZ, pharmacogenetic testing based on the determination of MGMT methylation status is a useful tool for predicting responses to TMZ [71]. In 2016, Buckner et al. analyzed the clinical outcomes of 254 patients younger than 40 years randomized to receive radiotherapy (n. 128) or radiotherapy with chemotherapy (n. 126). The patients had astrocytoma, oligodendroglioma, or oligoastrocytoma and, after STR, were randomly separated into two treatment groups. The results showed that, regardless of histologic type, patients who received radiotherapy with chemotherapy had a longer median OS than those who received chemotherapy alone (13.3 years vs. 7.8 years; p = 0.003). The two OS curves did not separate immediately but rather after one year in astrocytoma and about three years in oligoastrocytoma and oligodendroglioma. The two curves, in all cases, remained well separated and distinct until the end of observation, about 12 years. The study showed that disease-free survival was also higher in patients who received chemotherapy and radiotherapy than those who received only radiotherapy, but the data are less reliable because these patients were promptly treated in various ways to improve prognosis [75]. The standard of care for gliomas is continuously evolving as new treatment options and strategies are developed. Recent studies have investigated the potential benefits of immunotherapy, targeted therapy, and other therapeutic approaches [76], and clinical trials are ongoing to determine the safety and efficacy of these new treatment options [77]. Table 3 gives a brief description of each of the treatments for gliomas.