CAR-T Cells Therapy in Glioblastoma: A Systematic Review on Molecular Targets and Treatment Strategies.

The most common primary brain tumor is glioblastoma (GBM), yet the current therapeutic options for this disease are not promising. Although immunotherapeutic techniques have shown poor success in GBM thus far despite efforts, new developments provide optimism. One of these developments is chimeric antigen receptor (CAR)-T cell treatment, which includes removing and genetically modifying autologous T cells to produce a receptor that targets a GBM antigen before reintroducing the cells into the patient's body. A number of preclinical studies have produced encouraging results, which have led to the start of clinical trials assessing these CAR-T cell treatments for GBM and other brain tumors. Although results in tumors such as diffuse intrinsic pontine gliomas and lymphomas have been promising, preliminary findings in GBM have not produced any clinical benefits. The paucity of particular antigens in GBM, their inconsistent expression patterns, and the possible immunoediting-induced loss of these antigens after antigen-targeted therapy are some possible causes for this discrepancy. The goal of this systematic literature review is to assess potential approaches for creating CAR-T cells that are more effective for this indication, as well as the clinical experiences that are already being had with CAR-T cell therapy in GBM. Up until 9 May 2024, a thorough search was carried out across the three main medical databases: PubMed, Web of Science, and Scopus. Relevant Medical Subject Heading (MeSH) terms and keywords associated with "glioblastoma", "CAR-T", "T cell therapy", "overall survival", and "progression free survival" were employed in the search approach. Preclinical and clinical research on the application of CAR-T cells as a therapeutic approach for GBM are included in the review. A total of 838 papers were identified. Of these, 379 articles were assessed for eligibility, resulting in 8 articles meeting the inclusion criteria. The included studies were conducted between 2015 and 2023, with a total of 151 patients enrolled. The studies varied in CAR-T cell types. EGFRvIII CAR-T cells were the most frequently investigated, used in three studies (37.5%). Intravenous delivery was the most common method of delivery (62.5%). Median OS ranged from 5.5 to 11.1 months across the studies. PFS was reported in only two studies, with values of 7.5 months and 1.3 months. This systematic review highlights the evolving research on CAR-T cell therapy for GBM, emphasizing its potential despite challenges. Targeting antigens like EGFRvIII and IL13Rα2 shows promise in treating recurrent GBM. However, issues such as antigen escape, tumor heterogeneity, and immunosuppression require further optimization. Innovative delivery methods, combination therapies, and personalized approaches are crucial for enhancing CAR-T cell efficacy. Ongoing research is essential to refine these therapies and improve outcomes for GBM patients.

Glioma Stem Cells as Promoter of Glioma Progression: A Systematic Review of Molecular Pathways and Targeted Therapies.

Gliomas' aggressive nature and resistance to therapy make them a major problem in oncology. Gliomas continue to have dismal prognoses despite significant advancements in medical science, and traditional treatments like surgery, radiation (RT), and chemotherapy (CT) frequently prove to be ineffective. After glioma stem cells (GSCs) were discovered, the traditional view of gliomas as homogeneous masses changed. GSCs are essential for tumor growth, treatment resistance, and recurrence. These cells' distinct capacities for differentiation and self-renewal are changing our knowledge of the biology of gliomas. This systematic literature review aims to uncover the molecular mechanisms driving glioma progression associated with GSCs. The systematic review adhered to PRISMA guidelines, with a thorough literature search conducted on PubMed, Ovid MED-LINE, and Ovid EMBASE. The first literature search was performed on 1 March 2024, and the search was updated on 15 May 2024. Employing MeSH terms and Boolean operators, the search focused on molecular mechanisms associated with GCSs-mediated glioma progression. Inclusion criteria encompassed English language studies, preclinical studies, and clinical trials. A number of 957 papers were initially identified, of which 65 studies spanning from 2005 to 2024 were finally included in the review. The main GSC model distribution is arranged in decreasing order of frequency: U87: 20 studies (32.0%); U251: 13 studies (20.0%); A172: 4 studies (6.2%); and T98G: 2 studies (3.17%). From most to least frequent, the distribution of the primary GSC pathway is as follows: Notch: 8 studies (12.3%); STAT3: 6 studies (9.2%); Wnt/ß-catenin: 6 studies (9.2%); HIF: 5 studies (7.7%); and PI3K/AKT: 4 studies (6.2%). The distribution of molecular effects, from most to least common, is as follows: inhibition of differentiation: 22 studies (33.8%); increased proliferation: 18 studies (27.7%); enhanced invasive ability: 15 studies (23.1%); increased self-renewal: 5 studies (7.7%); and inhibition of apoptosis: 3 studies (4.6%). This work highlights GSC heterogeneity and the dynamic interplay within the glioblastoma microenvironment, underscoring the need for a tailored approach. A few key pathways influencing GSC behavior are JAK/STAT3, PI3K/AKT, Wnt/ß-catenin, and Notch. Therapy may target these pathways. This research urges more study to fill in knowledge gaps in the biology of GSCs and translate findings into useful treatment approaches that could improve GBM patient outcomes.

From data to practice: brain meningioma treatment in elderly patients - a survey of the Italian Society of Neurosurgery (SINch®) and systematic review and meta-analysis.

The management of meningioma in elderly patients (MEP) presents a complex and evolving challenge. Data available offer conflicting information on treatment options and complications. This survey aimed to examine the current approach to MEP, comparing the national profile to data in the current literature. A survey addressing the treatments options and management of meningioma in elderly was designed on behalf of SINch® (Società Italiana di Neurochirurgia) and sent via email to all Chiefs of Neurosurgical Departments. The survey remained open for responses from May 5th, 2022, until November 21st, 2022. A search of the literature published between January 2000 and March 2023, in accordance to PRISMA guidelines, was included. A total of 51 Neurosurgical centers participated in the survey. The caseload profile of each center influences the choice of treatment selection (Stereotactic Radiosurgery versus open surgery) (p = 0.01) and the consolidated practice of discussing cases within a multidisciplinary group (p = 0.02). The pooled meta-analysis demonstrated a significant increased risk in the elderly group for permanent deficits (p < 0.00001), postoperative infections (p = 0.0004) and hemorrhage (p = 0.0001), perioperative mortality (p < 0.00001), and medical complications (p < 0.00001) as compared to the young population. This study presents the initial comprehensive analysis of the existing trends in the surgical management of MEP in Italy. The significant variation in practices primarily stems from the absence of standardized guidelines. While most centers have adopted an integrated approach, there is a need to promote a multidisciplinary care model. Prospective studies are needed to gather robust evidence in this clinical setting.

The Current Diagnostic Performance of MRI-Based Radiomics for Glioma Grading: A Meta-Analysis.

BACKGROUND: Multiple radiomics models have been proposed for grading glioma using different algorithms, features, and sequences of magnetic resonance imaging. The research seeks to assess the present overall performance of radiomics for grading glioma. METHODS: A systematic literature review of the databases Ovid MEDLINE PubMed, and Ovid EMBASE for publications published on radiomics for glioma grading between 2012 and 2023 was performed. The systematic review was carried out following the criteria of Preferred Reporting Items for Systematic Reviews and Meta-Analysis. RESULTS: In the meta-analysis, a total of 7654 patients from 40 articles, were assessed. R-package mada was used for modeling the joint estimates of specificity (SPE) and sensitivity (SEN). Pooled event rates across studies were performed with a random-effects meta-analysis. The heterogeneity of SPE and SEN were based on the χ2 test. Overall values for SPE and SEN in the differentiation between high-grade gliomas (HGGs) and low-grade gliomas (LGGs) were 84% and 91%, respectively. With regards to the discrimination between World Health Organization (WHO) grade 4 and WHO grade 3, the overall SPE was 81% and the SEN was 89%. The modern non-linear classifiers showed a better trend, whereas textural features tend to be the best-performing (29%) and the most used. CONCLUSIONS: Our findings confirm that present radiomics' diagnostic performance for glioma grading is superior in terms of SEN and SPE for the HGGs vs. LGGs discrimination task when compared to the WHO grade 4 vs. 3 task.

Role of glioma stem cells in promoting tumor chemo- and radioresistance: A systematic review of potential targeted treatments.

BACKGROUND: Gliomas pose a significant challenge to effective treatment despite advancements in chemotherapy and radiotherapy. Glioma stem cells (GSCs), a subset within tumors, contribute to resistance, tumor heterogeneity, and plasticity. Recent studies reveal GSCs' role in therapeutic resistance, driven by DNA repair mechanisms and dynamic transitions between cellular states. Resistance mechanisms can involve different cellular pathways, most of which have been recently reported in the literature. Despite progress, targeted therapeutic approaches lack consensus due to GSCs' high plasticity. AIM: To analyze targeted therapies against GSC-mediated resistance to radio- and chemotherapy in gliomas, focusing on underlying mechanisms. METHODS: A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to September 30, 2023. The search strategy utilized relevant Medical Subject Heading terms and keywords related to including "glioma stem cells", "radiotherapy", "chemotherapy", "resistance", and "targeted therapies". Studies included in this review were publications focusing on targeted therapies against the molecular mechanism of GSC-mediated resistance to radiotherapy resistance (RTR). RESULTS: In a comprehensive review of 66 studies on stem cell therapies for SCI, 452 papers were initially identified, with 203 chosen for full-text analysis. Among them, 201 were deemed eligible after excluding 168 for various reasons. The temporal breakdown of studies illustrates this trend: 2005-2010 (33.3%), 2011-2015 (36.4%), and 2016-2022 (30.3%). Key GSC models, particularly U87 (33.3%), U251 (15.2%), and T98G (15.2%), emerge as significant in research, reflecting their representativeness of glioma characteristics. Pathway analysis indicates a focus on phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) (27.3%) and Notch (12.1%) pathways, suggesting their crucial roles in resistance development. Targeted molecules with mTOR (18.2%), CHK1/2 (15.2%), and ATP binding cassette G2 (12.1%) as frequent targets underscore their importance in overcoming GSC-mediated resistance. Various therapeutic agents, notably RNA inhibitor/short hairpin RNA (27.3%), inhibitors (e.g., LY294002, NVP-BEZ235) (24.2%), and monoclonal antibodies (e.g., cetuximab) (9.1%), demonstrate versatility in targeted therapies. among 20 studies (60.6%), the most common effect on the chemotherapy resistance response is a reduction in temozolomide resistance (51.5%), followed by reductions in carmustine resistance (9.1%) and doxorubicin resistance (3.0%), while resistance to RTR is reduced in 42.4% of studies. CONCLUSION: GSCs play a complex role in mediating radioresistance and chemoresistance, emphasizing the necessity for precision therapies that consider the heterogeneity within the GSC population and the dynamic tumor microenvironment to enhance outcomes for glioblastoma patients.

Chordoma Genetic Aberrations and Targeted Therapies Panorama: A Systematic Literature Review.

Background: Chordomas pose a challenge in treatment due to their local invasiveness, high recurrence, and potential lethality. Despite being slow-growing and rarely metastasizing, these tumors often resist conventional chemotherapies (CTs) and radiotherapies (RTs), making surgical resection a crucial intervention. However, achieving radical resection for chordomas is seldom possible, presenting therapeutic challenges. The accurate diagnosis of these tumors is vital for their distinct prognoses, yet differentiation is hindered by overlapping radiological and histopathological features. Fortunately, recent molecular and genetic studies, including extracranial location analysis, offer valuable insights for precise diagnosis. This literature review delves into the genetic aberrations and molecular biology of chordomas, aiming to provide an overview of more successful therapeutic strategies. Methods: A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 28 January 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "chordomas", "molecular biology", "gene aberrations", and "target therapies". The studies included in this review consist of preclinical cell studies, case reports, case series, randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on genetic and biological aberrations in chordomas. Results: Of the initial 297 articles identified, 40 articles were included in the article. Two tables highlighted clinical studies and ongoing clinical trials, encompassing 18 and 22 studies, respectively. The clinical studies involved 185 patients diagnosed with chordomas. The tumor sites were predominantly sacral (n = 8, 44.4%), followed by clivus (n = 7, 38.9%) and lumbar spine (n = 3, 16.7%). Primary treatments preceding targeted therapies included surgery (n = 10, 55.6%), RT (n = 9, 50.0%), and systemic treatments (n = 7, 38.9%). Various agents targeting specific molecular pathways were analyzed in the studies, such as imatinib (a tyrosine kinase inhibitor), erlotinib, and bevacizumab, which target EGFR/VEGFR. Common adverse events included fatigue (47.1%), skin reactions (32.4%), hypertension (23.5%), diarrhea (17.6%), and thyroid abnormalities (5.9%). Clinical outcomes were systematically assessed based on progression-free survival (PFS), overall survival (OS), and tumor response evaluated using RECIST or CHOI criteria. Notably, stable disease (SD) occurred in 58.1% of cases, and partial responses (PRs) were observed in 28.2% of patients, while 13.7% experienced disease progression (PD) despite targeted therapy. Among the 22 clinical trials included in the analysis, Phase II trials were the most prevalent (40.9%), followed by I-II trials (31.8%) and Phase I trials (27.3%). PD-1 inhibitors were the most frequently utilized, appearing in 50% of the trials, followed by PD-L1 inhibitors (36.4%), CTLA-4 inhibitors (22.7%), and mTOR inhibitors (13.6%). Conclusions: This systematic review provides an extensive overview of the state of targeted therapy for chordomas, highlighting their potential to stabilize the illness and enhance clinical outcomes.

Comparative Efficacy of Transsphenoidal and Transcranial Approaches for Treating Tuberculum Sellae Meningiomas: A Systematic Review and Meta-Analysis.

Background/Objectives: Tuberculum sellae meningiomas (TSMs) constitute 5-10% of intracranial meningiomas, often causing visual impairment. Traditional microsurgical transcranial approaches (MTAs) have been effective, but the emergence of innovative surgical trajectories, such as endoscopic endonasal approaches (EEAs), has sparked debate. While EEAs offer advantages like reduced brain retraction, they are linked to higher cerebrospinal fluid leak (CSF leak) risk. This meta-analysis aims to comprehensively compare the efficacy and safety of EEAs and MTAs for the resection of TSMs, offering insights into their respective outcomes and complications. Methods: A comprehensive literature review of the databases PubMed, Ovid MEDLINE, and Ovid EMBASE was conducted for articles published on TSMs treated with either EEA or MTA until 2024. The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Meta-analysis was performed to estimate pooled event rates and assess heterogeneity. Fixed- and random-effects were used to assess 95% confidential intervals (CIs) of presenting symptoms, outcomes, and complications. Results: A total of 291 papers were initially identified, of which 18 studies spanning from 2000 to 2024 met the inclusion criteria. The exclusion of 180 articles was due to reasons such as irrelevance, non-reporting of selected results, systematic literature review or meta-analysis, and a lack of details on method/results. The 18 studies comprised a total sample of 1093 patients: 444 patients who underwent EEAs and 649 patients who underwent MTAs for TSMs. Gross total resection (GTR) rates ranged from 80.9% for EEAs to 79.8% for MTAs. The rate of visual improvement was 86.6% in the EEA group and 65.4% in the MTA group. The recurrence rate in the EEA group was 6.9%, while it was 5.1% in MTA group. The postoperative complications analyzed were CSF leak, infections, dysosmia, intracranial hemorrhage (ICH), and endocrine disorders. The rate of CSF leak was 9.8% in the EEA group and 2.1% in MTA group. The rate of infections in the EEA group was 5.7%, while it was 3.7% in the MTA group. The rate of dysosmia ranged from 10.3% for MTAs to 12.9% for EEAs. The rate of ICH in the EEA group was 0.9%, while that in the MTA group was 3.8%. The rate of endocrine disorders in the EEA group was 10.8%, while that in the MTA group was 10.2%. No significant difference was detected in the rate of GTR between the EEA and MTA groups (OR 1.15, 95% CI 0.7-0.95; p = 0.53), while a significant benefit in visual outcomes was shown in EEAs (OR 3.54, 95% CI 2.2-5.72; p < 0.01). There was no significant variation in the recurrence rate between EEA and MTA groups (OR 0.92, 95% CI 0.19-4.46; p = 0.89). While a considerably increased chance of CSF leak from EEAs was shown (OR 4.47, 95% CI 2.52-7.92; p < 0.01), no significant difference between EEA and MTA groups was detected in the rate of infections (OR 1.92, 95% CI 0.73-5.06; p = 0.15), the rate of dysosmia (OR 1.25, 95% CI 0.31-4.99; p = 0.71), the rate of ICH (OR 0.61, 95% CI 0.20-1.87; p = 0.33), and the rate of endocrine disorders (OR 1.16, 95% CI 0.69-1.95; p = 0.53). Conclusions: This meta-analysis suggests that both EEAs and MTAs are viable options for TSM resection, with distinct advantages and drawbacks. The EEAs demonstrate superior visual outcomes in selected cases while GTR and recurrence rates support the overall effectiveness of MTAs and EEAs. Endoscopic endonasal approaches had a higher chance of CSF leaks, but there are no appreciable variations in other complications. These results provide additional insights regarding patient outcomes in the intricate clinical setting of TSMs.

Current status and future perspectives on stem cell transplantation for spinal cord injury.

BACKGROUND: Previous assessments of stem cell therapy for spinal cord injuries (SCI) have encountered challenges and constraints. Current research primarily emphasizes safety in early-phase clinical trials, while systematic reviews prioritize effectiveness, often overlooking safety and translational feasibility. This situation prompts inquiries regarding the readiness for clinical adoption. AIM: To offer an up-to-date systematic literature review of clinical trial results con cerning stem cell therapy for SCI. METHODS: A systematic search was conducted across major medical databases [PubMed, Embase, Reference Citation Analysis (RCA), and Cochrane Library] up to October 14, 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "spinal cord", "injury", "clinical trials", "stem cells", "functional outcomes", and "adverse events". Studies included in this review consisted of randomized controlled trials and non-randomized controlled trials reporting on the use of stem cell therapies for the treatment of SCI. RESULTS: In a comprehensive review of 66 studies on stem cell therapies for SCI, 496 papers were initially identified, with 237 chosen for full-text analysis. Among them, 236 were deemed eligible after excluding 170 for various reasons. These studies encompassed 1086 patients with varying SCI levels, with cervical injuries being the most common (42.2%). Bone marrow stem cells were the predominant stem cell type used (71.1%), with various administration methods. Follow-up durations averaged around 84.4 months. The 32.7% of patients showed functional impro vement from American spinal injury association Impairment Scale (AIS) A to B, 40.8% from AIS A to C, 5.3% from AIS A to D, and 2.1% from AIS B to C. Sensory improvements were observed in 30.9% of patients. A relatively small number of adverse events were recorded, including fever (15.1%), headaches (4.3%), muscle tension (3.1%), and dizziness (2.6%), highlighting the potential for SCI recovery with stem cell therapy. CONCLUSION: In the realm of SCI treatment, stem cell-based therapies show promise, but clinical trials reveal potential adverse events and limitations, underscoring the need for meticulous optimization of transplantation conditions and parameters, caution against swift clinical implementation, a deeper understanding of SCI pathophysiology, and addressing ethical, tumorigenicity, immunogenicity, and immunotoxicity concerns before gradual and careful adoption in clinical practice.

Advancing the Management of Skull Base Chondrosarcomas: A Systematic Review of Targeted Therapies.

BACKGROUND: Chondrosarcomas rank as the second most common primary bone malignancy. Characterized by the production of a cartilaginous matrix, these tumors typically exhibit resistance to both radiotherapy (RT) and chemotherapy (CT), resulting in overall poor outcomes: a high rate of mortality, especially among children and adolescents. Due to the considerable resistance to current conventional therapies such as surgery, CT, and RT, there is an urgent need to identify factors contributing to resistance and discover new strategies for optimal treatment. Over the past decade, researchers have delved into the dysregulation of genes associated with tumor development and therapy resistance to identify potential therapeutic targets for overcoming resistance. Recent studies have suggested several promising biomarkers and therapeutic targets for chondrosarcoma, including isocitrate dehydrogenase (IDH1/2) and COL2A1. Molecule-targeting agents and immunotherapies have demonstrated favorable antitumor activity in clinical studies involving patients with advanced chondrosarcomas. In this systematic review, we delineate the clinical features of chondrosarcoma and provide a summary of gene dysregulation and mutation associated with tumor development, as well as targeted therapies as a promising molecular approach. Finally, we analyze the probable role of the tumor microenvironment in chondrosarcoma drug resistance. METHODS: A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 10 November 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "chondrosarcomas", "target therapies", "immunotherapies", and "outcomes". The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of target therapies for the treatment of chondrosarcoma in human subjects. RESULTS: Of the initial 279 articles identified, 40 articles were included in the article. The exclusion of 140 articles was due to reasons such as irrelevance, non-reporting of selected results, systematic literature review or meta-analysis, and lack of details on the method/results. Three tables highlighted clinical studies, preclinical studies, and ongoing clinical trials, encompassing 13, 7, and 20 studies, respectively. For the clinical study, a range of molecular targets, such as death receptors 4/5 (DR4 and DR5) (15%), platelet-derived growth factor receptor-alpha or -beta (PDGFR-α, PDGFR-ß) (31%), were investigated. Adverse events were mainly constitutional symptoms emphasizing that to improve therapy tolerance, careful observation and tailored management are essential. Preclinical studies analyzed various molecular targets such as DR4/5 (28.6%) and COX-2 (28.6%). The prevalent indicator of antitumoral activity was the apoptotic rate of both a single agent (tumor necrosis factor-related apoptosis-inducing ligand: TRAIL) and double agents (TRAIL-DOX, TRAIL-MG132). Ongoing clinical trials, the majority in Phase II (53.9%), highlighted possible therapeutic strategies such as IDH1 inhibitors and PD-1/PD-L1 inhibitors (30.8%). CONCLUSIONS: The present review offers a comprehensive analysis of targeted therapeutics for skull base chondrosarcomas, highlighting a complex landscape characterized by a range of treatment approaches and new opportunities for tailored interventions. The combination of results from molecular research and clinical trials emphasizes the necessity for specialized treatment strategies and the complexity of chondrosarcoma biology.

Navigating the Nose-to-Brain Route: A Systematic Review on Lipid-Based Nanocarriers for Central Nervous System Disorders.

BACKGROUND: The blood-brain barrier (BBB) regulates brain substance entry, posing challenges for treating brain diseases. Traditional methods face limitations, leading to the exploration of non-invasive intranasal drug delivery. This approach exploits the direct nose-to-brain connection, overcoming BBB restrictions. Intranasal delivery enhances drug bioavailability, reduces dosage, and minimizes systemic side effects. Notably, lipid nanoparticles, such as solid lipid nanoparticles and nanostructured lipid carriers, offer advantages like improved stability and controlled release. Their nanoscale size facilitates efficient drug loading, enhancing solubility and bioavailability. Tailored lipid compositions enable optimal drug release, which is crucial for chronic brain diseases. This review assesses lipid nanoparticles in treating neuro-oncological and neurodegenerative conditions, providing insights for effective nose-to-brain drug delivery. METHODS: A systematic search was conducted across major medical databases (PubMed, Ovid MEDLINE, and Scopus) up to 6 January 2024. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "lipid nanoparticles", "intranasal administration", "neuro-oncological diseases", and "neurodegenerative disorders". This review consists of studies in vitro, in vivo, or ex vivo on the intranasal administration of lipid-based nanocarriers for the treatment of brain diseases. RESULTS: Out of the initial 891 papers identified, 26 articles met the eligibility criteria after a rigorous analysis. The exclusion of 360 articles was due to reasons such as irrelevance, non-reporting selected outcomes, the article being a systematic literature review or meta-analysis, and lack of method/results details. This systematic literature review, focusing on nose-to-brain drug delivery via lipid-based nanocarriers for neuro-oncological, neurodegenerative, and other brain diseases, encompassed 60 studies. A temporal distribution analysis indicated a peak in research interest between 2018 and 2020 (28.3%), with a steady increase over time. Regarding drug categories, Alzheimer's disease was prominent (26.7%), followed by antiblastic drugs (25.0%). Among the 65 drugs investigated, Rivastigmine, Doxorubicin, and Carmustine were the most studied (5.0%), showcasing a diverse approach to neurological disorders. Notably, solid lipid nanoparticles (SLNs) were predominant (65.0%), followed by nanostructured lipid carriers (NLCs) (28.3%), highlighting their efficacy in intranasal drug delivery. Various lipids were employed, with glyceryl monostearate being prominent (20.0%), indicating preferences in formulation. Performance assessment assays were balanced, with in vivo studies taking precedence (43.3%), emphasizing the translation of findings to complex biological systems for potential clinical applications. CONCLUSIONS: This systematic review reveals the transformative potential of intranasal lipid nanoparticles in treating brain diseases, overcoming the BBB. Positive outcomes highlight the effectiveness of SLNs and NLCs, which are promising new approaches for ailments from AD to stroke and gliomas. While celebrating progress, addressing challenges like nanoparticle toxicity is also crucial.

Hydrocephalus and the First Report of an External Ventriculostomy: The Contributions of Fabrici d'Acquapendente in the Italian Renaissance.

In our historical study, we are unveiling one of the very first surgical treatments of hydrocephalus originally scripted in Latin by Fabrici d'Acquapendente and then transcribed into the French language by Chez Pierre Ravaud. During the European Renaissance, Italian pioneering surgeon Fabricid'Acquapendente illustrated the technique performed at that time. Fabrici described the drainage of fluid for hydrocephalus using the insertion of a cannula. The cannula was kept in place for several days and the fluid was drained slowly and in regulated controlled amounts. Layers of bandage drapes were applied to prevent the leakage of fluid escaping from the wound. Unfortunately, we are missing some significant information regarding the surgical techniques as these were not documented by Fabrici. Although skull trephination was relatively well known, it is unsure whether at the time the cannula was inserted deep within the ventricles. Drainage of the fluid may have still occurred from the extracranial space. Moreover, we are unaware of how long the cannula was kept in place. Nonetheless, Fabrici d'Acquapendente may be considered among the first in Italy and possibly in Europe to lay down the foundations for external ventricular drainage system for hydrocephalus.

Radiomics for differentiation of gliomas from primary central nervous system lymphomas: a systematic review and meta-analysis.

Background and objective: Numerous radiomics-based models have been proposed to discriminate between central nervous system (CNS) gliomas and primary central nervous system lymphomas (PCNSLs). Given the heterogeneity of the existing models, we aimed to define their overall performance and identify the most critical variables to pilot future algorithms. Methods: A systematic review of the literature and a meta-analysis were conducted, encompassing 12 studies and a total of 1779 patients, focusing on radiomics to differentiate gliomas from PCNSLs. A comprehensive literature search was performed through PubMed, Ovid MEDLINE, Ovid EMBASE, Web of Science, and Scopus databases. Overall sensitivity (SEN) and specificity (SPE) were estimated. Event rates were pooled using a random-effects meta-analysis, and the heterogeneity was assessed using the χ2 test. Results: The overall SEN and SPE for differentiation between CNS gliomas and PCNSLs were 88% (95% CI = 0.83 - 0.91) and 87% (95% CI = 0.83 - 0.91), respectively. The best-performing features were the ones extracted from the Gray Level Run Length Matrix (GLRLM; ACC 97%), followed by those obtained from the Neighboring Gray Tone Difference Matrix (NGTDM; ACC 93%), and shape-based features (ACC 91%). The 18F-FDG-PET/CT was the best-performing imaging modality (ACC 97%), followed by the MRI CE-T1W (ACC 87% - 95%). Most studies applied a cross-validation analysis (92%). Conclusion: The current SEN and SPE of radiomics to discriminate CNS gliomas from PCNSLs are high, making radiomics a helpful method to differentiate these tumor types. The best-performing features are the GLRLM, NGTDM, and shape-based features. The 18F-FDG-PET/CT imaging modality is the best-performing, while the MRI CE-T1W is the most used.

A Systematic Review of the Metabolism of High-Grade Gliomas: Current Targeted Therapies and Future Perspectives.

High-grade glial tumors (HGGs) exhibit aggressive growth patterns and high recurrence rates. The prevailing treatment approach comprises radiation therapy (RT), chemotherapy (CMT), and surgical resection. Despite the progress made in traditional treatments, the outlook for patients with HGGs remains bleak. Tumor metabolism is emerging as a potential target for glioma therapies, a promising approach that harnesses the metabolism to target tumor cells. However, the efficacy of therapies targeting the metabolism of HGGs remains unclear, compelling a comprehensive review. This study aimed to assess the outcome of present trials on HGG therapies targeting metabolism. A comprehensive search of PubMed, Ovid MEDLINE, and Ovid EMBASE was conducted until November 2023. The search method used pertinent Medical Subject Heading (MeSH) terminologies and keywords referring to "high-grade gliomas", "metabolism", "target therapies", "monoclonal antibodies", "overall survival", and "progression-free survival". The review analyzed studies that focused on therapies targeting the metabolism of HGGs in human subjects. These studies included both randomized controlled trials (RCTs) and non-randomized controlled trials (NRCTs). Out of 284 articles identified, 23 trials met the inclusion criteria and were thoroughly analyzed. Phase II trials were the most numerous (62%). Targeted metabolic therapies were predominantly used for recurrent HGGs (67%). The most common targeted pathways were the vascular endothelial growth factor (VEGF, 43%), the human epidermal growth factor receptor (HER, 22%), the platelet-derived growth factor (PDGF, 17%), and the mammalian target of rapamycin (mTOR, 17%). In 39% of studies, the subject treatment was combined with CMT (22%), RT (4%), or both (13%). The median OS widely ranged from 4 to 26.3 months, while the median PFS ranged from 1.5 to 13 months. This systematic literature review offers a thorough exploration of the present state of metabolic therapies for HGGs. The multitude of targeted pathways underscores the intricate nature of addressing the metabolic aspects of these tumors. Despite existing challenges, these findings provide valuable insights, guiding future research endeavors. The results serve as a foundation for refining treatment strategies and enhancing patient outcomes within the complex landscape of HGGs.

Advancing Craniopharyngioma Management: A Systematic Review of Current Targeted Therapies and Future Perspectives.

Craniopharyngiomas present unique challenges in surgical management due to their proximity to critical neurovascular structures. This systematic review investigates genetic and immunological markers as potential targets for therapy in craniopharyngiomas, assessing their involvement in tumorigenesis, and their influence on prognosis and treatment strategies. The systematic review adhered to PRISMA guidelines, with a thorough literature search conducted on PubMed, Ovid MED-LINE, and Ovid EMBASE. Employing MeSH terms and Boolean operators, the search focused on craniopharyngiomas, targeted or molecular therapy, and clinical outcomes or adverse events. Inclusion criteria encompassed English language studies, clinical trials (randomized or non-randomized), and investigations into adamantinomatous or papillary craniopharyngiomas. Targeted therapies, either standalone or combined with chemotherapy and/or radiotherapy, were examined if they included clinical outcomes or adverse event analysis. Primary outcomes assessed disease response through follow-up MRI scans, categorizing responses as follows: complete response (CR), near-complete response (NCR), partial response, and stable or progressive disease based on lesion regression percentages. Secondary outcomes included treatment type and duration, as well as adverse events. A total of 891 papers were initially identified, of which 26 studies spanning from 2000 to 2023 were finally included in the review. Two tables highlighted adamantinomatous and papillary craniopharyngiomas, encompassing 7 and 19 studies, respectively. For adamantinomatous craniopharyngiomas, Interferon-2α was the predominant targeted therapy (29%), whereas dabrafenib took precedence (70%) for papillary craniopharyngiomas. Treatment durations varied, ranging from 1.7 to 28 months. Positive responses, including CR or NCR, were observed in both types of craniopharyngiomas (29% CR for adamantinomatous; 32% CR for papillary). Adverse events, such as constitutional symptoms and skin changes, were reported, emphasizing the need for vigilant monitoring and personalized management to enhance treatment tolerability. Overall, the data highlighted a diverse landscape of targeted therapies with encouraging responses and manageable adverse events, underscoring the importance of ongoing research and individualized patient care in the exploration of treatment options for craniopharyngiomas. In the realm of targeted therapies for craniopharyngiomas, tocilizumab and dabrafenib emerged as prominent choices for adamantinomatous and papillary cases, respectively. While adverse events were common, their manageable nature underscored the importance of vigilant monitoring and personalized management. Acknowledging limitations, future research should prioritize larger, well-designed clinical trials and standardized treatment protocols to enhance our understanding of the impact of targeted therapies on craniopharyngioma patients.

Neuropsychological Evaluation and Functional Magnetic Resonance Imaging Tasks in the Preoperative Assessment of Patients with Brain Tumors: A Systematic Review.

BACKGROUND: Current surgical treatment of gliomas relies on a function-preserving, maximally safe resection approach. Functional Magnetic Resonance Imaging (fMRI) is a widely employed technology for this purpose. A preoperative neuropsychological evaluation should accompany this exam. However, only a few studies have reported both neuropsychological tests and fMRI tasks for preoperative planning-the current study aimed to systematically review the scientific literature on the topic. METHODS: PRISMA guidelines were followed. We included studies that reported both neuropsychological tests and fMRI. Exclusion criteria were: no brain tumors, underage patients, no preoperative assessment, resting-state fMRI only, or healthy sample population/preclinical studies. RESULTS: We identified 123 papers, but only 15 articles were included. Eight articles focused on language; three evaluated cognitive performance; single papers studied sensorimotor cortex, prefrontal functions, insular cortex, and cerebellar activation. Two qualitative studies focused on visuomotor function and language. According to some authors, there was a strong correlation between performance in presurgical neuropsychological tests and fMRI. Several papers suggested that selecting well-adjusted and individualized neuropsychological tasks may enable the development of personalized and more efficient protocols. The fMRI findings may also help identify plasticity phenomena to avoid unintentional damage during neurosurgery. CONCLUSIONS: Most studies have focused on language, the most commonly evaluated cognitive function. The correlation between neuropsychological and fMRI results suggests that altered functions during the neuropsychological assessment may help identify patients who could benefit from an fMRI and, possibly, functions that should be tested. Neuropsychological evaluation and fMRI have complementary roles in the preoperative assessment.

Glioblastoma Immunotherapy: A Systematic Review of the Present Strategies and Prospects for Advancements.

Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients remains poor. Immunotherapy has recently emerged as a potential treatment option. The aim of this systematic review is to assess the current strategies and future perspectives of the GBM immunotherapy strategies. A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 3 September 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "glioblastomas," "immunotherapies," and "treatment." The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of immunotherapies for the treatment of gliomas in human subjects. A total of 1588 papers are initially identified. Eligibility is confirmed for 752 articles, while 655 are excluded for various reasons, including irrelevance to the research topic (627), insufficient method and results details (12), and being case-series or cohort studies (22), systematic literature reviews, or meta-analyses (3). All the studies within the systematic review were clinical trials spanning from 1995 to 2023, involving 6383 patients. Neuro-oncology published the most glioma immunotherapy-related clinical trials (15/97, 16%). Most studies were released between 2018 and 2022, averaging nine publications annually during this period. Adoptive cellular transfer chimeric antigen receptor (CAR) T cells were the primary focus in 11% of the studies, with immune checkpoint inhibitors (ICIs), oncolytic viruses (OVs), and cancer vaccines (CVs) comprising 26%, 12%, and 51%, respectively. Phase-I trials constituted the majority at 51%, while phase-III trials were only 7% of the total. Among these trials, 60% were single arm, 39% double arm, and one multi-arm. Immunotherapies were predominantly employed for recurrent GBM (55%). The review also revealed ongoing clinical trials, including 9 on ICIs, 7 on CVs, 10 on OVs, and 8 on CAR T cells, totaling 34 trials, with phase-I trials representing the majority at 53%, and only one in phase III. Overcoming immunotolerance, stimulating robust tumor antigen responses, and countering immunosuppressive microenvironment mechanisms are critical for curative GBM immunotherapy. Immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors, show promise, with the ongoing research aiming to enhance their effectiveness. Personalized cancer vaccines, especially targeting neoantigens, offer substantial potential. Oncolytic viruses exhibited dual mechanisms and a breakthrough status in the clinical trials. CAR T-cell therapy, engineered for specific antigen targeting, yields encouraging results, particularly against IL13 Rα2 and EGFRvIII. The development of second-generation CAR T cells with improved specificity exemplifies their adaptability.

Surgical Treatment of Spheno-Orbital Meningiomas: A Systematic Review and Meta-Analysis of Surgical Techniques and Outcomes.

BACKGROUND: Spheno-orbital meningiomas (SOMs) are rare tumors arising from the meninges surrounding the sphenoid bone and orbital structures. Surgical resection is the primary treatment approach for SOMs. Several surgical approaches have been described during the decades, including microsurgical transcranial (MTAs), endoscopic endonasal (EEAs), endoscopic transorbital (ETOAs), and combined approaches, and the choice of surgical approach remains a topic of debate. PURPOSE: This systematic review and meta-analysis aim to compare the clinical and surgical outcomes of different surgical approaches used for the treatment of SOMs, discussing surgical techniques, outcomes, and factors influencing surgical decision making. METHODS: A comprehensive literature review of the databases PubMed, Ovid MEDLINE, and Ovid EMBASE was conducted for articles published on the role of surgery for the treatment of SOMs until 2023. The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Meta-analysis was performed to estimate pooled event rates and assess heterogeneity. Fixed- and random-effects were used to assess 95% confidential intervals (CIs) of presenting symptoms, outcomes, and complications. RESULTS: A total of 59 studies comprising 1903 patients were included in the systematic review and meta-analysis. Gross total resection (GTR) rates ranged from 23.5% for ETOAs to 59.8% for MTAs. Overall recurrence rate after surgery was 20.7%. Progression-free survival (PFS) rates at 5 and 10 years were 75.5% and 49.1%, respectively. Visual acuity and proptosis improvement rates were 57.5% and 79.3%, respectively. Postoperative cranial nerve (CN) focal deficits were observed in 20.6% of cases. The overall cerebro-spinal fluid (CSF) leak rate was 3.9%, and other complications occurred in 13.9% of cases. MTAs showed the highest GTR rates (59.8%, 95%CI = 49.5-70.2%; p = 0.001) but were associated with increased CN deficits (21.0%, 95%CI = 14.5-27.6%). ETOAs had the lowest GTR rates (23.5%, 95%CI = 0.0-52.5%; p = 0.001), while combined ETOA and EEA had the highest CSF leak rates (20.3%, 95%CI = 0.0-46.7%; p = 0.551). ETOAs were associated with better proptosis improvement (79.4%, 95%CI = 57.3-100%; p = 0.002), while anatomical class I lesions were associated with better visual acuity (71.5%, 95%CI = 63.7-79.4; p = 0.003) and proptosis (60.1%, 95%CI = 38.0-82.2; p = 0.001) recovery. No significant differences were found in PFS rates between surgical approaches. CONCLUSION: Surgical treatment of SOMs aims to preserve visual function and improve proptosis. Different surgical approaches offer varying rates of GTR, complications, and functional outcomes. A multidisciplinary approach involving a skull base team is crucial for optimizing patient outcomes.

Liquid Biopsy in Low-Grade Glioma: A Systematic Review and a Proposal for a Clinical Utility Score.

Liquid biopsy research on Low-Grade gliomas (LGG) has remained less conspicuous than that on other malignant brain tumors. Reliable serum markers would be precious for diagnosis, follow- up and treatment. We propose a clinical utility score (CUS) for biomarkers in LGG that mirrors their clinical usefulness. We conducted a PRISMA review. We examined each biomarker classifying them by CUS and Level of Evidence (LOE). We identified four classes of biomarkers: (1). Circulating protein-(a) vitronectin discriminates LGG from HGG (Sn:98%, Sp:91%, CUS: 3, LOE: III), (b) CTLA-4 discriminates LGG from HGG, (cutoff: 220.43 pg/ml, Sn: 82%, Sp: 78%, CUS:3, LOE:III), (c) pre-operative TGF b1 predict astrocytoma (cutoff: 2.52 ng/ml, Sn: 94.9%, Sp: 100%, CUS:3, LOE:VI). (2). micro-RNA (miR)-(a) miR-16 discriminates between WHO IV and WHO II and III groups (AUC = 0.98, CUS:3, LOE: III), (b) miR-454-3p is higher in HGG than in LGG (p = 0.013, CUS:3, LOE: III), (c) miR-210 expression is related to WHO grades (Sn 83.2%, Sp 94.3%, CUS: 3, LOE: III). (3). Circulating DNA-(a) IDH1R132H mutation detected in plasma by combined COLD and digital PCR (Sn: 60%, Sp: 100%, CUS: 3, LOE: III). 4. Exosomes-(a) SDC1 serum levels could discriminate GBM from LGG (Sn: 71%, Sp: 91%, CUS: 2C, LOE: VI). Our investigation showed that miRs appear to have the highest clinical utility. The LOE of the studies assessed is generally low. A combined approach between different biomarkers and traditional diagnostics may be considered. We identified four main classes of biomarkers produced by LGG. We examined each biomarker, classifying them by clinical utility score (CUS) and level of evidence (LOE). Micro-RNA (miRs) appears to have the highest CUS and LOE.

Stem Cells in Facial Regenerative Surgery: Current Clinical Applications. A Multidisciplinary, Systematic Review.

BACKGROUND: Facial reconstruction represents one of the main challenges for surgeons. Stem cells (SC) represent the most studied solution for tissue regeneration. This approach appears particularly promising in combination with bioengineered scaffolds and 3D bioprinting. The purpose of this systematic review is to define the main domains of current application of SC therapy within contemporary clinical workflows, evaluate indications and limitations, report current knowledge in this innovative field of research, and define the landscape of evidence for such approaches. METHODS: A systematic review was performed on the pertinent literature regarding stem cell-based cell therapies currently available in the reconstruction of the face. The review used the main databases for scientific literature based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: A total of 15 papers were selected after an independent search was performed. The two major domains for current application of stem cells in clinical practice were bone and skin categories. CONCLUSIONS: Cell therapy in the field of facial reconstruction represents a promising approach. The evidence regarding the current clinical use, however, seems to show this option to be limited. Bioengineering advances and the parallel development of 3D bioprinting technology can potentially enhance the role of stem cells in the future.

The impact of COVID-19 pandemic on surgical neuro-oncology: A survey from the Italian society of neurosurgery (SINch).

Background: The COVID-19 pandemic and its impact on hospitals' activity and organization has imposed a vast change in standard neurosurgical oncology practice to accommodate for shifting resources. Aims: This investigation aims to analyse the nationwide capability in reorganizing the surgical neuro-oncological activity during the COVID-19 pandemic to evaluate whether COVID-19-pandemic influenced the surgical management in these patients. Method: A web-based dataset model organized by the Italian Neurosurgical Society (SINCh) was sent to all the Italian neurosurgical departments in May 2021, requesting to report the types and numbers of surgical procedures performed in the pre-pandemic period (from March 9th 2019 to March 9th 2020) compared to the pandemic period (from March 10th 2020 to March 10th 2021). Results: This multicentre investigation included the surgical activity of 35 Italian Neurosurgical Departments in a pre-pandemic year versus a pandemic year. During the COVID period, 699 fewer neuro-oncological patients were operated on than in the pre-COVID period. We noted a slight increase in urgency and a more severe decrease in elective and benign pathology. None of these differences was statistically significant. Surgically treated patients who tested positive for SARS-CoV-2 were 36, of which 11 died. Death was found to be COVID-related only in 2 cases. Conclusion: The reorganization of the Italian Neurosurgical Departments was able to guarantee a redistribution of the CNS tumors during the inter-pandemic periods, demonstrating that patients even in the pandemic era could be treated without compromising the efficacy and safety of the surgical procedure.