Neuropsychological functioning during chemotherapy with temozolomide in high-grade glioma patients: a retrospective single centre study.

PURPOSE: starting from a lack of precise and coherent data in literature, aim of this work is to retrospectively study the influence of chemotherapy with Temozolomide (TMZ) on a wide series of neuropsychological functions in a population of adult high-grade glioma patients. METHODS: an extensive neuropsychological battery was administered pre-operatively (T0) and after 6 (T1) and 12 months (T2) from surgery. After full recovery from surgery, TMZ was delivered concomitant to radiotherapy and, subsequently, adjuvantly for 5-day cycles per month. Parametric and non-parametric analyses were conducted to verify the influence of several aspects of chemotherapy on the adjusted scores of each cognitive test at the two post-operative follow-ups. RESULTS: Sixty-one patients were included at T0; patients with a lower adjuvant TMZ dosage reported a better performance at the visual attention test at T1, and at the deductive reasoning test at T2. Undergoing more than 8 cycles of adjuvant therapy was slightly associated with a better performance at the long-term verbal memory tasks at T2. No other associations were found with the other cognitive tests and autonomy scales administered. CONCLUSIONS: TMZ proved to be a secure treatment with no negative side effects on cognition and on level of daily autonomy, even at the highest dosage used. This is a positive finding which enables clinicians to reassure patients about the absence of significant negative effects of TMZ on their daily life functioning. In this view, eventual cognitive changes during treatment might not be attributed to chemotherapy but to other events such as tumour relapse.

Surgery vs. Radiosurgery for Patients with Localized Metastatic Brain Disease: A Systematic Review with Meta-Analysis of Randomized Controlled Trials.

Purpose: To analyze the efficacy and safety of surgery compared to radiosurgery (RS), combined or not with whole brain radiotherapy (WBRT), for localized metastatic brain disease. Methods: A systematic review with meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The inclusion criteria were limited to randomized controlled trials (RCTs) that compared surgery and RS for patients with up to 3 metastases (median diameter ≤ 4 cm). The primary outcomes were represented by overall survival (OS) and local brain progression-free survival (PFS), with the rate of complications as a secondary outcome. The pooled estimates were calculated using random forest models. The risk of bias was evaluated using the RoB2 revised tool and the certainty of the evidence was assessed according to the GRADE guidelines. Results: In total, 11,256 records were identified through database and register searches. After study selection, 3 RCTs and 353 patients were included in the quantitative synthesis. Surgery and RS represented the main intervention arms in all the included RCTs. Conclusions: A low level of evidence suggests that RS alone and surgery followed by WBRT provide an equal rate of local brain PFS in patients with localized metastatic brain disease. There is a very low level of evidence that surgery and RS as main interventions offer equivalent OS in the population investigated. A reliable assessment of the complication rates among surgery and RS was not achievable. The lack of high-certainty evidence either for superiority or equivalence of these treatments emphasizes the need for further, more accurate, RCTs comparing surgery and RS as local treatment in patients with oligometastatic brain disease.

Epigenetic Rewiring of Metastatic Cancer to the Brain: Focus on Lung and Colon Cancers.

Distant metastasis occurs when cancer cells adapt to a tissue microenvironment that is different from the primary organ. This process requires genetic and epigenetic changes in cancer cells and the concomitant modification of the tumor stroma to facilitate invasion by metastatic cells. In this study, we analyzed differences in the epigenome of brain metastasis from the colon (n = 4) and lung (n = 14) cancer and we compared these signatures with those found in primary tumors. Results show that CRC tumors showed a high degree of genome-wide methylation compared to lung cancers. Further, brain metastasis from lung cancer deeply activates neural signatures able to modify the brain microenvironment favoring tumor cells adaptation. At the protein level, brain metastases from lung cancer show expression of the neural/glial marker Nestin. On the other hand, colon brain metastases show activation of metabolic signaling. These signatures are specific for metastatic tumors since primary cancers did not show such epigenetic derangements. In conclusion, our data shed light on the epi/molecular mechanisms that colon and lung cancers adopt to thrive in the brain environment.

Brain tumours in the time of COVID-19: An online survey on patients' disease experience in one Italian region.

Background: Since the outbreak, in 2019, of COVID-19, the world has experienced marked changes in daily habits, partly reflecting the exceptional social restrictions and health measures adopted to contain the disease. All these measures significantly affected not only peoples's daily lives and psychological well-being but also the possibility for the healthcare system to function properly. In this setting, brain tumour patients were at risk due to their higher physical and mental fragility and their need for regular care. The aim of the present study was to assess, using a self-reported online questionnaire, the patients's perceptions regarding their disease experience. Materials and methods: We developed an online anonymous self-report survey to assess patients's disease experience during the pandemic. We investigated the impact of the COVID-19 pandemic on patients's cancer care schedules, their psychological distress and emotions felt during the pandemic, their levels of worry about COVID-19, and their oncological conditions. Results: 107 patients answered our survey, most of them suffering from a glioma. Less than one-third of the sample had their appointments cancelled, delayed or converted into online visits due to the pandemic. Of the patients who answered the survey, 95% declared they were satisfied with their Institute's oncological management. The feelings reported most often were peacefulness or anxiety/worry; the majority of the sample reported high levels of loneliness, which tended to increase with age, whilst the psychological distress was correlated with age and with having a recurrence of the disease. Half of the sample declared severe worry about their oncological condition, in particular subjects with a recurrence or who were receiving adjuvant therapies. Patients with recurrence tended to worry more about the possibility of contracting COVID-19, and its effects. Conclusion: Our findings illustrate how fragile and in need of care patients with a brain tumour may be, especially those with more severe clinical conditions. These data may help boost healthcare professionals's knowledge about brain tumour patients's needs and fears, so as to be able to offer them a better hospital experience and improve their clinical management, while possibly also reducing the psychological burden on patients and their families.

Predicting tumor consistency and extent of resection in non-functioning pituitary tumors.

PURPOSE: To (1) identify a radiological parameter to predict non-functioning pituitary tumor (NFPT) consistency, (2) examine the relationship between NFPT consistency and extent of resection (EOR), (3) investigate if tumor consistency predictors can anticipate EOR. METHODS: The ratio (T2SIR) between the T2 min signal intensity (SI) of the tumor and the T2 mean SI of the CSF was the main radiological parameter, being determined through a radiomic-voxel analysis and calculated using the following formula: T2SIR = [(T2 tumor mean SI - SD)/T2 CSF SI]. The tumor consistency was pathologically estimated as collagen percentage (CP). EOR of NFPTs was evaluated by exploiting a volumetric technique and its relationship with the following explanatory variables was explored: CP, Knosp-grade, tumor volume, inter-carotid distance, sphenoidal sinus morphology, Hardy-grade, suprasellar tumor extension. RESULTS: A statistically significant inverse correlation between T2SIR and CP was demonstrated (p = 0.0001), with high diagnostic power of T2SIR in predicting NFPT consistency (ROC curve analysis' AUC = 0.88; p = 0.0001). The following predictors of EOR were identified in the univariate analysis: CP (p = 0.007), preoperative volume (p = 0.045), Knosp grade (p = 0.0001), tumor suprasellar extension (p = 0.044). The multivariate analysis demonstrated two variables as unique predictors of EOR: CP (p = 0.002) and Knosp grade (p = 0.001). The T2SIR was a significant predictor of EOR both in the univariate (p = 0.01) and multivariate model (p = 0.003). CONCLUSION: This study offers the potential to improve NFPT preoperative surgical planning and patient counseling by employing the T2SIR as a preoperative predictor of tumor consistency and EOR. Meanwhile, tumor consistency and Knosp grade were found to play an important role in predicting EOR.

Role of Luteolin as Potential New Therapeutic Option for Patients with Glioblastoma through Regulation of Sphingolipid Rheostat.

Glioblastoma (GBM) is the most aggressive brain tumor, still considered incurable. In this study, conducted on primary GBM stem cells (GSCs), specifically selected as the most therapy-resistant, we examined the efficacy of luteolin, a natural flavonoid, as an anti-tumoral compound. Luteolin is known to impact the sphingolipid rheostat, a pathway regulated by the proliferative sphingosine-1-phosphate (S1P) and the proapoptotic ceramide (Cer), and implicated in numerous oncopromoter biological processes. Here, we report that luteolin is able to inhibit the expression of SphK1/2, the two kinases implicated in S1P formation, and to increase the expression of both SGPL1, the lyase responsible for S1P degradation, and CERS1, the ceramide synthase 1, thus shifting the balance toward the production of ceramide. In addition, luteolin proved to decrease the expression of protumoral signaling as MAPK, RAS/MEK/ERK and PI3K/AKT/mTOR and cyclins involved in cell cycle progression. In parallel, luteolin succeeded in upregulation of proapoptotic mediators as caspases and Bcl-2 family and cell cycle controllers as p53 and p27. Furthermore, luteolin determined the shutdown of autophagy contributing to cell survival. Overall, our data support the use of luteolin as add-on therapy, having demonstrated a good ability in impairing GSC viability and survival and increasing cell sensitivity to TMZ.

Indication and eligibility of glioma patients for awake surgery: A scoping review by a multidisciplinary perspective.

Background: Awake surgery (AS) permits intraoperative mapping of cognitive and motor functions, allowing neurosurgeons to tailor the resection according to patient functional boundaries thus preserving long-term patient integrity and maximizing extent of resection. Given the increased risks of the awake scenario, the growing importance of AS in surgical practice favored the debate about patient selection concerning both indication and eligibility criteria. Nonetheless, a systematic investigation is lacking in the literature. Objective: To provide a scoping review of the literature concerning indication and eligibility criteria for AS in patients with gliomas to answer the questions:1) "What are the functions mostly tested during AS protocols?" and 2) "When and why should a patient be excluded from AS?". Materials and methods: Pertinent studies were retrieved from PubMed, PsycArticles and Cochrane Central Register of Controlled Trials (CENTRAL), published until April 2021 according to the PRISMA Statement Extension for Scoping Reviews. The retrieved abstracts were checked for the following features being clearly stated: 1) the population described as being composed of glioma(LGG or HGG) patients; 2) the paper had to declare which cognitive or sensorimotor function was tested, or 2bis)the decisional process of inclusion/exclusion for AS had to be described from at least one of the following perspectives: neurosurgical, neurophysiological, anesthesiologic and psychological/neuropsychological. Results: One hundred and seventy-eight studies stated the functions being tested on 8004 patients. Language is the main indication for AS, even if tasks and stimulation techniques changed over the years. It is followed by monitoring of sensorimotor and visuospatial pathways. This review demonstrated an increasing interest in addressing other superior cognitive functions, such as executive functions and emotions. Forty-five studies on 2645 glioma patients stated the inclusion/exclusion criteria for AS eligibility. Inability to cooperate due to psychological disorder(i.e. anxiety),severe language deficits and other medical conditions(i.e.cardiovascular diseases, obesity, etc.)are widely reported as exclusion criteria for AS. However, a very few papers gave scale exact cut-off. Likewise, age and tumor histology are not standardized parameters for patient selection. Conclusion: Given the broad spectrum of functions that might be safely and effectively monitored via AS, neurosurgeons and their teams should tailor intraoperative testing on patient needs and background as well as on tumor location and features. Whenever the aforementioned exclusion criteria are not fulfilled, AS should be strongly considered for glioma patients.

Diffusion tensor imaging, intra-operative neurophysiological monitoring and small craniotomy: Results in a consecutive series of 103 gliomas.

Diffusion tensor imaging (DTI) allows visualization of the main white matter tracts while intraoperative neurophysiological monitoring (IONM) represents the gold standard for surgical resection of gliomas. In recent years, the use of small craniotomies has gained popularity thanks to neuronavigation and to the low morbidity rates associated with shorter surgical procedures. The aim of this study was to review a series of patients operated for glioma using DTI, IONM, and tumor-targeted craniotomies. The retrospective analysis included patients with supratentorial glioma who met the following inclusion criteria: preoperative DTI, intraoperative IONM, tumor-targeted craniotomy, pre- and postoperative MRI, and complete clinical charts. The DTI was performed on a 3T scanner. The IONM included electroencephalography (EEG), transcranial (TC) and/or cortical motor-evoked potentials (MEP), electrocorticography (ECoG), and direct electrical stimulation (DES). Outcomes included postoperative neurological deficits, volumetric extent of resection (EOR), and overall survival (OS). One hundred and three patients (61 men, 42 women; mean age 54 ± 14 years) were included and presented the following WHO histologies: 65 grade IV, 19 grade III, and 19 grade II gliomas. After 3 months, only three patients had new neurological deficits. The median postoperative volume was 0cc (IQR 3). The median OS for grade IV gliomas was 15 months, while for low-grade gliomas it was not reached. In our experience, a small craniotomy and a tumor resection supported by IONM and DTI permitted to achieve satisfactory results in terms of neurological outcomes, EOR, and OS for glioma patients.

A Frailty-Adjusted Stratification Score to Predict Surgical Risk, Post-Operative, Long-Term Functional Outcome, and Quality of Life after Surgery in Intracranial Meningiomas.

Object: To investigate those parameters affecting early and follow-up functional outcomes in patients undergoing resection of meningiomas and to design a dedicated predictive score, the Milan Bio(metric)-Surgical Score (MBSS) is hereby presented. Methods: Patients undergoing transcranial surgery for intracranial meningiomas were included. The most significant parameters in the regression analyses were implemented in a patient stratification score and were validated by testing its classification consistency with a clinical−radiological grading scale (CRGS), Milan complexity scale (MCS), and Charlson Comorbidity Index (CCI) scores. Results: The ASA score, Frailty index, skull base and posterior cranial fossa locations, a diameter of >25 mm, and the absence of a brain−tumour interface were predictive of early post-operative deterioration and were collected in MBSS Part A (AUC: 0.965; 95%C.I. 0.890−1.022), while the frailty index, posterior cranial fossa location, a diameter of >25 mm, a edema/tumour volume index of >2, dural sinus invasion, DWI hyperintensity, and the absence of a brain−tumour interface were predictive of a long-term unfavourable outcome and were collected in MBSS Part B (AUC: 0.877; 95%C.I. 0.811−0.942). The score was consistent with CRGS, MCS, and CCI. Conclusion: Patients' multi-domain evaluation and the implementation of frailty indexes might help predict the perioperative complexity of cases; the functional, clinical, and neurological early outcomes; survival; and overall QoL after surgery.

A Deep Learning Model for Preoperative Differentiation of Glioblastoma, Brain Metastasis and Primary Central Nervous System Lymphoma: A Pilot Study.

Background: Neuroimaging differentiation of glioblastoma, primary central nervous system lymphoma (PCNSL) and solitary brain metastasis (BM) remains challenging in specific cases showing similar appearances or atypical features. Overall, advanced MRI protocols have high diagnostic reliability, but their limited worldwide availability, coupled with the overlapping of specific neuroimaging features among tumor subgroups, represent significant drawbacks and entail disparities in the planning and management of these oncological patients. Objective: To evaluate the classification performance metrics of a deep learning algorithm trained on T1-weighted gadolinium-enhanced (T1Gd) MRI scans of glioblastomas, atypical PCNSLs and BMs. Materials and Methods: We enrolled 121 patients (glioblastoma: n=47; PCNSL: n=37; BM: n=37) who had undergone preoperative T1Gd-MRI and histopathological confirmation. Each lesion was segmented, and all ROIs were exported in a DICOM dataset. The patient cohort was then split in a training and hold-out test sets following a 70/30 ratio. A Resnet101 model, a deep neural network (DNN), was trained on the training set and validated on the hold-out test set to differentiate glioblastomas, PCNSLs and BMs on T1Gd-MRI scans. Results: The DNN achieved optimal classification performance in distinguishing PCNSLs (AUC: 0.98; 95%CI: 0.95 - 1.00) and glioblastomas (AUC: 0.90; 95%CI: 0.81 - 0.97) and moderate ability in differentiating BMs (AUC: 0.81; 95%CI: 0.70 - 0.95). This performance may allow clinicians to correctly identify patients eligible for lesion biopsy or surgical resection. Conclusion: We trained and internally validated a deep learning model able to reliably differentiate ambiguous cases of PCNSLs, glioblastoma and BMs by means of T1Gd-MRI. The proposed predictive model may provide a low-cost, easily-accessible and high-speed decision-making support for eligibility to diagnostic brain biopsy or maximal tumor resection in atypical cases.

Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics.

BACKGROUND: Glioblastoma is the most aggressive primary brain malignancy in adults, with a poor prognosis of about 14 months. Recent evidence ascribed to metformin (MET), an antihyperglycemic drug, the potential to reduce cancer incidence and progression, but the molecular mechanisms underlying these effects need to be better investigated. METHODS: Here, we tested the efficacy of MET on n = 10 primary glioblastoma endothelial cells (GECs), by viability and proliferation tests, as MTT and Live/Dead assays, apoptosis tests, as annexin V assay and caspase 3/7 activity, functional tests as tube-like structure formation and migration assay and by mRNA and protein expression performed by quantitative real-time PCR analysis (qRT-PCR) and Western Blot, respectively. RESULTS: Data resulting revealed a time- and µ-dependent ability of MET to decrease cell viability and proliferation, increasing pro-apoptotic mechanisms mediated by caspases 3/7. Also, MET impacted GEC functionality with a significant decrease of angiogenesis and invasiveness potential. Mechanistically, MET was able to interfere with sphingolipid metabolism, weakening the oncopromoter signaling promoted by sphingosine-1-phosphate (S1P) and shifting the balance toward the production of the pro-apoptotic ceramide. CONCLUSIONS: These observations ascribed to MET the potential to serve as add-on therapy against glioblastoma, suggesting a repurposing of an old, totally safe and tolerable drug for novel oncology therapeutics.

Plasma levels of extracellular vesicles and the risk of post-operative pulmonary embolism in patients with primary brain tumors: a prospective study.

Primary brain tumors are associated with an increased risk of pulmonary embolism (PE), particularly in the early post-operative period. The pathophysiological mechanisms of PE are poorly understood. This study aims to describe prospectively extracellular vesicles (EVs) levels and investigate whether or not their variations allow to identify patients at increased risk of post-operative PE. Consecutive meningioma or glioma patients candidate to tumor resection were included in the study if a pulmonary perfusion scan (Q-scan) performed before surgery ruled out PE. EVs derived from platelets (CD41+) or endothelial cells (CD144+), tissue factor-bearing EVs (CD142+) and their procoagulant subtype (annexin V+) were analyzed by flow cytometry before surgery (T0), within 24 h (T1), two (T2) and seven days (T7) after surgery. Q-scan was repeated at T2. Ninety-three patients with meningioma, 59 with glioma and 76 healthy controls were included in the study. CD142+ and annexin V+/CD142+ EVs were increased at T0 in meningioma and glioma patients compared to healthy controls. Twenty-nine meningioma (32%) and 16 glioma patients (27%) developed PE at T2. EVs levels were similar in meningioma patients with or without PE, whereas annexin V+ and annexin V+/CD142+ EVs were significantly higher at T1 and T2 in glioma patients with PE than in those without. Procoagulant EVs, particularly annexin V+/CD142+, increase after surgery and are more prevalent in glioma patients who developed PE after surgery than in those who did not.

Surgery for Glioblastoma in Elderly Patients.

The management of glioblastoma in the elderly population represents a field of growing interest owing a longer life expectancy. In this age group, more than in the young adult, biological age is much more important than chronologic one. The date of birth should not exclude a priori access of treatments. Maximal safe resection is proved to be the first option when performance status and general health is good. Adjuvant therapy and decision about management of recurrence should be choose in a multidisciplinary group according to performance of the patients and O6-methylguanine-DNA methyl-transferase methylation.

Frontiers in Anti-Cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-Angiogenic Add-On Therapy in Glioblastoma.

Glioblastoma is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. Glioblastoma shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), has demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including glioblastoma. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss metformin's potential antitumoral effects on glioblastoma, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of glioblastoma patients.

Insular lobe surgery and cognitive impairment in gliomas operated with intraoperative neurophysiological monitoring.

BACKGROUND: For a long time, surgery of insular gliomas was considered at high risk for postoperative cognitive deficits, but recent studies highlighted the feasibility of the surgical approach. The aims of our study were to investigate the presence of language impairment before and after surgery and the relationship between language impairment and tumor volume preoperatively and extent of resection (EOR) 3 months after surgery. METHODS: Thirty-five patients with insular gliomas underwent an extensive language assessment before and few days after surgery, and after 3 months. Intraoperative neurophysiological monitoring (IOM) and brain mapping with direct electrical stimulation (DES) were used in all the cases; 8 patients underwent awake craniotomy. Statistical analysis was performed on the language tests administered. RESULTS: Patients with pure left insular lesion showed language impairment before and after surgery. Overall, patients with a left lesion showed a drop of performance after surgery followed by a partial recovery. Moreover, when the tumor involved the insula and adjacent networks, we observed a more severe deficit. No correlations were found between tumor volume, EOR, and language impairment. CONCLUSIONS: Left insular lobe is an important hub in language networks; its involvement determines pre- and postsurgical deficits, together with the involvement of white matter connections. Tumor volume and EOR are not risk factors per se directly related to language functioning. Surgery of insular gliomas is possible with a pre- and intraoperative extensive study of the patient with IOM and awake surgery, and encouraged by the trend of cognitive recovery highlighted.

Association of supratotal resection with progression-free survival, malignant transformation, and overall survival in lower-grade gliomas.

BACKGROUND: Supratotal resection is advocated in lower-grade gliomas (LGGs) based on theoretical advantages but with limited verification of functional risk and data on oncological outcomes. We assessed the association of supratotal resection in molecularly defined LGGs with oncological outcomes. METHODS: Included were 460 presumptive LGGs; 404 resected; 347 were LGGs, 319 isocitrate dehydrogenase (IDH)-mutated, 28 wildtype. All patients had clinical, imaging, and molecular data. Resection aimed at supratotal resection without any patient or tumor a priori selection. The association of extent of resection (EOR), categorized on volumetric fluid attenuated inversion recovery images as residual tumor volume, along with postsurgical management with progression-free survival (PFS), malignant (M)PFS, and overall survival (OS) assessed by univariate, multivariate, and propensity score analysis. The study mainly focused on IDH-mutated LGGs, the "typical LGGs." RESULTS: Median follow-up was 6.8 years (interquartile range, 5-8). Out of 319 IDH-mutated LGGs, 190 (59.6%) progressed, median PFS: 4.7 years (95% CI: 4-5.3). Total and supratotal resection obtained in 39% and 35% of patients with IDH1-mutated tumors. In IDH-mutated tumors, most patients in the partial/subtotal group progressed, 82.4% in total, only 6 (5.4%) in supratotal. Median PFS was 29 months (95% CI: 25-36) in subtotal, 46 months (95% CI: 38-48) in total, while at 92 months, PFS in supratotal was 94.0%. There was no association with molecular subtypes and grade. At random forest analysis, PFS strongly associated with EOR, radiotherapy, and previous treatment. In the propensity score analysis, EOR associated with PFS (hazard ratio, 0.03; 95% CI: 0.01-0.13). MPFS occurred in 32.1% of subtotal total groups; 1 event in supratotal. EOR, grade III, previous treatment correlated to MPFS. At random forest analysis, OS associated with EOR as well. CONCLUSIONS: Supratotal resection strongly associated with PFS, MPFS, and OS in LGGs, regardless of molecular subtypes and grade, right from the beginning of clinical presentation.

Personalized and translational approach for malignant brain tumors in the era of precision medicine: the strategic contribution of an experienced neurosurgery laboratory in a modern neurosurgery and neuro-oncology department.

Personalized medicine (PM) aims to optimize patient management, taking into account the individual traits of each patient. The main purpose of PM is to obtain the best response, improving health care and lowering costs. Extending traditional approaches, PM introduces novel patient-specific paradigms from diagnosis to treatment, with greater precision. In neuro-oncology, the concept of PM is well established. Indeed, every neurosurgical intervention for brain tumors has always been highly personalized. In recent years, PM has been introduced in neuro-oncology also to design and prescribe specific therapies for the patient and the patient's tumor. The huge advances in basic and translational research in the fields of genetics, molecular and cellular biology, transcriptomics, proteomics, and metabolomics have led to the introduction of PM into clinical practice. The identification of a patient's individual variation map may allow to design selected therapeutic protocols that ensure successful outcomes and minimize harmful side effects. Thus, clinicians can switch from the "one-size-fits-all" approach to PM, ensuring better patient care and high safety margin. Here, we review emerging trends and the current literature about the development of PM in neuro-oncology, considering the positive impact of innovative advanced researches conducted by a neurosurgical laboratory.

Interplay Between V-ATPase G1 and Small EV-miRNAs Modulates ERK1/2 Activation in GBM Stem Cells and Nonneoplastic Milieu.

The ATP6V1G1 subunit (V1G1) of the vacuolar proton ATPase (V-ATPase) pump is crucial for glioma stem cells (GSC) maintenance and in vivo tumorigenicity. Moreover, V-ATPase reprograms the tumor microenvironment through acidification and release of extracellular vesicles (EV). Therefore, we investigated the role of V1G1 in GSC small EVs and their effects on primary brain cultures. To this end, small EVs were isolated from patients-derived GSCs grown as neurospheres (NS) with high (V1G1HIGH-NS) or low (V1G1LOW-NS) V1G1 expression and analyzed for V-ATPase subunits presence, miRNA contents, and cellular responses in recipient cultures. Our results show that NS-derived small EVs stimulate proliferation and motility of recipient cells, with small EV derived from V1G1HIGH-NS showing the most pronounced activity. This involved activation of ERK1/2 signaling, in a response reversed by V-ATPase inhibition in NS-producing small EV. The miRNA profile of V1G1HIGH-NS-derived small EVs differed significantly from that of V1G1LOW-NS, which included miRNAs predicted to target MAPK/ERK signaling. Mechanistically, forced expression of a MAPK-targeting pool of miRNAs in recipient cells suppressed MAPK/ERK pathway activation and blunted the prooncogenic effects of V1G1HIGH small EV. These findings propose that the GSC influences the brain milieu through a V1G1-coordinated EVs release of MAPK/ERK-targeting miRNAs. Interfering with V-ATPase activity could prevent ERK-dependent oncogenic reprogramming of the microenvironment, potentially hampering local GBM infiltration. IMPLICATIONS: Our data identify a novel molecular mechanism of gliomagenesis specific of the GBM stem cell niche, which coordinates a V-ATPase-dependent reprogramming of the brain microenvironment through the release of specialized EVs.

Tumor-Educated Platelets and Angiogenesis in Glioblastoma: Another Brick in the Wall for Novel Prognostic and Targetable Biomarkers, Changing the Vision from a Localized Tumor to a Systemic Pathology.

: Circulating platelets (PLTs) are able to affect glioblastoma (GBM) microenvironment by supplying oncopromoter and pro-angiogenic factors. Among these mediators, sphingosine-1-phophate (S1P) has emerged as a potent bioactive lipid enhancing cell proliferation and survival. Here, we investigated the effect of "tumor education", characterizing PLTs from GBM patients in terms of activation state, protein content, and pro-angiogenic potential. PLTs from healthy donors (HD-PLTs) and GBM patients (GBM-PLTs) were collected, activated, and analyzed by flow cytometry, immunofluorescence, and Western blotting. To assess the pro-angiogenic contribution of GBM-PLTs, a functional cord formation assay was performed on GBM endothelial cells (GECs) with PLT-releasate. GBM-PLTs expressed higher positivity for P-selectin compared to HD-PLTs, both in basal conditions and after stimulation with adenosine triphosphate (ADP) and thrombin receptor activating peptide (TRAP). PLTs showed higher expression of VEGFR-1, VEGFR-2, VWF, S1P, S1PR1, SphK1, and SPNS. Interestingly, increased concentrations of VEGF and its receptors VEGFR1 and VEGFR2, VWF, and S1P were found in GBM-PLT-releasate with respect to HD-PLTs. Finally, GBM-PLT-releasate showed a pro-angiogenic effect on GECs, increasing the vascular network's complexity. Overall, our results demonstrated the contribution of PLTs to GBM angiogenesis and aggressiveness, advancing the potential of an anti-PLT therapy and the usefulness of PLT cargo as predictive and monitoring biomarkers.