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The vacuolar proton-translocating ATPase (V-ATPase) is a transmembrane multi-protein complex fundamental in maintaining a normal intracellular pH. In the tumoral contest, its role is crucial since the metabolism underlying carcinogenesis is mainly based on anaerobic glycolytic reactions. Moreover, neoplastic cells use the V-ATPase to extrude chemotherapy drugs into the extra-cellular compartment as a drug resistance mechanism. In glioblastoma (GBM), the most malignant and incurable primary brain tumor, the expression of this pump is upregulated, making it a new possible therapeutic target. In this work, the bafilomycin A1-induced inhibition of V-ATPase in patient-derived glioma stem cell (GSC) lines was evaluated together with temozolomide, the first-line therapy against GBM. In contrast with previous published data, the proposed treatment did not overcome resistance to the standard therapy. In addition, our data showed that nanomolar dosages of bafilomycin A1 led to the blockage of the autophagy process and cellular necrosis, making the drug unusable in models which are more complex. Nevertheless, the increased expression of V-ATPase following bafilomycin A1 suggests a critical role of the proton pump in GBM stem components, encouraging the search for novel strategies to limit its activity in order to circumvent resistance to conventional therapy.

Introduction The current standard of care for glioblastoma (GBM) is surgical resection, followed by adjuvant radiotherapy. Complete resection remains challenging because of unclearly defined tumor margins. Presurgery tumor segmentation is generally done by a neurosurgeon on the contrast-enhanced T1 (T1c) scan. A semi-automated tumor segmentation can ease this process, exploiting also information contained in other scans besides T1c. The aim of this study is to propose a settlement to qualitatively assess segmentations on a multicentric GBM cohort. The Brats-Toolkit [1] tool was considered. Methods Preoperative MRI studies of 72 GBM patients (41 males, 31 females, mean age 63 yr.) surgically treated at Fondazione IRCCS San Gerardo were considered. Images were acquired with heterogeneous protocols, all containing T1, T1c, T2 and T2 FLAIR scans. T1c images were manually segmented by a neurosurgeon, as to clinical practice (unique Region of Interest containing core + necrosis + core enhanced). BraTSPreprocessor, BraTS-Segmentor (8 Docker images from the repository), and BraTS-Fusionator (SIMPLE method) were applied, providing as output core + necrosis, core-enhanced and edema contours [2], [3]. Manual and BraTS segmentations were visually evaluated by a senior neuroradiologist. Results/Discussion MRI studies were classified in 6 groups based on scans characteristics (Group1: 3T - isotropic T1, T1c, FLAIR - anisotropic T2; Group2: 1.5T - isotropic T1, T1c, FLAIR - anisotropic T2; Group3: 3T - isotropic T1c, FLAIR - anisotropic T1, T2; Group4 1.5T - isotropic T1c, FLAIR - anisotropic T1, T2; Group5: 1.5T - isotropic T1, T1c - anisotropic FLAIR, T2; Group6: 1.5T - isotropic T1c - anisotropic T1, FLAIR, T2). A 5-point scale was defined: 1 (correctly overlapped), 2 (not-perfectly overlapped but including all pathologic tissue), 3 (miss of pathologic tissue inclusion, not compromising overall tumor core segmentation), 4 (miss of pathologic tissue inclusion resulting in substa

Despite the efforts made in recent decades, glioblastoma is still the deadliest primary brain cancer without cure. The potential role in tumour maintenance and progression of the peritumoural brain zone (PBZ), the apparently normal area surrounding the tumour, has emerged. Little is known about this area due to a lack of common definition and due to difficult sampling related to the functional role of peritumoural healthy brain. The aim of this work was to better characterize the PBZ and to identify genes that may have role in its malignant transformation. Starting from our previous study on the comparison of the genomic profiles of matched tumour core and PBZ biopsies, we selected CDK4 and EXT2 as putative malignant drivers of PBZ. The gene expression analysis confirmed their over-expression in PBZ, similarly to what happens in low-grade glioma and glioblastoma, and CDK4 high levels seem to negatively influence patient overall survival. The prognostic role of CDK4 and EXT2 was further confirmed by analysing the TCGA cohort and bioinformatics prediction on their gene networks and protein–protein interactions. These preliminary data constitute a good premise for future investigations on the possible role of CDK4 and EXT2 in the malignant transformation of PBZ.

BACKGROUNDː To achieve a consensus on the minimum set of outcome measures and predictors to be used in the neurosurgical practice and on the timing of outcome assessment. METHODSː A consensus building approach was employed. All neurosurgical departments in Lombardy (Italy) were invited to participate by the Fondazione IRCCS Istituto Neurologico Carlo Besta. Three workshops were organized during which a multidisciplinary group called Neurosurgical Outcome Network (NEON) was created and the methodology to select outcome measures, predictors, and timing of outcome assessment was established. Eight working groups were created for the different neurosurgical diseases (neuro-oncological, skull base, vascular, traumatic, spinal, peripheral nervous system, malformation, functional) and 8 workshops were organized to identify the outcome measures and predictors specific for each of the neurosurgical diseases based on the experts’ clinical practice and the existing literature. RESULTSː A total of 20 neurosurgical departments participated in this study. Specific outcome measures, predictors and the timing of outcome assessment were identified for each of the 8 neurosurgical diseases. Moreover, a list of variables common to all pathologies were identified by the NEON group as further data to be collected. CONCLUSIONSː A consensus on the minimum set of outcome measures and predictors and the timing of outcome assessments for 8 neurosurgical diseases was achieved by a group of neurosurgeons of the Lombardy region, called NEON. These sets could be used in future studies for a more homogeneous data collection and as a starting point to reach further agreement also at national and international level.

Background: The exoscope is a high-definition telescope recently introduced in neurosurgery. In the past few years, several reports have described the advantages and disadvantages of such technology. No studies have compared results of surgery with standard microscope and exoscope in patients with glioblastoma multiforme (GBM). Methods: Our retrospective study encompassed 177 patients operated on for GBM (WHO 2021) between February 2017 and August 2022. A total of 144 patients were operated on with a microscope only and the others with a 3D4K exoscope only. All clinical and radiological data were collected. Progression-free survival (PFS) and overall survival (OS) have been estimated in the two groups and compared by the Cox model adjusting for potential confounders (e.g., sex, age, Karnofsky performance status, gross total resection, MGMT methylated promoter, and operator’s experience). Results: IDH was mutated in 9 (5.2%) patients and MGMT was methylated in 76 (44.4%). Overall, 122 patients received a gross total resection, 14 patients received a subtotal resection, and 41 patients received a partial resection. During follow-up, 139 (73.5%) patients experienced tumor recurrence and 18.7% of them received a second surgery. After truncation to 12 months, the median PFS for patients operated on with the microscope was 8.82 months, while for patients operated on with the exoscope it was >12 months. Instead, the OS was comparable in the two groups. The multivariable Cox model showed that the use of microscope compared to the exoscope was associated with lower progression-free survival (hazard ratio = 3.55, 95%CI = 1.66–7.56, p = 0.001). Conclusions: The exoscope has proven efficacy in terms of surgical resection, which was not different to that of the microscope. Furthermore, patients operated on with the exoscope had a longer PFS. A comparable OS was observed between microscope and exoscope, but further prospective studies with longer follow-up are needed.

Background: The aim of this study was to achieve a consensus on the minimum set of outcome measures and predictors to be used in the neurosurgical practice and on the timing of outcome assessment. Methods: A consensus building approach was employed. All neurosurgical departments in Lombardy (Italy) were invited to participate by the Carlo Besta Neurologic Institute IRCCS Foundation. Three workshops were organized during which a multidisciplinary group called Neurosurgical Outcome Network (NEON) was created and the methodology to select outcome measures, predictors, and timing of outcome assessment was established. Eight working groups were created for the different neurosurgical diseases (neuro-oncological, skull base, vascular, traumatic, spinal, peripheral nervous system, malformation, functional) and 8 workshops were organized to identify the outcome measures and predictors specific for each of the neurosurgical diseases based on the experts' clinical practice and the existing literature. Results: A total of 20 neurosurgical departments participated in this study. Specific outcome measures, predictors and the timing of outcome assessment were identified for each of the 8 neurosurgical diseases. Moreover, a list of variables common to all pathologies were identified by the NEON group as further data to be collected. Conclusions: A consensus on the minimum set of outcome measures and predictors and the timing of outcome assessments for 8 neurosurgical diseases was achieved by a group of neurosurgeons of the Lombardy region, called NEON. These sets could be used in future studies for a more homogeneous data collection and as a starting point to reach further agreement also at national and international level.

Glioblastoma (GBM) is the most aggressive and invasive primary brain tumor. Current therapies are not curative, and patients' outcomes remain poor with an overall survival of 20.9 months after surgery. The typical growing pattern of GBM develops by infiltrating the surrounding apparent normal brain tissue within which the recurrence is expected to appear in the majority of cases. Thus, in the last decades, an increased interest has developed to investigate the cellular and molecular interactions between GBM and the peritumoral brain zone (PBZ) bordering the tumor tissue. The aim of this review is to provide up-to-date knowledge about the oncogenic properties of the PBZ to highlight possible druggable targets for more effective treatment of GBM by limiting the formation of recurrence, which is almost inevitable in the majority of patients. Starting from the description of the cellular components, passing through the illustration of the molecular profiles, we finally focused on more clinical aspects, represented by imaging and radiological details. The complete picture that emerges from this review could provide new input for future investigations aimed at identifying new effective strategies to eradicate this still incurable tumor.

(1) Background: Neuroimaging differentiation of glioblastoma, primary central nervous system lymphoma (PCNSL) and solitary brain metastasis (BM) represents a diagnostic and therapeutic challenge in neurosurgical practice, expanding the burden of care and exposing patients to additional risks related to further invasive procedures and treatment delays. In addition, atypical cases and overlapping features have not been entirely addressed by modern diagnostic research. The aim of this study was to validate a previously designed and internally validated ResNet101 deep learning model to differentiate glioblastomas, PCNSLs and BMs. (2) Methods: We enrolled 126 patients (glioblastoma: n = 64; PCNSL: n = 27; BM: n = 35) with preoperative T1Gd-MRI scans and histopathological confirmation. Each lesion was segmented, and all regions of interest were exported in a DICOM dataset. A pre-trained ResNet101 deep neural network model implemented in a previous work on 121 patients was externally validated on the current cohort to differentiate glioblastomas, PCNSLs and BMs on T1Gd-MRI scans. (3) Results: The model achieved optimal classification performance in distinguishing PCNSLs (AUC: 0.73; 95%CI: 0.62–0.85), glioblastomas (AUC: 0.78; 95%CI: 0.71–0.87) and moderate to low ability in differentiating BMs (AUC: 0.63; 95%CI: 0.52–0.76). The performance of expert neuro-radiologists on conventional plus advanced MR imaging, assessed by retrospectively reviewing the diagnostic reports of the selected cohort of patients, was found superior in accuracy for BMs (89.69%) and not inferior for PCNSL (82.90%) and glioblastomas (84.09%). (4) Conclusions: We investigated whether the previously published deep learning model was generalizable to an external population recruited at a different institution—this validation confirmed the consistency of the model and laid the groundwork for future clinical applications in brain tumour classification. This artificial intelligence-based model might represe

Introduction: The surgical goal in glioblastoma treatment is the maximal safe resection of the tumor. Currently the lack of consensus on surgical technique opens different approaches. This study describes the “perilesional technique” and its outcomes in terms of the extent of resection, progression free survival and overall survival. Methods: Patients included (n = 40) received a diagnosis of glioblastoma and underwent surgery using the perilesional dissection technique at “San Gerardo Hospital”between 2018 and 2021. The tumor core was progressively isolated using a circumferential movement, healthy brain margins were protected with Cottonoid patties in a “shingles on the roof” fashion, then the tumorwas removed en bloc. Intraoperative ultrasound (iOUS) was used and at least 1 bioptic sample of “healthy” margin of the resection was collected and analyzed. The extent of resection was quantified. Extent of surgical resection (EOR) and progression free survival (PFS)were safety endpoints of the procedure. Results: Thirty-four patients (85%) received a gross total resection(GTR) while 3 (7.5%) patients received a sub-total resection (STR), and 3 (7.5%) a partial resection (PR). The mean post-operative residual volume was 1.44 cm3 (range 0–15.9 cm3).During surgery, a total of 76 margins were collected: 51 (67.1%) were tumor free, 25 (32.9%) were infiltrated. The median PFS was 13.4 months, 15.3 in the GTR group and 9.6 months in the STR-PR group. Conclusions: Perilesional resection is an efficient technique which aims to bring the surgeon to a safe environment, carefully reaching the “healthy” brain before removing the tumoren bloc. This technique can achieve excellent tumor margins, extent of resection, and preservation of apatient’s functions.

Objective: To evaluate the viability of exoscopes in the context of neurosurgical education and compare the use of a 4k3D exoscope to a traditional operative microscope in the execution of a task of anatomic structure identification on a model of cranial approach. Material and methods: A cohort of volunteer residents performed a task of anatomical structure identification with both devices three times across an experimental period of 2 months. We timed the residents’ performances, and the times achieved were analyzed. The volunteers answered two questionnaires concerning their opinions of the two devices. Results: Across tries, execution speed improved for the whole cohort. When using the exoscopes, residents were quicker to identify a single anatomical structure starting from outside the surgical field when deep structures were included in the pool. In all other settings, the two devices did not differ in a statistically significant manner. The volunteers described the exoscope as superior to the microscope in all the aspects the questionnaires inquired about, besides the depth of field perception, which was felt to be better with the microscope. Volunteers furthermore showed overwhelming support for training on different devices and with models of surgical approaches. Conclusion: The exoscope appeared to be non-inferior to the microscope in the execution of a task of timed identification of anatomical structures on a model of cranial approach carried out by our cohort of residents. In the questionnaires, the residents reported the exoscope to be superior to the microscope in eight of nine investigated domains. Further studies are needed to investigate the use of the exoscope in learning of microsurgical skills.

(1) Background: brain metastases (BMs) are the most common neoplasm of the central nervous system; despite the high incidence of this type of tumour, to date there is no universal consensus on the most effective treatment in patients with BMs, even if surgery still plays a primary role. Despite this, the adjunct systems that help to reach the GTR, which are well structured for other tumour forms such as ultrasound and fluorescence systems, are not yet well employed and standardised in surgical practice. The aim of this review is to provide a picture of the current state-of-art of the roles of iOUS and intraoperative fluorescence to better understand their potential roles as surgical tools. (2) Methods: to reach this goal, the PubMed database was searched using the following string as the keyword: (((Brain cerebral metastasis [MeSH Major Topic])OR (brain metastasis, [MeSH Major Topic])) AND ((5-ala, [MeSH Terms]) OR (Aminolevulinicacid [All fields]) OR (fluorescein, [MeSH Terms]) OR (contrast enhanced ultrasound [MeSH Terms])OR ((intraoperative ultrasound. [MeSH Terms]))) AND (english [Filter]) AND ((english [Filter]) AND (2010:2022 [pdat])) AND (english [Filter]). (3) Results: from our research, a total of 661 articles emerged; of these, 57 were selected. 21 of these included BMs generically as a secondary class for comparisons with gliomas, without going deeply into specific details. Therefore, for our purposes, 36 articles were considered. (4) Conclusions: with regard to BMs treatment and their surgical adjuncts, there is still much to be explored. This is mainly related to the heterogeneity of patients, the primary tumour histology and the extent of systemic disease; regardless, surgery plays a paramount role in obtaining a local disease control, and more standardised surgical protocols need to be made, with the aim of optimizing the use of the available surgical adjuncts and in order to increase the rate of GTR.