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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.

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 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.

(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.

Recently, the emergence of the three-dimensional (3D) exoscope has proven to be a viable alternative to the operative microscope (OM) as a novel workhorse of microneurosurgical procedures. Through its current iteration, the 3D exoscope has been demonstrated to be at least equivalent to the operative microscope in terms of surgical outcomes in many settings. With its superior ergonomics and simplicity of use, the 3D exoscope has been shown in multiple studies to be a powerful visualizing tool during surgical procedures. Moreover, the exoscopic systems, through their current iterations and by means of a high-resolution 3D monitor and 3D glasses, have allowed all participants present in the operative room to attain an unprecedented level of intraoperative visualization of anatomical structures and surgical maneuvers which are traditionally available only to the first operator. Although long-term data are still lacking regarding its future as a replacement of the OM, the 3D exoscope has revealed itself as an intense subject of discussion in neurosurgery regarding its implication for surgical education, especially for residents and junior neurosurgeons. This article is a review of the current state of the literature on the role of the exoscope in surgical education, underlining its strength as a learning tool and its potential future implications in terms of surgical education.

Introduction: Intradiploic pseudomeningoceles, also called intradiploic cerebrospinal fluid (CSF) fistulas, are abnormal CSF collection between the two bony tables of the calvaria resulting from post-surgical CSF leakage. To date, only six cases of intradiploic pseudomeningocele have been reported, all occurring in the occipital area. In this paper, we report the seventh case of late-onset occipital intradiploic pseudomeningocele (OIP) occurring in a young female patient who underwent surgery for the removal of a cerebellar pilocytic astrocytoma. At this regard, we also review the literature on the few recognized cases of OIP. Case presentation: The case of an 18-year-old female patient known to our institute for an operation 12 years earlier to remove a pilocytic astrocytoma is illustrated. At admission the patient complained only of occasional orthostatic headache. Brain imaging demonstrated a pseudomeningocele extended intradiploically from the occipital squama to the condylar and clivus regions, thinning both occipital bone tables and dilating the CSF-filled diploe. Watertight duroplasty and cranioplasty were effectively performed. Conclusion: Pediatric patients undergoing posterior cranial fossa craniotomy/craniectomy may postoperatively develop OIP. In this setting, treatment of any dural CSF fistula should be considered because of the risk of progressive extension and bone erosion.

Introduction: Intradiploic pseudomeningoceles, also called intradiploic cerebrospinal fluid (CSF) fistulas, are abnormal CSF collections between the two bony tables of the calvaria resulting from postsurgical CSF leakage. To date, only six cases of intradiploic pseudomeningocele have been reported, all occurring in the occipital area. In this paper, we report the seventh case of late-onset occipital intradiploic pseudomeningocele (OIP) occurring in a young female patient who underwent surgery for the removal of a cerebellar pilocytic astrocytoma. In this regard, we also review the literature on the few recognized cases of OIP. Case Presentation: The case of an 18-year-old female patient known to our institute for an operation 12 years earlier to remove a pilocytic astrocytoma is illustrated. At admission, the patient complained only of occasional orthostatic headache. Brain imaging demonstrated a pseudomeningocele extended intradiploically from the occipital squama to the condylar and clivus regions, thinning both occipital bone tables and dilating the CSF-filled diploe. Watertight duroplasty and cranioplasty were effectively performed. Conclusion: Pediatric patients undergoing posterior cranial fossa craniotomy/craniectomy may postoperatively develop OIP. In this setting, treatment of any dural CSF fistula should be considered because of the risk of progressive extension and bone erosion.

Recently, the emergence of the three-dimensional (3D) exoscope has proven to be a viable alternative to the operative microscope (OM) as a novel workhorse of microneurosurgical procedures. Through its current iteration, the 3D exoscope has been demonstrated to be at least equivalent to the operative microscope in terms of surgical outcomes in many settings. With its superior ergonomics and simplicity of use, the 3D exoscope has been shown in multiple studies to be a powerful visualizing tool during surgical procedures. Moreover, the exoscopic systems, through their current iterations and by means of a high-resolution 3D monitor and 3D glasses, have allowed all participants present in the operative room to attain an unprecedented level of intraoperative visualization of anatomical structures and surgical maneuvers which are traditionally available only to the first operator. Although long-term data are still lacking regarding its future as a replacement of the OM, the 3D exoscope has revealed itself as an intense subject of discussion in neurosurgery regarding its implication for surgical education, especially for residents and junior neurosurgeons. This article is a review of the current state of the literature on the role of the exoscope in surgical education, underlining its strength as a learning tool and its potential future implications in terms of surgical education.

Background: Chronic subdural hematoma (CSDH) is one of the most common neurosurgical diseases that affect elderly and fragile patients and as a consequence, management can be challenging. Surgery represents the standard treatment; however, alternative options are under investigation. Middle meningeal artery (MMA) embolization is considered a minimally invasive treatment although with poor evidence. In this review, we tried to summarize the findings about MMA embolization as a treatment for a CSDH to provide a useful guidance for clinical practice and for future speculative aspects. Methods: Literature review on PubMed until March 2021 was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. We conducted a research on PubMed with a various combinations of the keywords "CSDH"and "middle meningeal artery"and "embolization,""refractory subdural hematoma,"and then we reviewed the references of the relevant studies as additional source of eligible articles. Results: Among the 35 studies eligible for this review, 22 were case series, 11 were case reports, one was a technical note, and 1 was a randomized trial. A total of 746 patients were found in the literature. Failure rate of MMA embolization was between 3.9 and 8.9% of the cases according the indication to treat CSDH (upfront vs. after surgery). Conclusion: The global impression deriving from the data available and the literature is that MMA embolization is a safe procedure with very low complications and with a low failure rate, both when associated with surgery or in case of a standalone treatment.

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.

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.

Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder caused by mutations in the TP53 gene, predisposing to a wide spectrum of early-onset cancers, including brain tumors. In medulloblastoma patients, the role of TP53 has been extensively investigated, though the prevalence of de novo mutations has not been addressed. We characterized TP53 mutations in a monocentric cohort of consecutive Sonic Hedgehog (SHH)-activated medulloblastoma patients. Germline testing was offered based on tumor p53 immunostaining positivity. Among 24 patients, three (12.5%) showed tumor p53 overexpression, of whom two consented to undergo germline testing and resulted as carriers of TP53 mutations. In the first case, family history was uneventful and the mutation was not found in either of the parents. The second patient, with a family history suggestive of LFS, unexpectedly resulted as a carrier of the mosaic mutation c.742=/C>T p.(Arg248=/Trp). The allele frequency was 26% in normal tissues and 42–77% in tumor specimens. Loss of heterozygosity (LOH) in the tumor was also confirmed. Notably, the mosaic case has been in complete remission for more than one year, while the first patient, as most TP53-mutated medulloblastoma cases from other cohorts, showed a severe and rapidly progressive disease. Our study reported the first TP53 mosaic mutation in medulloblastoma patients and confirmed the importance of germline testing in p53 overexpressed SHH-medulloblastoma, regardless of family history.

The authors present an unusual case of a patient suffering from visual deficit due to pituitary granulomatosis with polyangiitis (GPA) associated with Rathke's cleft cyst (RCC). The patient was referred to our Neurosurgery Department presenting right eye amaurosis, third cranial nerve palsy, and left temporal hemianopsia. Magnetic resonance imaging documented a sellar or suprasellar lesion with solid and cystic components. The dura mater of the skull base was also strongly enhanced. The patient underwent surgery. Histologic examination revealed RCC associated with pituitary GPA. To our knowledge, this is the first reported case of concomitant pituitary GPA and RCC. Pituitary involvement in GPA is rare, usually diagnosed in hormonal dysfunctions. The patient in case first presented optic chiasm compression, probably due to inflammation of both the pituitary gland and the previously asymptomatic RCC. We focus on the symptoms that led us to diagnose GPA pituitary involvement and on the peculiar and unusual Magnetic resonance imaging of the case presented.

Surgical treatment of elderly patients with meningioma is has proved to be safe, especially when patients are selected using dedicated surgical scores. These scores take into account tumor size, edema, location and patient’s co-morbidities. Neuropsychological functioning (NPF) of this kind of patients has been poorly studied in literature and it is not taken into account by these scores. Aim of our study was to describe the long-term outcome in terms of NPF of elderly patients undergoing surgery. Patients older than 70 years of age affected by intracranial meningioma and selected with the Clinical-Radiological Grading Score were included in our study. Neuropsychological testing was performed using a dedicated battery of tests before surgery, 3 and 12 months after surgery. Clinical, neurological and radiological outcomes were studied as well. Forty-one patients with a median age of 74 years were included in this study. Preoperatively only 1/41 patients showed a normal NPF with all tests scoring normally. Four out of 39 patients showed a complete neuropsychological recovery after 3 months; while 10/37 patients had a complete recovery after 12 months. NPF showed a trend of progressive improvement after surgery. Our study is the first experience reported in literature describing a long term follow-up in elderly patients after surgery for intracranial meningioma. In our series, surgery determined an improvement of NPF over time; especially with a low complication rate related to the selection of patients obtained through the CRGS. Further studies need to be performed in order to understand how brain edema, tumor size, volume and tumor location affect NPF in both short and long term.