NKG2C/KLRC2 tumor cell expression enhances immunotherapeutic efficacy against glioblastoma.

BACKGROUND: Activating and inhibitory receptors of natural killer (NK) cells such as NKp, NKG2, or CLEC are highly relevant to cold tumors including glioblastoma (GBM). Here, we aimed to characterize the expression of these receptors in GBM to gain insight into their potential role as modulators of the intratumoral microenvironment. METHODS: We performed a transcriptomic analysis of several NK receptors with a focus on the activating receptor encoded by KLRC2, NKG2C, among bulk and single-cell RNA sequencing GBM data sets. We also evaluated the effects of KLRC2-overexpressing GL261 cells in mice treated with or without programmed cell death protein-1 (PD-1) monoclonal antibody (mAb). Finally, we analyzed samples from two clinical trials evaluating PD-1 mAb effects in patients with GBM to determine the potential of NKG2C to serve as a biomarker of response. RESULTS: We observed significant expression of several inhibitory NK receptors on GBM-infiltrating NK and T cells, which contrasts with the strong expression of KLRC2 on tumor cells, mainly at the infiltrative margin. Neoplastic KLRC2 expression was associated with a reduction in the number of myeloid-derived suppressor cells and with a higher level of tumor-resident lymphocytes. A stronger antitumor activity after PD-1 mAb treatment was observed in NKG2Chigh-expressing tumors both in mouse models and patients with GBM whereas the expression of inhibitory NK receptors showed an inverse association. CONCLUSIONS: This study explored the role of neoplastic NKG2C/KLRC2 expression in shaping the immune profile of GBM and suggests that it is a predictive biomarker for positive responses to immune checkpoint inhibitor treatment in patients with GBM. Future studies could further validate this finding in prospective trials.

Sexual-biased necroinflammation is revealed as a predictor of bevacizumab benefit in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is a highly malignant brain tumor that affects men more often than women. In addition, the former shows a poorer survival prognosis. To date, the reason for this sex-specific aggressiveness remains unclear. Therefore, the aim of this study is to investigate tumor processes that explain these sex differences. METHODS: This was a retrospective study of GBM patients which was stratified according to sex. A cohort with 73 tumors was analyzed with immunohistochemistry, RNA-seq and RT-qPCR to characterize differences in vascular and immunological profiles. Transcriptomic profiling, gene set enrichment analysis, and pathway enrichment analysis were used for discovering molecular pathways predominant in each group. We further investigated the therapeutic effect of bevacizumab (vascular endothelial growth factor A (VEGFA) blocking antibody) in a retrospective GBM cohort (36 tumors) based on sex differences. RESULTS: We found that under hypoxic tumor conditions, 2 distinct tumor immuno-angiogenic ecosystems develop linked to sex differences and ESR1 expression is generated. One of these subgroups, which includes male patients with low ESR1 expression, is characterized by vascular fragility associated with the appearance of regions of necrosis and high inflammation (called necroinflamed tumors). This male-specific tumor subtype shows high inflammation related to myeloid-derived suppressor cells infiltration. Using this stratification, we identified a possible group of patients who could respond to bevacizumab (BVZ) and revealed a genetic signature that may find clinical applications as a predictor of those who may benefit most from this treatment. CONCLUSIONS: This study provides a stratification based on the sexual differences in GBM, which associates the poor prognosis with the presence of immunosuppressive myeloid cells in the necrotic areas. This new stratification could change the current prognosis of GBM and identifies those who respond to BVZ treatment.

Predicting Regions of Local Recurrence in Glioblastomas Using Voxel-Based Radiomic Features of Multiparametric Postoperative MRI.

The globally accepted surgical strategy in glioblastomas is removing the enhancing tumor. However, the peritumoral region harbors infiltration areas responsible for future tumor recurrence. This study aimed to evaluate a predictive model that identifies areas of future recurrence using a voxel-based radiomics analysis of magnetic resonance imaging (MRI) data. This multi-institutional study included a retrospective analysis of patients diagnosed with glioblastoma who underwent surgery with complete resection of the enhancing tumor. Fifty-five patients met the selection criteria. The study sample was split into training (N = 40) and testing (N = 15) datasets. Follow-up MRI was used for ground truth definition, and postoperative structural multiparametric MRI was used to extract voxel-based radiomic features. Deformable coregistration was used to register the MRI sequences for each patient, followed by segmentation of the peritumoral region in the postoperative scan and the enhancing tumor in the follow-up scan. Peritumoral voxels overlapping with enhancing tumor voxels were labeled as recurrence, while non-overlapping voxels were labeled as nonrecurrence. Voxel-based radiomic features were extracted from the peritumoral region. Four machine learning-based classifiers were trained for recurrence prediction. A region-based evaluation approach was used for model evaluation. The Categorical Boosting (CatBoost) classifier obtained the best performance on the testing dataset with an average area under the curve (AUC) of 0.81 ± 0.09 and an accuracy of 0.84 ± 0.06, using region-based evaluation. There was a clear visual correspondence between predicted and actual recurrence regions. We have developed a method that accurately predicts the region of future tumor recurrence in MRI scans of glioblastoma patients. This could enable the adaptation of surgical and radiotherapy treatment to these areas to potentially prolong the survival of these patients.

Trotabresib, an oral potent bromodomain and extraterminal inhibitor, in patients with high-grade gliomas: A phase I, "window-of-opportunity" study.

BACKGROUND: The bromodomain and extraterminal protein (BET) inhibitor trotabresib has demonstrated antitumor activity in patients with advanced solid tumors, including high-grade gliomas. CC-90010-GBM-001 (NCT04047303) is a phase I study investigating the pharmacokinetics, pharmacodynamics, and CNS penetration of trotabresib in patients with recurrent high-grade gliomas scheduled for salvage resection. METHODS: Patients received trotabresib 30 mg/day on days 1-4 before surgery, followed by maintenance trotabresib 45 mg/day 4 days on/24 days off after surgery. Primary endpoints were plasma pharmacokinetics and trotabresib concentrations in resected tissue. Secondary and exploratory endpoints included safety, pharmacodynamics, and antitumor activity. RESULTS: Twenty patients received preoperative trotabresib and underwent resection with no delays or cancelations of surgery; 16 patients received maintenance trotabresib after recovery from surgery. Trotabresib plasma pharmacokinetics were consistent with previous data. Mean trotabresib brain tumor tissue:plasma ratio was 0.84 (estimated unbound partition coefficient [KPUU] 0.37), and modulation of pharmacodynamic markers was observed in blood and brain tumor tissue. Trotabresib was well tolerated; the most frequent grade 3/4 treatment-related adverse event during maintenance treatment was thrombocytopenia (5/16 patients). Six-month progression-free survival was 12%. Two patients remain on treatment with stable disease at cycles 25 and 30. CONCLUSIONS: Trotabresib penetrates the blood-brain-tumor barrier in patients with recurrent high-grade glioma and demonstrates target engagement in resected tumor tissue. Plasma pharmacokinetics, blood pharmacodynamics, and safety were comparable with previous results for trotabresib in patients with advanced solid tumors. Investigation of adjuvant trotabresib + temozolomide and concomitant trotabresib + temozolomide + radiotherapy in patients with newly diagnosed glioblastoma is ongoing (NCT04324840).

Low grade gliomas guide-lines elaborated by the tumor section of Spanish Society of Neurosurgery.

Adult low-grade gliomas (Low Grade Gliomas, LGG) are tumors that originate from the glial cells of the brain and whose management involves great controversy, starting from the diagnosis, to the treatment and subsequent follow-up. For this reason, the Tumor Group of the Spanish Society of Neurosurgery (GT-SENEC) has held a consensus meeting, in which the most relevant neurosurgical issues have been discussed, reaching recommendations based on the best scientific evidence. In order to obtain the maximum benefit from these treatments, an individualised assessment of each patient should be made by a multidisciplinary team. Experts in each LGG treatment field have briefly described it based in their experience and the reviewed of the literature. Each area has been summarized and focused on the best published evidence. LGG have been surrounded by treatment controversy, although during the last years more accurate data has been published in order to reach treatment consensus. Neurosurgeons must know treatment options, indications and risks to participate actively in the decision making and to offer the best surgical treatment in every case.

Patients awaiting surgery for neurosurgical diseases during the first wave of the COVID-19 pandemic in Spain: a multicentre cohort study.

OBJECTIVES: The large number of infected patients requiring mechanical ventilation has led to the postponement of scheduled neurosurgical procedures during the first wave of the COVID-19 pandemic. The aims of this study were to investigate the factors that influence the decision to postpone scheduled neurosurgical procedures and to evaluate the effect of the restriction in scheduled surgery adopted to deal with the first outbreak of the COVID-19 pandemic in Spain on the outcome of patients awaiting surgery. DESIGN: This was an observational retrospective study. SETTINGS: A tertiary-level multicentre study of neurosurgery activity between 1 March and 30 June 2020. PARTICIPANTS: A total of 680 patients awaiting any scheduled neurosurgical procedure were enrolled. 470 patients (69.1%) were awaiting surgery because of spine degenerative disease, 86 patients (12.6%) due to functional disorders, 58 patients (8.5%) due to brain or spine tumours, 25 patients (3.7%) due to cerebrospinal fluid (CSF) disorders and 17 patients (2.5%) due to cerebrovascular disease. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was mortality due to any reason and any deterioration of the specific neurosurgical condition. Second, we analysed the rate of confirmed SARS-CoV-2 infection. RESULTS: More than one-quarter of patients experienced clinical or radiological deterioration. The rate of worsening was higher among patients with functional (39.5%) or CSF disorders (40%). Two patients died (0.4%) during the waiting period, both because of a concurrent disease. We performed a multivariate logistic regression analysis to determine independent covariates associated with maintaining the surgical indication. We found that community SARS-CoV-2 incidence (OR=1.011, p<0.001), degenerative spine (OR=0.296, p=0.027) and expedited indications (OR=6.095, p<0.001) were independent factors for being operated on during the pandemic. CONCLUSIONS: Patients awaiting neurosurgery experienced significant collateral damage even when they were considered for scheduled procedures.

Prognostic value of circulating endothelial cells in glioblastoma patients: a pilot study.

Aim: Glioblastoma (GB) is an aggressive tumor type and the detection of circulating endothelial cells (CECs) in peripheral blood has been related to angiogenesis. Materials & methods: A prospective single-center pilot study of CEC detection at diagnosis in 22 patients with GB was performed, using the US FDA-approved CellSearch system. Results: A CEC cutoff value was estimated using a receiver operating curve (ROC) and patients were classified into two groups: <40 CEC/4 ml and >40 CEC/4 ml blood. Median overall survival was 25.33 months for group 1 and 8.23 months for group 2 cases (p = 0.02). There was no correlation between CEC and PWI (perfusion-weighted imaging) RM. Conclusion: CEC detection has a prognostic value in GB cases at diagnosis.

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism.

Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.

Synthetic MRI improves radiomics-based glioblastoma survival prediction.

Glioblastoma is an aggressive and fast-growing brain tumor with poor prognosis. Predicting the expected survival of patients with glioblastoma is a key task for efficient treatment and surgery planning. Survival predictions could be enhanced by means of a radiomic system. However, these systems demand high numbers of multicontrast images, the acquisitions of which are time consuming, giving rise to patient discomfort and low healthcare system efficiency. Synthetic MRI could favor deployment of radiomic systems in the clinic by allowing practitioners not only to reduce acquisition time, but also to retrospectively complete databases or to replace artifacted images. In this work we analyze the replacement of an actually acquired MR weighted image by a synthesized version to predict survival of glioblastoma patients with a radiomic system. Each synthesized version was realistically generated from two acquired images with a deep learning synthetic MRI approach based on a convolutional neural network. Specifically, two weighted images were considered for the replacement one at a time, a T2w and a FLAIR, which were synthesized from the pairs T1w and FLAIR, and T1w and T2w, respectively. Furthermore, a radiomic system for survival prediction, which can classify patients into two groups (survival >480 days and ≤ 480 days), was built. Results show that the radiomic system fed with the synthesized image achieves similar performance compared with using the acquired one, and better performance than a model that does not include this image. Hence, our results confirm that synthetic MRI does add to glioblastoma survival prediction within a radiomics-based approach.

A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis.

We report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere.

Impact of the first wave of the SARS-CoV-2 pandemic on the outcome of neurosurgical patients: a nationwide study in Spain.

OBJECTIVE: To assess the effect of the first wave of the SARS-CoV-2 pandemic on the outcome of neurosurgical patients in Spain. SETTINGS: The initial flood of COVID-19 patients overwhelmed an unprepared healthcare system. Different measures were taken to deal with this overburden. The effect of these measures on neurosurgical patients, as well as the effect of COVID-19 itself, has not been thoroughly studied. PARTICIPANTS: This was a multicentre, nationwide, observational retrospective study of patients who underwent any neurosurgical operation from March to July 2020. INTERVENTIONS: An exploratory factorial analysis was performed to select the most relevant variables of the sample. PRIMARY AND SECONDARY OUTCOME MEASURES: Univariate and multivariate analyses were performed to identify independent predictors of mortality and postoperative SARS-CoV-2 infection. RESULTS: Sixteen hospitals registered 1677 operated patients. The overall mortality was 6.4%, and 2.9% (44 patients) suffered a perioperative SARS-CoV-2 infection. Of those infections, 24 were diagnosed postoperatively. Age (OR 1.05), perioperative SARS-CoV-2 infection (OR 4.7), community COVID-19 incidence (cases/105 people/week) (OR 1.006), postoperative neurological worsening (OR 5.9), postoperative need for airway support (OR 5.38), ASA grade ≥3 (OR 2.5) and preoperative GCS 3-8 (OR 2.82) were independently associated with mortality. For SARS-CoV-2 postoperative infection, screening swab test <72 hours preoperatively (OR 0.76), community COVID-19 incidence (cases/105 people/week) (OR 1.011), preoperative cognitive impairment (OR 2.784), postoperative sepsis (OR 3.807) and an absence of postoperative complications (OR 0.188) were independently associated. CONCLUSIONS: Perioperative SARS-CoV-2 infection in neurosurgical patients was associated with an increase in mortality by almost fivefold. Community COVID-19 incidence (cases/105 people/week) was a statistically independent predictor of mortality. TRIAL REGISTRATION NUMBER: CEIM 20/217.

Predicting Short-Term Survival after Gross Total or Near Total Resection in Glioblastomas by Machine Learning-Based Radiomic Analysis of Preoperative MRI.

Radiomics, in combination with artificial intelligence, has emerged as a powerful tool for the development of predictive models in neuro-oncology. Our study aims to find an answer to a clinically relevant question: is there a radiomic profile that can identify glioblastoma (GBM) patients with short-term survival after complete tumor resection? A retrospective study of GBM patients who underwent surgery was conducted in two institutions between January 2019 and January 2020, along with cases from public databases. Cases with gross total or near total tumor resection were included. Preoperative structural multiparametric magnetic resonance imaging (mpMRI) sequences were pre-processed, and a total of 15,720 radiomic features were extracted. After feature reduction, machine learning-based classifiers were used to predict early mortality (<6 months). Additionally, a survival analysis was performed using the random survival forest (RSF) algorithm. A total of 203 patients were enrolled in this study. In the classification task, the naive Bayes classifier obtained the best results in the test data set, with an area under the curve (AUC) of 0.769 and classification accuracy of 80%. The RSF model allowed the stratification of patients into low- and high-risk groups. In the test data set, this model obtained values of C-Index = 0.61, IBS = 0.123 and integrated AUC at six months of 0.761. In this study, we developed a reliable predictive model of short-term survival in GBM by applying open-source and user-friendly computational means. These new tools will assist clinicians in adapting our therapeutic approach considering individual patient characteristics.

GoRG: Towards a GPU-Accelerated Multiview Hyperspectral Depth Estimation Tool for Medical Applications.

HyperSpectral (HS) images have been successfully used for brain tumor boundary detection during resection operations. Nowadays, these classification maps coexist with other technologies such as MRI or IOUS that improve a neurosurgeon's action, with their incorporation being a neurosurgeon's task. The project in which this work is framed generates an unified and more accurate 3D immersive model using HS, MRI, and IOUS information. To do so, the HS images need to include 3D information and it needs to be generated in real-time operating room conditions, around a few seconds. This work presents Graph cuts Reference depth estimation in GPU (GoRG), a GPU-accelerated multiview depth estimation tool for HS images also able to process YUV images in less than 5.5 s on average. Compared to a high-quality SoA algorithm, MPEG DERS, GoRG YUV obtain quality losses of -0.93 dB, -0.6 dB, and -1.96% for WS-PSNR, IV-PSNR, and VMAF, respectively, using a video synthesis processing chain. For HS test images, GoRG obtains an average RMSE of 7.5 cm, with most of its errors in the background, needing around 850 ms to process one frame and view. These results demonstrate the feasibility of using GoRG during a tumor resection operation.

Tumor-Derived Pericytes Driven by EGFR Mutations Govern the Vascular and Immune Microenvironment of Gliomas.

The extraordinary plasticity of glioma cells allows them to contribute to different cellular compartments in tumor vessels, reinforcing the vascular architecture. It was recently revealed that targeting glioma-derived pericytes, which represent a big percentage of the mural cell population in aggressive tumors, increases the permeability of the vessels and improves the efficiency of chemotherapy. However, the molecular determinants of this transdifferentiation process have not been elucidated. Here we show that mutations in EGFR stimulate the capacity of glioma cells to function as pericytes in a BMX- (bone marrow and X-linked) and SOX9-dependent manner. Subsequent activation of platelet-derived growth factor receptor beta in the vessel walls of EGFR-mutant gliomas stabilized the vasculature and facilitated the recruitment of immune cells. These changes in the tumor microenvironment conferred a growth advantage to the tumors but also rendered them sensitive to pericyte-targeting molecules such as ibrutinib or sunitinib. In the absence of EGFR mutations, high-grade gliomas were enriched in blood vessels, but showed a highly disrupted blood-brain barrier due to the decreased BMX/SOX9 activation and pericyte coverage, which led to poor oxygenation, necrosis, and hypoxia. Overall, these findings identify EGFR mutations as key regulators of the glioma-to-pericyte transdifferentiation, highlighting the intricate relationship between the tumor cells and their vascular and immune milieu. Our results lay the foundations for a vascular-dependent stratification of gliomas and suggest different therapeutic vulnerabilities determined by the genetic status of EGFR. SIGNIFICANCE: This study identifies the EGFR-related mechanisms that govern the capacity of glioma cells to transdifferentiate into pericytes, regulating the vascular and immune phenotypes of the tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/2142/F1.large.jpg.

Immune Profiling of Gliomas Reveals a Connection with IDH1/2 Mutations, Tau Function and the Vascular Phenotype.

BACKGROUND: Gliomas remain refractory to all attempted treatments, including those using immune checkpoint inhibitors. The characterization of the tumor (immune) microenvironment has been recognized as an important challenge to explain this lack of response and to improve the therapy of glial tumors. METHODS: We designed a prospective analysis of the immune cells of gliomas by flow cytometry. Tumors with or without isocitrate dehydrogenase 1/2 (IDH1/2) mutations were included in the study. The genetic profile and the presence of different molecular and cellular features of the gliomas were analyzed in parallel. The findings were validated in syngeneic mouse models. RESULTS: We observed that few immune cells infiltrate mutant IDH1/2 gliomas whereas the immune content of IDH1/2 wild-type tumors was more heterogeneous. Some of them contained an important immune infiltrate, particularly enriched in myeloid cells with immunosuppressive features, but others were more similar to mutant IDH1/2 gliomas, with few immune cells and a less immunosuppressive profile. Notably, we observed a direct correlation between the percentage of leukocytes and the presence of vascular alterations, which were associated with a reduced expression of Tau, a microtubule-binding protein that controls the formation of tumor vessels in gliomas. Furthermore, overexpression of Tau was able to reduce the immune content in orthotopic allografts of GL261 cells, delaying tumor growth. CONCLUSIONS: We have confirmed the reduced infiltration of immune cells in IDH1/2 mutant gliomas. By contrast, in IDH1/2 wild-type gliomas, we have found a direct correlation between the presence of vascular alterations and the entrance of leukocytes into the tumors. Interestingly, high levels of Tau inversely correlated with the vascular and the immune content of gliomas. Altogether, our results could be exploited for the design of more successful clinical trials with immunomodulatory molecules.

Snorting the Brain Away: Cerebral Damage as an Extension of Cocaine-Induced Midline Destructive Lesions.

Cocaine consumption is associated with a variety of clinical manifestations. Though cocaine intranasal inhalation always determines nasal mucosal damages, extensive septum perforations, and midline destructions-known as cocaine-induced midline destructive lesions (CIMDL)-affect only a limited fraction of patients. CIMDL is viewed as a cocaine-associated autoimmune phenomenon in which the presence of atypical anti-neutrophil cytoplasmic antibody (ANCA) promotes and/or defines the disease phenotype. A 51-year-old man presented with an intracranial tumor-like lesion by its space-occupying effect. CT also revealed the destruction of the nasal septum and skull base. A diagnosis of CIMDL was made in light of the patient's history as well as findings of the physical and endoscopic examinations, imaging studies, and laboratory testing. There was no evidence of other pathologies. Histopathological results from cerebral biopsy led us to consider the intracranial pathology as an extension of the CIMDL. CIMDL is the result of a necrotizing inflammatory tissue response triggered by cocaine abuse in a subset of predisposed patients. The reported case is the first CIMDL consistent with brain extension mimicking a tumor-like lesion. While the presence of atypical ANCA seems to promote and/or define the disease phenotype, the specific role of these and other circulating autoantibodies needs further investigation.

Reduction in the infection rate of cranioplasty with a tailored antibiotic prophylaxis: a nonrandomized study.

BACKGROUND: Cranioplasty carries a high risk of surgical site infections (SSIs) for a scheduled procedure, particularly with antibiotic-resistant bacteria. METHODS: The goal of this retrospective study was to measure the effect of tailored antibiotic prophylaxis on SSIs resulting from cranioplasties. The authors collected a prospective database of cranioplasties from 2009 to 2018. Risk factors for SSI were registered, as well as infection occurring during the first year postoperatively. A new protocol was initiated in 2016 consisting of antibiotic prophylaxis tailored to the colonizing flora of the skin of the scalp and decolonization of patients who were nasal carriers of methicillin-resistant S. aureus (MRSA); infection rates were compared. RESULTS: One hundred nine cranioplasties were identified, 64 in the old protocol and 45 in the new protocol. Of the 109 cranioplasties, 16 (14.7%) suffered an infection, 14 (21.9%) in the old protocol group and 2 (4.4%) in the new protocol group (OR for the new protocol 0.166, 95% CI 0.036-0.772). Multiple surgeries (OR 3.44), Barthel ≤ 70 (OR 3.53), and previous infection (OR 3.9) were risk factors for SSI. Of the bacteria identified in the skin of the scalp, 22.2% were resistant to routine prophylaxis (cefazoline). Only one patient was identified as a nasal carrier of MRSA and was decolonized. CONCLUSIONS: A high percentage of bacteria resistant to routine prophylaxis (cefazoline) was identified in the skin of these patients' scalps. The use of tailored antibiotic prophylaxis reduced significantly the infection rate in this particular set of patients.

Neuropsychological management of the awake patient surgery: A protocol based on 3-year experience with glial tumors. / Protocolo de intervención neuropsicológica en la cirugía del paciente despierto: experiencia de 3 años con tumores gliales.

INTRODUCTION: Glial brain tumours usually require neurosurgical treatment and they are associated with cognitive, emotional and behavioural impairments. Awake intraoperative brain mapping is the gold standard technique used to optimize the onco-functional balance. Neuropsychological assessment and intervention have relevance in this type of procedures. Currently, there is a lack of protocolled structure for the neuropsychological intervention being able to satisfy patient needs. METHOD: A retrospective descriptive study of 52 patients was performed, all of them with a diagnosis of glial tumour. The structure of the protocol developed in our centre is reported, also data of neuropsychological evaluation, comparing baseline performance with both immediate posterior performance, and long term performance. RESULTS: We describe our experience in each step of the intervention, highlighting the development of eight neurocognitive protocols for intraoperative brain mapping. The results of the neuropsychological examination objectify deficits in the immediate after surgery assessment which are reduced in the long-term assessment. CONCLUSIONS: We emphasize the need of providing and structuring the cognitive and emotional aspects of patients suffering from any pathology that entails acquired brain damage in hospital environment. This type of approach is aimed at increasing the quality of life of cancer patients by structuring and optimizing tasks during their surgical intervention and attending to the neuropsychological difficulties they suffer.

The IDH-TAU-EGFR triad defines the neovascular landscape of diffuse gliomas.

Gliomas that express the mutated isoforms of isocitrate dehydrogenase 1/2 (IDH1/2) have better prognosis than wild-type (wt) IDH1/2 gliomas. However, how these mutant (mut) proteins affect the tumor microenvironment is still a pending question. Here, we describe that the transcription of microtubule-associated protein TAU (MAPT), a gene that has been classically associated with neurodegenerative diseases, is epigenetically controlled by the balance between wt and mut IDH1/2 in mouse and human gliomas. In IDH1/2 mut tumors, we found high expression of TAU that decreased with tumor progression. Furthermore, MAPT was almost absent from tumors with epidermal growth factor receptor (EGFR) mutations, whereas its trancription negatively correlated with overall survival in gliomas carrying wt or amplified (amp) EGFR We demonstrated that the overexpression of TAU, through the stabilization of microtubules, impaired the mesenchymal/pericyte-like transformation of glioma cells by blocking EGFR, nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and the transcriptional coactivator with PDZ-binding motif (TAZ). Our data also showed that mut EGFR induced a constitutive activation of this pathway, which was no longer sensitive to TAU. By inhibiting the transdifferentiation capacity of EGFRamp/wt tumor cells, TAU protein inhibited angiogenesis and favored vascular normalization, decreasing glioma aggressiveness and increasing their sensitivity to chemotherapy.

True Dural Spinal Epidural Cysts: Report of 5 Cases.

BACKGROUND: Spinal arachnoid cysts are a rare cause of compressive myelopathy. Spinal extradural arachnoid cysts (SEACs) are even rarer. METHODS: We retrospectively reviewed the SEACs operated on in our hospital between 2015 and 2019, according to their clinical and radiologic findings, treatments performed, and outcomes. RESULTS: We identified 5 cases (2 males and 3 females), ranging in age from 21 months to 78 years. Except for the pediatric case, all patients presented with pain and 3 had some grade of neurologic impairment. Preoperative magnetic resonance imaging showed multiloculated cyst in 4 cases, and the communication with the dura was properly identified in only 1 case. The patients were operated through a laminectomy or laminoplasty and total removal of the cyst, and the communication with the dura was identified and repaired in all cases. In all cases, the defect was near the exit of a nerve root, and rootlets were seen through it, producing a ball-like valve mechanism. Histology of the cyst wall showed true dura in every case. One patient needed a reoperation for evacuation of a fluid collection (related to the dural sealant). Following Odom's criteria, 3 patients had an excellent outcome and 2 had a fair outcome. CONCLUSIONS: Total excision of a symptomatic SEAC through either laminectomy or laminoplasty is a safe and effective treatment option. Although isolated repair of the dural communication without cyst removal may seem appealing, we have found it very difficult to identify the point of communication preoperatively.