Role of microsurgical tumor burden reduction in patients with breast cancer brain metastases considering molecular subtypes: a two-center volumetric survival analysis.

BACKGROUND: Advancements in metastatic breast cancer (BC) treatment have enhanced overall survival (OS), leading to increased rates of brain metastases (BM). This study analyzes the association between microsurgical tumor reduction and OS in patients with BCBM, considering tumor molecular subtypes and perioperative treatment approaches. METHODS: Retrospective analysis of surgically treated patients with BCBM from two tertiary brain tumor Swiss centers. The association of extent of resection (EOR), gross-total resection (GTR) achievement, and postoperative residual tumor volume (RV) with OS and intracranial progression-free survival (IC-PFS) was evaluated using Cox proportional hazard model. RESULTS: 101 patients were included in the final analysis, most patients (38%) exhibited HER2-/HR + BC molecular subtype, followed by HER2 + /HR + (25%), HER2-/HR- (21%), and HER2 + /HR- subtypes (13%). The majority received postoperative systemic treatment (75%) and radiotherapy (84%). Median OS and intracranial PFS were 22 and 8 months, respectively. The mean pre-surgery intracranial tumor volume was 26 cm3, reduced to 3 cm3 post-surgery. EOR, GTR achievement and RV were not significantly associated with OS or IC-PFS, but higher EOR and lower RV correlated with extended OS in patients without extracranial metastases. HER2-positive tumor status was associated with longer OS, extracranial metastases at BM diagnosis and symptomatic lesions with shorter OS and IC-PFS. CONCLUSIONS: Our study found that BC molecular subtypes, extracranial disease status, and BM-related symptoms were associated with OS in surgically treated patients with BCBM. Additionally, while extensive resection to minimize residual tumor volume did not significantly affect OS across the entire cohort, it appeared beneficial for patients without extracranial metastases.

Transient deoxyhemoglobin formation as a contrast for perfusion MRI studies in patients with brain tumors: a feasibility study.

Background: Transient hypoxia-induced deoxyhemoglobin (dOHb) has recently been shown to represent a comparable contrast to gadolinium-based contrast agents for generating resting perfusion measures in healthy subjects. Here, we investigate the feasibility of translating this non-invasive approach to patients with brain tumors. Methods: A computer-controlled gas blender was used to induce transient precise isocapnic lung hypoxia and thereby transient arterial dOHb during echo-planar-imaging acquisition in a cohort of patients with different types of brain tumors (n = 9). We calculated relative cerebral blood volume (rCBV), cerebral blood flow (rCBF), and mean transit time (MTT) using a standard model-based analysis. The transient hypoxia induced-dOHb MRI perfusion maps were compared to available clinical DSC-MRI. Results: Transient hypoxia induced-dOHb based maps of resting perfusion displayed perfusion patterns consistent with underlying tumor histology and showed high spatial coherence to gadolinium-based DSC MR perfusion maps. Conclusion: Non-invasive transient hypoxia induced-dOHb was well-tolerated in patients with different types of brain tumors, and the generated rCBV, rCBF and MTT maps appear in good agreement with perfusion maps generated with gadolinium-based DSC MR perfusion.

Identifying clusters of objective functional impairment in patients with degenerative lumbar spinal disease using unsupervised learning.

OBJECTIVES: The five-repetition sit-to-stand (5R-STS) test was designed to capture objective functional impairment (OFI), and thus provides an adjunctive dimension in patient assessment. It is conceivable that there are different subsets of patients with OFI and degenerative lumbar disease. We aim to identify clusters of objectively functionally impaired individuals based on 5R-STS and unsupervised machine learning (ML). METHODS: Data from two prospective cohort studies on patients with surgery for degenerative lumbar disease and 5R-STS times of ≥ 10.5 s-indicating presence of OFI. K-means clustering-an unsupervised ML algorithm-was applied to identify clusters of OFI. Cluster hallmarks were then identified using descriptive and inferential statistical analyses. RESULTS: We included 173 patients (mean age [standard deviation]: 46.7 [12.7] years, 45% male) and identified three types of OFI. OFI Type 1 (57 pts., 32.9%), Type 2 (81 pts., 46.8%), and Type 3 (35 pts., 20.2%) exhibited mean 5R-STS test times of 14.0 (3.2), 14.5 (3.3), and 27.1 (4.4) seconds, respectively. The grades of OFI according to the validated baseline severity stratification of the 5R-STS increased significantly with each OFI type, as did extreme anxiety and depression symptoms, issues with mobility and daily activities. Types 1 and 2 are characterized by mild to moderate OFI-with female gender, lower body mass index, and less smokers as Type I hallmarks. CONCLUSIONS: Unsupervised learning techniques identified three distinct clusters of patients with OFI that may represent a more holistic clinical classification of patients with OFI than test-time stratifications alone, by accounting for individual patient characteristics.

Safety of microneurosurgical interventions for superficial and deep-seated brain metastases: single-center cohort study of 637 consecutive cases.

PURPOSE: Microneurosurgical techniques have greatly improved over the past years due to the introduction of new technology and surgical concepts. To reevaluate the role of micro-neurosurgery in brain metastases (BM) resection in the era of new systemic and local treatment options, its safety profile needs to be reassessed. The aim of this study was to analyze the rate of adverse events (AEs) according to a systematic, comprehensive and reliably reproducible grading system after microneurosurgical BM resection in a large and modern microneurosurgical series with special emphasis on anatomical location. METHODS: Prospectively collected cases of BM resection between 2013 and 2022 were retrospectively analyzed. Number of AEs, defined as any deviations from the expected postoperative course according to Clavien-Dindo-Grade (CDG) were evaluated. Patient, surgical, and lesion characteristics, including exact anatomic tumor locations, were analyzed using uni- and multivariate logistic regression and survival analysis to identify predictive factors for AEs. RESULTS: We identified 664 eligible patients with lung cancer being the most common primary tumor (44%), followed by melanoma (25%) and breast cancer (11%). 29 patients (4%) underwent biopsy only whereas BM were resected in 637 (96%) of cases. The overall rate of AEs was 8% at discharge. However, severe AEs (≥ CDG 3a; requiring surgical intervention under local/general anesthesia or ICU treatment) occurred in only 1.9% (n = 12) of cases with a perioperative mortality of 0.6% (n = 4). Infratentorial tumor location (OR 5.46, 95% 2.31-13.8, p = .001), reoperation (OR 2.31, 95% 1.07-4.81, p = .033) and central region tumor location (OR 3.03, 95% 1.03-8.60) showed to be significant predictors in a multivariate analysis for major AEs (CDG ≥ 2 or new neurological deficits). Neither deep supratentorial nor central region tumors were associated with more major AEs compared to convexity lesions. CONCLUSIONS: Modern microneurosurgical resection can be considered an excellent option in the management of BM in terms of safety, as the overall rate of major AEs are very rare even in eloquent and deep-seated lesions.

Tailored therapy for recurrent glioblastoma: report of a personalized molecular approach.

BACKGROUND: Failure of clinical trials with targeted therapies in glioblastoma (GBM) is probably related to the enrollment of molecularly unselected patients. In this study we report the results of a precision medicine protocol in recurrent GBM. METHODS: We prospectively evaluated 34 patients with recurrent GBM. We determined the expression of vascular endothelial growth factor (VEGF), epidermal growth factor receptor variant III (EGFRvIII), and phosphatase and tensin homolog (PTEN). According to the molecular pattern we administered bevacizumab alone in patients with VEGF overexpression, absence of EGFRvIII, and normal PTEN (group A; N.=16); bevacizumab + erlotinib in patients with VEGF overexpression, expression of EGFRvIII, and normal PTEN (group B; N.=14); and bevacizumab + sirolimus in patients with VEGF overexpression and loss of PTEN, irrespective of the EGFRvIII status (group C; N.=4). We evaluated the response rate, the clinical benefit rate, the 6-month progression-free survival (PFS-6), the 12-month PFS (PFS-12) and the safety profile of the treatment. Moreover, we compared our results with the ones of EORTC 26101 trial. RESULTS: Response rate was 50% in the whole cohort with the highest rate in group C (75%). Clinical benefit rate was 71% with the highest rate in group C (75%). PFS-6 was 56% in the whole cohort with the highest rate in group B (64%). PFS-12 was 21% in the whole cohort with the highest rate in group B (29%). When comparing our results with those from the combination arm of the EORTC 26101 trial we found a significantly higher PFS-6 and PFS-12 in our cohort. CONCLUSIONS: The precision medicine protocol for recurrent GBM is feasible and leads to improved results if compared with studies lacking molecular selection.

Sex-related differences in postoperative complications following elective craniotomy for intracranial lesions: An observational study.

INTRODUCTION: The integration of sex-related differences in neurosurgery is crucial for new, possible sex-specific, therapeutic approaches. In neurosurgical emergencies, such as traumatic brain injury and aneurysmal subarachnoid hemorrhage, these differences have been investigated. So far, little is known concerning the impact of sex on frequency of postoperative complications after elective craniotomy. This study investigates whether sex-related differences exist in frequency of postoperative complications in patients who underwent elective craniotomy for intracranial lesion. MATERIAL AND METHODS: All consecutive patients who underwent an elective intracranial procedure over a 2-year period at our center were eligible for inclusion in this retrospective study. Demographic data, comorbidities, frequency of postoperative complications at 24 hours following surgery and at discharge, and hospital length of stay were compared among females and males. RESULTS: Overall, 664 patients were considered for the analysis. Of those, 339 (50.2%) were females. Demographic data were comparable among females and males. More females than males suffered from allergic, muscular, and rheumatic disorders. No differences in frequency of postoperative complications at 24 hours after surgery and at discharge were observed among females and males. Similarly, the hospital length of stay was comparable. CONCLUSIONS: In the present study, no sex-related differences in frequency of early postoperative complications and at discharge following elective craniotomy for intracranial lesions were observed.

Hemodynamic Imaging in Cerebral Diffuse Glioma-Part B: Molecular Correlates, Treatment Effect Monitoring, Prognosis, and Future Directions.

Gliomas, and glioblastoma in particular, exhibit an extensive intra- and inter-tumoral molecular heterogeneity which represents complex biological features correlating to the efficacy of treatment response and survival. From a neuroimaging point of view, these specific molecular and histopathological features may be used to yield imaging biomarkers as surrogates for distinct tumor genotypes and phenotypes. The development of comprehensive glioma imaging markers has potential for improved glioma characterization that would assist in the clinical work-up of preoperative treatment planning and treatment effect monitoring. In particular, the differentiation of tumor recurrence or true progression from pseudoprogression, pseudoresponse, and radiation-induced necrosis can still not reliably be made through standard neuroimaging only. Given the abundant vascular and hemodynamic alterations present in diffuse glioma, advanced hemodynamic imaging approaches constitute an attractive area of clinical imaging development. In this context, the inclusion of objective measurable glioma imaging features may have the potential to enhance the individualized care of diffuse glioma patients, better informing of standard-of-care treatment efficacy and of novel therapies, such as the immunotherapies that are currently increasingly investigated. In Part B of this two-review series, we assess the available evidence pertaining to hemodynamic imaging for molecular feature prediction, in particular focusing on isocitrate dehydrogenase (IDH) mutation status, MGMT promoter methylation, 1p19q codeletion, and EGFR alterations. The results for the differentiation of tumor progression/recurrence from treatment effects have also been the focus of active research and are presented together with the prognostic correlations identified by advanced hemodynamic imaging studies. Finally, the state-of-the-art concepts and advancements of hemodynamic imaging modalities are reviewed together with the advantages derived from the implementation of radiomics and machine learning analyses pipelines.

Hemodynamic Imaging in Cerebral Diffuse Glioma-Part A: Concept, Differential Diagnosis and Tumor Grading.

Diffuse gliomas are the most common primary malignant intracranial neoplasms. Aside from the challenges pertaining to their treatment-glioblastomas, in particular, have a dismal prognosis and are currently incurable-their pre-operative assessment using standard neuroimaging has several drawbacks, including broad differentials diagnosis, imprecise characterization of tumor subtype and definition of its infiltration in the surrounding brain parenchyma for accurate resection planning. As the pathophysiological alterations of tumor tissue are tightly linked to an aberrant vascularization, advanced hemodynamic imaging, in addition to other innovative approaches, has attracted considerable interest as a means to improve diffuse glioma characterization. In the present part A of our two-review series, the fundamental concepts, techniques and parameters of hemodynamic imaging are discussed in conjunction with their potential role in the differential diagnosis and grading of diffuse gliomas. In particular, recent evidence on dynamic susceptibility contrast, dynamic contrast-enhanced and arterial spin labeling magnetic resonance imaging are reviewed together with perfusion-computed tomography. While these techniques have provided encouraging results in terms of their sensitivity and specificity, the limitations deriving from a lack of standardized acquisition and processing have prevented their widespread clinical adoption, with current efforts aimed at overcoming the existing barriers.

FUSE-ML: development and external validation of a clinical prediction model for mid-term outcomes after lumbar spinal fusion for degenerative disease.

BACKGROUND: Indications and outcomes in lumbar spinal fusion for degenerative disease are notoriously heterogenous. Selected subsets of patients show remarkable benefit. However, their objective identification is often difficult. Decision-making may be improved with reliable prediction of long-term outcomes for each individual patient, improving patient selection and avoiding ineffective procedures. METHODS: Clinical prediction models for long-term functional impairment [Oswestry Disability Index (ODI) or Core Outcome Measures Index (COMI)], back pain, and leg pain after lumbar fusion for degenerative disease were developed. Achievement of the minimum clinically important difference at 12 months postoperatively was defined as a reduction from baseline of at least 15 points for ODI, 2.2 points for COMI, or 2 points for pain severity. RESULTS: Models were developed and integrated into a web-app ( https://neurosurgery.shinyapps.io/fuseml/ ) based on a multinational cohort [N = 817; 42.7% male; mean (SD) age: 61.19 (12.36) years]. At external validation [N = 298; 35.6% male; mean (SD) age: 59.73 (12.64) years], areas under the curves for functional impairment [0.67, 95% confidence interval (CI): 0.59-0.74], back pain (0.72, 95%CI: 0.64-0.79), and leg pain (0.64, 95%CI: 0.54-0.73) demonstrated moderate ability to identify patients who are likely to benefit from surgery. Models demonstrated fair calibration of the predicted probabilities. CONCLUSIONS: Outcomes after lumbar spinal fusion for degenerative disease remain difficult to predict. Although assistive clinical prediction models can help in quantifying potential benefits of surgery and the externally validated FUSE-ML tool may aid in individualized risk-benefit estimation, truly impacting clinical practice in the era of "personalized medicine" necessitates more robust tools in this patient population.

Feasibility of glioblastoma tissue response mapping with physiologic BOLD imaging using precise oxygen and carbon dioxide challenge.

OBJECTIVES: Innovative physiologic MRI development focuses on depiction of heterogenous vascular and metabolic features in glioblastoma. For this feasibility study, we employed blood oxygenation level-dependent (BOLD) MRI with standardized and precise carbon dioxide (CO2) and oxygen (O2) modulation to investigate specific tumor tissue response patterns in patients with newly diagnosed glioblastoma. MATERIALS AND METHODS: Seven newly diagnosed untreated patients with suspected glioblastoma were prospectively included to undergo a BOLD study with combined CO2 and O2 standardized protocol. %BOLD signal change/mmHg during hypercapnic, hypoxic, and hyperoxic stimulus was calculated in the whole brain, tumor lesion and segmented volumes of interest (VOI) [contrast-enhancing (CE) - tumor, necrosis and edema] to analyze their tissue response patterns. RESULTS: Quantification of BOLD signal change after gas challenges can be used to identify specific responses to standardized stimuli in glioblastoma patients. Integration of this approach with automatic VOI segmentation grants improved characterization of tumor subzones and edema. Magnitude of BOLD signal change during the 3 stimuli can be visualized at voxel precision through color-coded maps overlayed onto whole brain and identified VOIs. CONCLUSIONS: Our preliminary investigation shows good feasibility of BOLD with standardized and precise CO2 and O2 modulation as an emerging physiologic imaging technique to detail specific glioblastoma characteristics. The unique tissue response patterns generated can be further investigated to better detail glioblastoma lesions and gauge treatment response.

Machine Learning in Pituitary Surgery.

Machine learning applications in neurosurgery are increasingly reported for diverse tasks such as faster and more accurate preoperative diagnosis, enhanced lesion characterization, as well as surgical outcome, complications and healthcare cost prediction. Even though the pertinent literature in pituitary surgery is less extensive with respect to other neurosurgical diseases, past research attempted to answer clinically relevant questions to better assist surgeons and clinicians. In the present chapter we review reported ML applications in pituitary surgery including differential diagnosis, preoperative lesion characterization (immunohistochemistry, cavernous sinus invasion, tumor consistency), surgical outcome and complication predictions (gross total resection, tumor recurrence, and endocrinological remission, cerebrospinal fluid leak, postoperative hyponatremia). Moreover, we briefly discuss from a practical standpoint the current barriers to clinical translation of machine learning research. On the topic of pituitary surgery, published reports can be considered mostly preliminary, requiring larger training populations and strong external validation. Thoughtful selection of clinically relevant outcomes of interest and transversal application of model development pipeline-together with accurate methodological planning and multicenter collaborations-have the potential to overcome current limitations and ultimately provide additional tools for more informed patient management.

Reassessing the Role of Brain Tumor Biopsy in the Era of Advanced Surgical, Molecular, and Imaging Techniques-A Single-Center Experience with Long-Term Follow-Up.

Brain biopsy is the gold standard in order to establish the diagnosis of unresectable brain tumors. Few studies have investigated the long-term outcomes of biopsy patients. The aim of this single-institution-based study was to assess the concordance between radiological and histopathological diagnoses, and the long-term patient outcome. Ninety-three patients who underwent brain biopsy in the last 5 years were analyzed. We included patients treated with stereotactically guided needle, open, and neuroendoscopic biopsies. Most patients (86%) received needle biopsy. Gliomas and primary brain lymphomas comprised 88.2% of cases. The diagnostic yield was 95.7%. Serious complication and death rates were 3.2% and 2.1%, respectively. The concordance rate between radiological and histological diagnoses was 93%. Notably, the positive predictive value of radiological diagnosis of lymphoma was 100%. Biopsy allowed specific treatment in 72% of cases. Disease-related neurological worsening was the main reason that precluded adjuvant treatment. Adjuvant treatment, in turn, was the strongest prognostic factor, since the median overall survival was 11 months with vs. 2 months without treatment (p = 0.0002). Finally, advanced molecular evaluations can be obtained on glioma biopsy specimens to provide integrated diagnoses and individually tailored treatments. We conclude that, despite the huge advances in imaging techniques, biopsy is required when an adjuvant treatment is recommended, particularly in gliomas.

Impact of intraoperative magnetic resonance imaging on gross total resection, extent of resection, and residual tumor volume in pituitary surgery: systematic review and meta-analysis.

BACKGROUND: Residual tumor tissue after pituitary adenoma surgery, is linked with additional morbidity and mortality. Intraoperative magnetic resonance imaging (ioMRI) could improve resection. We aim to assess the improvement in gross total resection (GTR), extent of resection (EOR), and residual tumor volume (RV) achieved using ioMRI. METHODS: A systematic review was carried out on PubMed/MEDLINE to identify any studies reporting intra- and postoperative (1) GTR, (2) EOR, or (3) RV in patients who underwent resection of pituitary adenomas with ioMRI. Random effects meta-analysis of the rate of improvement after ioMRI for these three surgical outcomes was intended. RESULTS: Among 34 included studies (2130 patients), the proportion of patients with conversion to GTR (∆GTR) after ioMRI was 0.19 (95% CI 0.15-0.23). Mean ∆EOR was + 9.07% after ioMRI. Mean ∆RV was 0.784 cm3. For endoscopically treated patients, ∆GTR was 0.17 (95% CI 0.09-0.25), while microscopic ∆GTR was 0.19 (95% CI 0.15-0.23). Low-field ioMRI studies demonstrated a ∆GTR of 0.19 (95% CI 0.11-0.28), while high-field and ultra-high-field ioMRI demonstrated a ∆GTR of 0.19 (95% CI 0.15-0.24) and 0.20 (95% CI 0.13-0.28), respectively. CONCLUSIONS: Our meta-analysis demonstrates that around one fifth of patients undergoing pituitary adenoma resection convert from non-GTR to GTR after the use of ioMRI. EOR and RV can also be improved to a certain extent using ioMRI. Endoscopic versus microscopic technique or field strength does not appear to alter the impact of ioMRI. Statistical heterogeneity was high, indicating that the improvement in surgical results due to ioMRI varies considerably by center.

Enhanced Recovery After Surgery strategies for elective craniotomy: a systematic review.

OBJECTIVE: Enhanced Recovery After Surgery (ERAS) has led to a paradigm shift in perioperative care through multimodal interventions. Still, ERAS remains a relatively new concept in neurosurgery, and there is no summary of evidence on ERAS applications in cranial neurosurgery. METHODS: The authors systematically reviewed the literature using the PubMed/MEDLINE, Embase, Scopus, and Cochrane Library databases for ERAS protocols and elements. Studies had to assess at least one pre-, peri-, or postoperative ERAS element and evaluate at least one of the following outcomes: 1) length of hospital stay, 2) length of ICU stay, 3) postoperative pain, 4) direct and indirect healthcare cost, 5) complication rate, 6) readmission rate, or 7) patient satisfaction. RESULTS: A final 27 articles were included in the qualitative analysis, with mixed quality of evidence ranging from high in 3 cases to very low in 1 case. Seventeen studies reported a complete ERAS protocol. Preoperative ERAS elements include patient selection through multidisciplinary team discussion, patient counseling and education to adjust expectations of the postoperative period, and mental state assessment; antimicrobial, steroidal, and antiepileptic prophylaxes; nutritional assessment, as well as preoperative oral carbohydrate loading; and postoperative nausea and vomiting (PONV) prophylaxis. Anesthesiology interventions included local anesthesia for pin sites, regional field block or scalp block, avoidance or minimization of the duration of invasive monitoring, and limitation of intraoperative mannitol. Other intraoperative elements include absorbable skin sutures and avoidance of wound drains. Postoperatively, the authors identified early extubation, observation in a step-down unit instead of routine ICU admission, early mobilization, early fluid de-escalation, early intake of solid food and liquids, early removal of invasive monitoring, professional nutritional assessment, PONV management, nonopioid rescue analgesia, and early postoperative imaging. Other postoperative interventions included discharge criteria standardization and home visits or progress monitoring by a nurse. CONCLUSIONS: A wide range of evidence-based interventions are available to improve recovery after elective craniotomy, although there are few published ERAS protocols. Patient-centered optimization of neurosurgical care spanning the pre-, intra-, and postoperative periods is feasible and has already provided positive results in terms of improved outcomes such as postoperative pain, patient satisfaction, reduced length of stay, and cost reduction with an excellent safety profile. Although fast-track recovery protocols and ERAS studies are gaining momentum for elective craniotomy, prospective trials are needed to provide stronger evidence.

Dilation of Brain Veins and Perivascular Infiltration by Glioblastoma Cells in an In Vivo Assay of Early Tumor Angiogenesis.

The cranial window (CW) technique provides a simple and low-cost method to assess tumor angiogenesis in the brain. The CW combined with histology using selective markers for tumor and endothelial cells can allow a sensitive monitoring of novel antiangiogenesis therapies in preclinical models. The CW was established in cyclosporine immunosuppressed rats that were stereotactically grafted with fluorescent U87MG glioblastoma cells. One to 3 weeks after grafting, brain vasculature was visualized in vivo and assessed by immunofluorescence microscopy using antibodies against endothelial and smooth-muscle cells and blood brain barrier. At 1-2 weeks after grafting, the CW reliably detected the hypertrophy of venous-venous anastomoses and cortical veins. These structures increased highly significantly their pregrafting diameter. Arterialized veins and hemorrhages were seen by three weeks after grafting. Immunofluorescence microscopy showed significant branching and dilation of microvessels, particularly those surrounded by tumor cells. Mechanistically, these changes lead to loss of vascular resistance, increased venous outflow, and opening of venous-venous anastomoses on the cortical surface. Data from the present study, namely, the hypertrophy of cortical venous-venous anastomoses, microvessel branching, and dilation of the microvessels surrounded by tumor cells, indicate the power of this in vivo model for the sensitive monitoring of early tumor angiogenesis.

The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling.

BACKGROUND: Metabolic reprogramming is a common feature in cancer, and it is critical to facilitate cancer cell growth. Isocitrate Dehydrogenase 1/2 (IDH1 and IDH2) mutations (IDHmut) are the most common genetic alteration in glioma grade II and III and secondary glioblastoma and these mutations increase reliance on glutamine metabolism, suggesting a potential vulnerability. In this study, we tested the hypothesis that the brain penetrant glutamine antagonist prodrug JHU-083 reduces glioma cell growth. MATERIAL AND METHODS: We performed cell growth, cell cycle, and protein expression in glutamine deprived or Glutaminase (GLS) gene silenced glioma cells. We tested the effect of JHU-083 on cell proliferation, metabolism, and mTOR signaling in cancer cell lines. An orthotopic IDH1R132H glioma model was used to test the efficacy of JHU-083 in vivo. RESULTS: Glutamine deprivation and GLS gene silencing reduced glioma cell proliferation in vitro in glioma cells. JHU-083 reduced glioma cell growth in vitro, modulated cell metabolism, and disrupted mTOR signaling and downregulated Cyclin D1 protein expression, through a mechanism independent of TSC2 modulation and glutaminolysis. IDH1R132H isogenic cells preferentially reduced cell growth and mTOR signaling downregulation. In addition, guanine supplementation partially rescued IDHmut glioma cell growth, mTOR signaling, and Cyclin D1 protein expression in vitro. Finally, JHU-083 extended survival in an intracranial IDH1 mut glioma model and reduced intracranial pS6 protein expression. CONCLUSION: Targeting glutamine metabolism with JHU-083 showed efficacy in preclinical models of IDHmut glioma and measurably decreased mTOR signaling.

Global adoption of robotic technology into neurosurgical practice and research.

Recent technological advancements have led to the development and implementation of robotic surgery in several specialties, including neurosurgery. Our aim was to carry out a worldwide survey among neurosurgeons to assess the adoption of and attitude toward robotic technology in the neurosurgical operating room and to identify factors associated with use of robotic technology. The online survey was made up of nine or ten compulsory questions and was distributed via the European Association of the Neurosurgical Societies (EANS) and the Congress of Neurological Surgeons (CNS) in February and March 2018. From a total of 7280 neurosurgeons who were sent the survey, we received 406 answers, corresponding to a response rate of 5.6%, mostly from Europe and North America. Overall, 197 neurosurgeons (48.5%) reported having used robotic technology in clinical practice. The highest rates of adoption of robotics were observed for Europe (54%) and North America (51%). Apart from geographical region, only age under 30, female gender, and absence of a non-academic setting were significantly associated with clinical use of robotics. The Mazor family (32%) and ROSA (26%) robots were most commonly reported among robot users. Our study provides a worldwide overview of neurosurgical adoption of robotic technology. Almost half of the surveyed neurosurgeons reported having clinical experience with at least one robotic system. Ongoing and future trials should aim to clarify superiority or non-inferiority of neurosurgical robotic applications and balance these potential benefits with considerations on acquisition and maintenance costs.

Comparison between VII-to-VII and XII-to-VII coaptation techniques for early facial nerve reanimation after surgical intra-cranial injuries: a systematic review and pooled analysis of the functional outcomes.

The surgical injury of the intracranial portion of the facial nerve (FN) is a severe complication of many skull base procedures, and it represents a relevant issue in terms of patients' discomfort, social interactions, risk for depression, and social costs. The aim of this study was to investigate the surgical and functional outcomes of the most common facial nerve rehabilitation techniques. The present study is a systematic review of the pertinent literature, according to the PRISMA guidelines. Two different online medical databases (PubMed, Scopus) were screened for studies reporting the functional outcome, measured by the House-Brackman (HB) scale, and complications, in FN early reanimation, following surgical injuries on its intracranial portion. Data on the VII-to-VII and XII-to-VII coaptation, the surgical technique, the use of a nerve graft, the duration of the deficit, and complications were collected and pooled. The XII-to-VII end-to-side coaptation seems to provide higher chances for functional restoration (HB 1-3) than the VII-to-VII (68.8% vs 60.6%), regardless of the duration of the palsy deficit, the use or not of a nerve graft, and the use of stitches or glues. However, its complication rate was as high as 28.6%, and a second procedure is then often needed. The XII-to-VII side-to-end coaptation is the most effective in providing a functional outcome (HB 1-3), even though it is associated to a higher complication rate. Further trials are needed to better investigate this relevant topic, in terms of health-related social costs and patients' quality of life.

Machine learning in neurosurgery: a global survey.

BACKGROUND: Recent technological advances have led to the development and implementation of machine learning (ML) in various disciplines, including neurosurgery. Our goal was to conduct a comprehensive survey of neurosurgeons to assess the acceptance of and attitudes toward ML in neurosurgical practice and to identify factors associated with its use. METHODS: The online survey consisted of nine or ten mandatory questions and was distributed in February and March 2019 through the European Association of Neurosurgical Societies (EANS) and the Congress of Neurosurgeons (CNS). RESULTS: Out of 7280 neurosurgeons who received the survey, we received 362 responses, with a response rate of 5%, mainly in Europe and North America. In total, 103 neurosurgeons (28.5%) reported using ML in their clinical practice, and 31.1% in research. Adoption rates of ML were relatively evenly distributed, with 25.6% for North America, 30.9% for Europe, 33.3% for Latin America and the Middle East, 44.4% for Asia and Pacific and 100% for Africa with only two responses. No predictors of clinical ML use were identified, although academic settings and subspecialties neuro-oncology, functional, trauma and epilepsy predicted use of ML in research. The most common applications were for predicting outcomes and complications, as well as interpretation of imaging. CONCLUSIONS: This report provides a global overview of the neurosurgical applications of ML. A relevant proportion of the surveyed neurosurgeons reported clinical experience with ML algorithms. Future studies should aim to clarify the role and potential benefits of ML in neurosurgery and to reconcile these potential advantages with bioethical considerations.

Mir-370-3p Impairs Glioblastoma Stem-Like Cell Malignancy Regulating a Complex Interplay between HMGA2/HIF1A and the Oncogenic Long Non-Coding RNA (lncRNA) NEAT1.

Glioblastoma (GBM) is the most aggressive and prevalent form of a human brain tumor in adults. Several data have demonstrated the implication of microRNAs (miRNAs) in tumorigenicity of GBM stem-like cells (GSCs). The regulatory functions of miRNAs in GSCs have emerged as potential therapeutic candidates for glioma treatment. The current study aimed at investigating the function of miR-370-3p in glioma progression, as aberrant expression of miR-370-3p, is involved in various human cancers, including glioma. Analyzing our collection of GBM samples and patient-derived GSC lines, we found the expression of miR-370-3p significantly downregulated compared to normal brain tissues and normal neural stem cells. Restoration of miR-370-3p expression in GSCs significantly decreased proliferation, migration, and clonogenic abilities of GSCs, in vitro, and tumor growth in vivo. Gene expression analysis performed on miR-370-3p transduced GSCs, identified several transcripts involved in Epithelial to Mesenchymal Transition (EMT), and Hypoxia signaling pathways. Among the genes downregulated by the restored expression of miR-370-3p, we found the EMT-inducer high-mobility group AT-hook 2 (HMGA2), the master transcriptional regulator of the adaptive response to hypoxia, Hypoxia-inducible factor (HIF)1A, and the long non-coding RNAs (lncRNAs) Nuclear Enriched Abundant Transcript (NEAT)1. NEAT1 acts as an oncogene in a series of human cancers including gliomas, where it is regulated by the Epidermal Growth Factor Receptor (EGFR) pathways, and contributes to tumor growth and invasion. Noteworthy, the expression levels of miR-370-3p and NEAT1 were inversely related in both GBM tumor specimens and GSCs, and a dual-luciferase reporter assay proved the direct binding between miR-370-3p and the lncRNAs NEAT1. Our results identify a critical role of miR-370-3p in the regulation of GBM development, indicating that miR-370-3p acts as a tumor-suppressor factor inhibiting glioma cell growth, migration and invasion by targeting the lncRNAs NEAT1, HMGA2, and HIF1A, thus, providing a potential candidate for GBM patient treatment.