Association of Clinical, Tumor, and Treatment Characteristics With Seizure Control in Patients With IDH1/2-Mutant Lower-Grade Glioma.

BACKGROUND AND OBJECTIVES: Patients with IDH1/2-mutant lower-grade glioma have a high frequency of seizures. We aimed to investigate the correlations between seizures and tumor/patient characteristics and the impact of surgery and adjuvant treatments (AT) on seizure control along the disease trajectory. METHODS: We retrospectively included patients with IDH1/2-mutant lower-grade glioma who underwent surgery at the neurosurgery divisions of the University of Turin and Milan and were treated at the Division of Neuro-Oncology of Turin. Inclusion criteria were a diagnosis according to the 2021 WHO Classification and presentation with seizures; exclusion criteria were presence of CDKN2A/B homozygous deletion, intense/ring contrast enhancement on MRI at presentation, and small tissue biopsy. We evaluated seizure freedom for 2 months after surgery, 6 months from starting observation or AT, at recurrence, and for 6 months after treatments of recurrence. RESULTS: We included 150 patients. There were 77 (51%) and 31 (21%) patients with IDH-mutant/1p19q-codeleted grade 2 and 3 oligodendroglioma and 30 (20%) and 12 (8%) with IDH-mutant grade 2 and 3 astrocytoma, respectively. Total resection was accomplished in 68 (45%). Seventy-five patients (50%) received AT while the remaining 75 were observed with MRI. After 6 months after AT, 28 of 29 patients (96.5%) displayed seizure reduction, 5 of 28 (18%) being seizure-free. 66 of 124 patients (53%) had seizures at recurrence. After 6 months after second-line treatments, 60 of 66 patients (91%) had seizure reduction, 11 (17%) being seizure-free. In multivariable analyses, grade 3 histology positively correlated with seizure freedom at 2 months after surgery (OR 3.5, 1.4-8.9, p = 0.008), 6 months after AT (OR 9.0, 1.5-54.9, p = 0.017), and 6 months after treatment of recurrence (OR 4.9, 1.5-16.5, p = 0.009). Adjuvant radiotherapy reduced seizures at recurrence in a univariate analysis (OR 0.14, 0.03-0.7, p = 0.020). Patients with seizure freedom after surgery and AT displayed longer progression-free survival (PFS) (65, 24.5-105, vs 48 months, 32-63.5, p = 0.037). DISCUSSION: This study analyzed seizure control in patients with IDH1/2-mutant lower-grade glioma across multiple time points. Grade 3 correlated with better seizure control throughout the entire disease trajectory, and seizure freedom after surgery and AT correlated with a longer PFS regardless of tumor grade. These results could serve as an external control arm in clinical trials evaluating the efficacy on seizures of antitumor agents in patients with IDH-mutant lower-grade glioma.

Object-oriented hand dexterity and grasping abilities, from the animal quarters to the neurosurgical OR: a systematic review of the underlying neural correlates in non-human, human primate and recent findings in awake brain surgery.

Introduction: The sensorimotor integrations subserving object-oriented manipulative actions have been extensively investigated in non-human primates via direct approaches, as intracortical micro-stimulation (ICMS), cytoarchitectonic analysis and anatomical tracers. However, the understanding of the mechanisms underlying complex motor behaviors is yet to be fully integrated in brain mapping paradigms and the consistency of these findings with intraoperative data obtained during awake neurosurgical procedures for brain tumor removal is still largely unexplored. Accordingly, there is a paucity of systematic studies reviewing the cross-species analogies in neural activities during object-oriented hand motor tasks in primates and investigating the concordance with intraoperative findings during brain mapping. The current systematic review was designed to summarize the cortical and subcortical neural correlates of object-oriented fine hand actions, as revealed by fMRI and PET studies, in non-human and human primates and how those were translated into neurosurgical studies testing dexterous hand-movements during intraoperative brain mapping. Methods: A systematic literature review was conducted following the PRISMA guidelines. PubMed, EMBASE and Web of Science databases were searched. Original articles were included if they: (1) investigated cortical activation sites on fMRI and/or PET during grasping task; (2) included humans or non-human primates. A second query was designed on the databases above to collect studies reporting motor, hand manipulation and dexterity tasks for intraoperative brain mapping in patients undergoing awake brain surgery for any condition. Due to the heterogeneity in neurosurgical applications, a qualitative synthesis was deemed more appropriate. Results: We provided an updated overview of the current state of the art in translational neuroscience about the extended frontoparietal grasping-praxis network with a specific focus on the comparative functioning in non-human primates, healthy humans and how the latter knowledge has been implemented in the neurosurgical operating room during brain tumor resection. Discussion: The anatomical and functional correlates we reviewed confirmed the evolutionary continuum from monkeys to humans, allowing a cautious but practical adoption of such evidence in intraoperative brain mapping protocols. Integrating the previous results in the surgical practice helps preserve complex motor abilities, prevent long-term disability and poor quality of life and allow the maximal safe resection of intrinsic brain tumors.

Transcranial versus direct electrical stimulation for intraoperative motor-evoked potential monitoring: Prognostic value comparison in asleep brain tumor surgery.

Objective: Safe resection of gliomas involving motor pathways in asleep-anesthesia requires the combination of brain mapping, to identify and spare essential motor sites, and continuous monitoring of motor-evoked potentials (MEPs), to detect possible vascular damage to the corticospinal tract (CST). MEP monitoring, according to intraoperative neurophysiology societies, is generally recommended by transcranial electrodes (TES), and no clear indications of direct cortical stimulation (DCS) or the preferential use of one of the two techniques based on the clinical context is available. The main aim of the study was to identify the best technique(s) based on different clinical conditions, evaluating the efficacy and prognostic value of both methodologies. Methods: A retrospective series of patients with tumors involving the motor pathways who underwent surgical resection with the aid of brain mapping and combined MEP monitoring via TES and DCS was evaluated. Irreversible MEP amplitude reduction (>50% compared to baseline) was used as an intraoperative warning and correlated to the postoperative motor outcome. Selectivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were computed for both techniques. Results: Four hundred sixty-two patients were retrospectively analyzed, and only 1.9% showed a long-term motor impairment. Both TES and DCS obtained high specificity and NPV for the acute and 1-month motor deficit. Sensitivity was rather low for the acute deficit but excellent considering the 1-month follow-up for both techniques. DCS was extremely reliable in predicting a postoperative motor decline (PPV of 100% and 90% for acute and long-term deficit, respectively). Conversely, TES produced a high number of false-positive results, especially for long-term deficits (65, 87.8% of all warnings) therefore obtaining poor PPV values (18% and 12% for acute and 1-month deficits, respectively). TES false-positive results were significantly associated with parietal tumors and lateral patient positioning. Conclusions: Data support the use of mapping and combined monitoring via TES and DCS. The sole TES monitoring is reliable in most procedures but not in parietal tumors or those requiring lateral positioning. Although no indications are available in international guidelines, DCS should be recommended, particularly for cases approached by a lateral position.

Preoperative Brain Tumor Imaging: Models and Software for Segmentation and Standardized Reporting.

For patients suffering from brain tumor, prognosis estimation and treatment decisions are made by a multidisciplinary team based on a set of preoperative MR scans. Currently, the lack of standardized and automatic methods for tumor detection and generation of clinical reports, incorporating a wide range of tumor characteristics, represents a major hurdle. In this study, we investigate the most occurring brain tumor types: glioblastomas, lower grade gliomas, meningiomas, and metastases, through four cohorts of up to 4,000 patients. Tumor segmentation models were trained using the AGU-Net architecture with different preprocessing steps and protocols. Segmentation performances were assessed in-depth using a wide-range of voxel and patient-wise metrics covering volume, distance, and probabilistic aspects. Finally, two software solutions have been developed, enabling an easy use of the trained models and standardized generation of clinical reports: Raidionics and Raidionics-Slicer. Segmentation performances were quite homogeneous across the four different brain tumor types, with an average true positive Dice ranging between 80 and 90%, patient-wise recall between 88 and 98%, and patient-wise precision around 95%. In conjunction to Dice, the identified most relevant other metrics were the relative absolute volume difference, the variation of information, and the Hausdorff, Mahalanobis, and object average symmetric surface distances. With our Raidionics software, running on a desktop computer with CPU support, tumor segmentation can be performed in 16-54 s depending on the dimensions of the MRI volume. For the generation of a standardized clinical report, including the tumor segmentation and features computation, 5-15 min are necessary. All trained models have been made open-access together with the source code for both software solutions and validation metrics computation. In the future, a method to convert results from a set of metrics into a final single score would be highly desirable for easier ranking across trained models. In addition, an automatic classification of the brain tumor type would be necessary to replace manual user input. Finally, the inclusion of post-operative segmentation in both software solutions will be key for generating complete post-operative standardized clinical reports.

Intraoperative AIRO mobile computer tomography in frameless stereotactic procedures.

BACKGROUND: Multiple factors can affect the accuracy of neuronavigation, that is a relevant issue, particularly for frameless stereotactic procedures, where precision and optimal image-guidance is crucial for the surgical performance, workflow, and outcome. OBJECTIVE: To investigate the impact of AIRO Mobile Computer Tomography in frameless stereotactic approaches. METHODS: A retrospective study on 12 patients was performed. All the procedures were deployed using a frameless stereotactic technique, both for the collection of biopsy pathological specimens for diagnosis and insertion of drainage in the treatment of intracranial cystic lesions. RESULTS: Twelve patients (eight males, four females) underwent the frameless stereotactic procedure. Mean age at surgery was 55 (±5 SE). The mean volume of the lesion was 23.85 cm3 (±3.13). Six diagnostic biopsies and six cyst drainages were performed. The mean trajectory length was 75.9 ± 11.8 mm. Three posterior fossa lesions (27%) were approached through a retro-sigmoidal burr-hole. A craniotomy for draining a haematoma was performed after detection with AIRO-CT. No permanent neurological dysfunction, in-hospital or 30-day mortality were recorded. CONCLUSION: The AIRO-CT resulted feasible with a potential utility for stereotactic procedures. We showed how it could grant the efficacy of the stereotactic procedures reducing some technical and physical sources of inaccuracy, also enhancing safety and allowing prompt detection and management of intraoperative complications.

Stimulation of frontal pathways disrupts hand muscle control during object manipulation.

The activity of frontal motor areas during hand-object interaction is coordinated by dense communication along specific white matter pathways. This architecture allows the continuous shaping of voluntary motor output but, despite extensive investigation in non-human primate studies, remains poorly understood in humans. Disclosure of this system is crucial for predicting and treatment of motor deficits after brain lesions. For this purpose, we investigated the effect of direct electrical stimulation on white matter pathways within the frontal lobe on hand-object manipulation. This was tested in 34 patients (15 left hemisphere, mean age 42 years, 17 male, 15 with tractography) undergoing awake neurosurgery for frontal lobe tumour removal with the aid of the brain mapping technique. The stimulation outcome was quantified based on hand-muscle activity required by task execution. The white matter pathways responsive to stimulation with an interference on muscles were identified by means of probabilistic density estimation of stimulated sites, tract-based lesion-symptom (disconnectome) analysis and diffusion tractography on the single patient level. Finally, we assessed the effect of permanent tract disconnection on motor outcome in the immediate postoperative period using a multivariate lesion-symptom mapping approach. The analysis showed that stimulation disrupted hand-muscle activity during task execution at 66 sites within the white matter below dorsal and ventral premotor regions. Two different EMG interference patterns associated with different structural architectures emerged: (i) an 'arrest' pattern, characterized by complete impairment of muscle activity associated with an abrupt task interruption, occurred when stimulating a white matter area below the dorsal premotor region. Local middle U-shaped fibres, superior fronto-striatal, corticospinal and dorsal fronto-parietal fibres intersected with this region. (ii) a 'clumsy' pattern, characterized by partial disruption of muscle activity associated with movement slowdown and/or uncoordinated finger movements, occurred when stimulating a white matter area below the ventral premotor region. Ventral fronto-parietal and inferior fronto-striatal tracts intersected with this region. Finally, only resections partially including the dorsal white matter region surrounding the supplementary motor area were associated with transient upper-limb deficit (P = 0.05; 5000 permutations). Overall, the results identify two distinct frontal white matter regions possibly mediating different aspects of hand-object interaction via distinct sets of structural connectivity. We suggest the dorsal region, associated with arrest pattern and postoperative immediate motor deficits, to be functionally proximal to motor output implementation, while the ventral region may be involved in sensorimotor integration required for task execution.

IDH wild-type grade 2 diffuse astrocytomas: prognostic factors and impact of treatments within molecular subgroups.

BACKGROUND: Prognostic factors and role of treatments are not well known in isocitrate dehydrogenase (IDH) wild-type (wt) grade 2 astrocytomas. The aim of this study was to define in these tumors clinical features, molecular characteristics, and prognostic factors, with particular focus on molecular subgroups defined by cIMPACT-NOW update 3. METHODS: We analyzed 120 patients with confirmed diagnosis of grade 2 IDHwt astrocytoma according to WHO 2016, collected from seven Italian centers between 1999 and 2017. RESULTS: Median PFS and OS of the whole cohort were 18.9 and 32.6 months. Patients older than 40 years and patients with modest contrast enhancement on MRI had a shorter PFS and OS. Gross total resection yielded superior PFS and OS over non-gross total resection. PFS and OS of patients with either pTERT mutation or EGRF amplification were significantly shorter. The prognostic value of age, contrast enhancement on MRI, and extent of surgery was different within the molecular subgroups. Gross total resection was associated with increased PFS (not reached versus 14 months, p = 0.023) and OS (117.9 versus 20 months, p = 0.023) in patients without EGFR amplification, and with increased OS in those without pTERT mutation (NR vs 53.7 months, p = 0.05). Conversely, for patients with EGFR amplification or pTERT mutation, gross total resection did not yield a significant survival benefit. CONCLUSION: Patients without EGFR amplification and pTERT mutation could be observed after gross total resection.

Asleep or awake motor mapping for resection of perirolandic glioma in the nondominant hemisphere? Development and validation of a multimodal score to tailor the surgical strategy.

OBJECTIVE: Resection of glioma in the nondominant hemisphere involving the motor areas and pathways requires the use of brain-mapping techniques to spare essential sites subserving motor control. No clear indications are available for performing motor mapping under either awake or asleep conditions or for the best mapping paradigm (e.g., resting or active, high-frequency [HF] or low-frequency [LF] stimulation) that provides the best oncological and functional outcomes when tailored to the clinical context. This work aimed to identify clinical and imaging factors that influence surgical strategy (asleep motor mapping vs awake motor mapping) and that are associated with the best functional and oncological outcomes and to design a "motor mapping score" for guiding tumor resection in this area. METHODS: The authors evaluated a retrospective series of patients with nondominant-hemisphere glioma-located or infiltrating within 2 cm anteriorly or posteriorly to the central sulcus and affecting the primary motor cortex, its fibers, and/or the praxis network-who underwent operations with asleep (HF monopolar probe) or awake (LF and HF probes) motor mapping. Clinical and imaging variables were used to design a motor mapping score. A prospective series of patients was used to validate this motor mapping score. RESULTS: One hundred thirty-five patients were retrospectively analyzed: 69 underwent operations with asleep (HF stimulation) motor mapping, and 66 underwent awake (LF and HF stimulation and praxis task evaluation) motor mapping. Previous motor (strength) deficit, previous treatment (surgery/radiotherapy), tumor volume > 30 cm3, and tumor involvement of the praxis network (on MRI) were identified and used to design the mapping score. Motor deficit, previous treatment, and location within or close to the central sulcus favor use of asleep motor mapping; large tumor volume and involvement of the praxis network favor use of awake motor mapping. The motor mapping score was validated in a prospective series of 52 patients-35 underwent operations with awake motor mapping and 17 with asleep motor mapping on the basis of the score indications-who had a low rate of postoperative motor-praxis deficit (3%) and a high extent of resection (median 97%; complete resection in > 70% of patients). CONCLUSIONS: Extensive resection of tumor involving the eloquent areas for motor control is feasible, and when an appropriate mapping strategy is applied, the incidence of postoperative motor-praxis deficit is low. Asleep (HF stimulation) motor mapping is preferable for lesions close to or involving the central sulcus and/or in patients with preoperative strength deficit and/or history of previous treatment. When a patient has no motor deficit or previous treatment and has a lesion (> 30 cm3) involving the praxis network, awake mapping is preferable.

On the cutting edge of glioblastoma surgery: where neurosurgeons agree and disagree on surgical decisions.

OBJECTIVE: The aim of glioblastoma surgery is to maximize the extent of resection while preserving functional integrity. Standards are lacking for surgical decision-making, and previous studies indicate treatment variations. These shortcomings reflect the need to evaluate larger populations from different care teams. In this study, the authors used probability maps to quantify and compare surgical decision-making throughout the brain by 12 neurosurgical teams for patients with glioblastoma. METHODS: The study included all adult patients who underwent first-time glioblastoma surgery in 2012-2013 and were treated by 1 of the 12 participating neurosurgical teams. Voxel-wise probability maps of tumor location, biopsy, and resection were constructed for each team to identify and compare patient treatment variations. Brain regions with different biopsy and resection results between teams were identified and analyzed for patient functional outcome and survival. RESULTS: The study cohort consisted of 1087 patients, of whom 363 underwent a biopsy and 724 a resection. Biopsy and resection decisions were generally comparable between teams, providing benchmarks for probability maps of resections and biopsies for glioblastoma. Differences in biopsy rates were identified for the right superior frontal gyrus and indicated variation in biopsy decisions. Differences in resection rates were identified for the left superior parietal lobule, indicating variations in resection decisions. CONCLUSIONS: Probability maps of glioblastoma surgery enabled capture of clinical practice decisions and indicated that teams generally agreed on which region to biopsy or to resect. However, treatment variations reflecting clinical dilemmas were observed and pinpointed by using the probability maps, which could therefore be useful for quality-of-care discussions between surgical teams for patients with glioblastoma.

Targeting Primary Motor Cortex (M1) Functional Components in M1 Gliomas Enhances Safe Resection and Reveals M1 Plasticity Potentials.

Primary-Motor-Cortex (M1) hosts two functional components, at its posterior and anterior borders, being the first faster and more excitable. We developed a mapping-technique for M1 components identification and determined their functional cortical-subcortical architecture in M1 gliomas and the impact of their identification on tumor resection and motor performance. A novel advanced mapping technique was used in 102 tumors within M1 or CorticoSpinal-Tract to identify M1-two components. High-Frequency-stimulation (2-5 pulses) with an on-line qualitative and quantitative analysis of motor responses was used; the two components' cortical/subcortical spatial distribution correlated to clinical, tumor-related factor and patients' motor outcome; a cohort treated with standard-mapping was used for comparison. The two functional components were always identified on-line; in tumors not affecting M1, its functional segregation was preserved. In M1 tumors, two architectures, both preserving the two components, were disclosed: in 50%, a normal cortical/subcortical architecture emerged, while 50% revealed a distorted architecture with loss of anatomical reference and somatotopy, not associated with tumor histo-molecular features or volume, but with a previous treatment. Motor performance was maintained, suggesting functional compensation. By preserving the highest and resecting the lowest excitability component, the complete-resection increased with low morbidity. The real-time identification of two M1 functional components and the preservation of the highest excitability one increases safe resection, revealing M1 plasticity potentials.

Raman Spectroscopy and Machine Learning for IDH Genotyping of Unprocessed Glioma Biopsies.

Isocitrate dehydrogenase (IDH) mutational status is pivotal in the management of gliomas. Patients with IDH-mutated (IDH-MUT) tumors have a better prognosis and benefit more from extended surgical resection than IDH wild-type (IDH-WT). Raman spectroscopy (RS) is a minimally invasive optical technique with great potential for intraoperative diagnosis. We evaluated the RS's ability to characterize the IDH mutational status onto unprocessed glioma biopsies. We extracted 2073 Raman spectra from thirty-eight unprocessed samples. The classification performance was assessed using the eXtreme Gradient Boosted trees (XGB) and Support Vector Machine with Radial Basis Function kernel (RBF-SVM). Measured Raman spectra displayed differences between IDH-MUT and IDH-WT tumor tissue. From the 103 Raman shifts screened as input features, the cross-validation loop identified 52 shifts with the highest performance in the distinction of the two groups. Raman analysis showed differences in spectral features of lipids, collagen, DNA and cholesterol/phospholipids. We were able to distinguish between IDH-MUT and IDH-WT tumors with an accuracy and precision of 87%. RS is a valuable and accurate tool for characterizing the mutational status of IDH mutation in unprocessed glioma samples. This study improves RS knowledge for future personalized surgical strategy or in situ target therapies for glioma tumors.

Glioblastoma Surgery Imaging-Reporting and Data System: Standardized Reporting of Tumor Volume, Location, and Resectability Based on Automated Segmentations.

Treatment decisions for patients with presumed glioblastoma are based on tumor characteristics available from a preoperative MR scan. Tumor characteristics, including volume, location, and resectability, are often estimated or manually delineated. This process is time consuming and subjective. Hence, comparison across cohorts, trials, or registries are subject to assessment bias. In this study, we propose a standardized Glioblastoma Surgery Imaging Reporting and Data System (GSI-RADS) based on an automated method of tumor segmentation that provides standard reports on tumor features that are potentially relevant for glioblastoma surgery. As clinical validation, we determine the agreement in extracted tumor features between the automated method and the current standard of manual segmentations from routine clinical MR scans before treatment. In an observational consecutive cohort of 1596 adult patients with a first time surgery of a glioblastoma from 13 institutions, we segmented gadolinium-enhanced tumor parts both by a human rater and by an automated algorithm. Tumor features were extracted from segmentations of both methods and compared to assess differences, concordance, and equivalence. The laterality, contralateral infiltration, and the laterality indices were in excellent agreement. The native and normalized tumor volumes had excellent agreement, consistency, and equivalence. Multifocality, but not the number of foci, had good agreement and equivalence. The location profiles of cortical and subcortical structures were in excellent agreement. The expected residual tumor volumes and resectability indices had excellent agreement, consistency, and equivalence. Tumor probability maps were in good agreement. In conclusion, automated segmentations are in excellent agreement with manual segmentations and practically equivalent regarding tumor features that are potentially relevant for neurosurgical purposes. Standard GSI-RADS reports can be generated by open access software.

Factors Influencing Mood Disorders and Health Related Quality of Life in Adults With Glioma: A Longitudinal Study.

OBJECTIVE: At present, it is not clear whether Mood Disorders (MD) and poor Health Related Quality of Life (HRQoL) in the glioma population correlate with features of the tumor, or rather with secondary symptoms associated with treatment. The aim of this study was to assess the prevalence of MD and decline in HRQoL in glioma patients, and to determine the main factors associated with these two variables. METHODS: 80 patients affected by lower-grade gliomas (LGGs) and 65 affected by high-grade gliomas (HGGs) were evaluated, from admission up to 12 months after surgery, for MD, HRQoL, clinical characteristics, and cognitive functions. Independent factors associated with MD and low HRQoL were identified by using bivariate analysis. RESULTS: Data showed that prevalence of low HRQoL was comparable in both groups during all the time points assessed (pre, 1, 3, 6 and 12 months after surgery). In contrast at 6 months following surgery, HGGs showed a higher prevalence of MD compared to LGGs;. Bivariate analysis revealed that factors associated with MD and HRQoL in LGGs and HGGs were different over the course of the disease. In LGGs, from the pre-operative period to one year post surgery, MD and low HRQOL were associated with the occurrence of cognitive deficits and, from the third month after surgery onward, they were also associated with the effect exerted by adjuvant treatments. In HGGs, MD were associated with cognitive deficits at 3 and 6 months after surgery, along with older age (65-75 years); HRQoL, in its Physical component in particular, was associated with older age only from 6 months after surgery. CONCLUSION: Factors associated with MD and low HRQoL were different in LGGs and HGGs over the course of the disease. In LGGs the effect of adjuvant treatments was prominent in determining the prevalence of both MD and poor HRQoL from the third month after surgery onward. In HGGs, MD and HRQoL were associated with age, at 3 and 6 months after surgery. In both, the occurrence of cognitive deficits was significantly associated with MD.

Timing of glioblastoma surgery and patient outcomes: a multicenter cohort study.

BACKGROUND: The impact of time-to-surgery on clinical outcome for patients with glioblastoma has not been determined. Any delay in treatment is perceived as detrimental, but guidelines do not specify acceptable timings. In this study, we relate the time to glioblastoma surgery with the extent of resection and residual tumor volume, performance change, and survival, and we explore the identification of patients for urgent surgery. METHODS: Adults with first-time surgery in 2012-2013 treated by 12 neuro-oncological teams were included in this study. We defined time-to-surgery as the number of days between the diagnostic MR scan and surgery. The relation between time-to-surgery and patient and tumor characteristics was explored in time-to-event analysis and proportional hazard models. Outcome according to time-to-surgery was analyzed by volumetric measurements, changes in performance status, and survival analysis with patient and tumor characteristics as modifiers. RESULTS: Included were 1033 patients of whom 729 had a resection and 304 a biopsy. The overall median time-to-surgery was 13 days. Surgery was within 3 days for 235 (23%) patients, and within a month for 889 (86%). The median volumetric doubling time was 22 days. Lower performance status (hazard ratio [HR] 0.942, 95% confidence interval [CI] 0.893-0.994) and larger tumor volume (HR 1.012, 95% CI 1.010-1.014) were independently associated with a shorter time-to-surgery. Extent of resection, residual tumor volume, postoperative performance change, and overall survival were not associated with time-to-surgery. CONCLUSIONS: With current decision-making for urgent surgery in selected patients with glioblastoma and surgery typically within 1 month, we found equal extent of resection, residual tumor volume, performance status, and survival after longer times-to-surgery.

Glioma biopsies Classification Using Raman Spectroscopy and Machine Learning Models on Fresh Tissue Samples.

Identifying tumor cells infiltrating normal-appearing brain tissue is critical to achieve a total glioma resection. Raman spectroscopy (RS) is an optical technique with potential for real-time glioma detection. Most RS reports are based on formalin-fixed or frozen samples, with only a few studies deployed on fresh untreated tissue. We aimed to probe RS on untreated brain biopsies exploring novel Raman bands useful in distinguishing glioma and normal brain tissue. Sixty-three fresh tissue biopsies were analyzed within few minutes after resection. A total of 3450 spectra were collected, with 1377 labelled as Healthy and 2073 as Tumor. Machine learning methods were used to classify spectra compared to the histo-pathological standard. The algorithms extracted information from 60 different Raman peaks identified as the most representative among 135 peaks screened. We were able to distinguish between tumor and healthy brain tissue with accuracy and precision of 83% and 82%, respectively. We identified 19 new Raman shifts with known biological significance. Raman spectroscopy was effective and accurate in discriminating glioma tissue from healthy brain ex-vivo in fresh samples. This study added new spectroscopic data that can contribute to further develop Raman Spectroscopy as an intraoperative tool for in-vivo glioma detection.

Challenging Giant Insular Gliomas With Brain Mapping: Evaluation of Neurosurgical, Neurological, Neuropsychological, and Quality of Life Results in a Large Mono-Institutional Series.

OBJECTIVE: Giant insular tumors are commonly not amenable to complete resection and are associated with a high postoperative morbidity rate. Transcortical approach and brain mapping techniques allow to identify peri-insular functional networks and, with neurophysiological monitoring, to reduce vascular-associated insults. Cognitive functions to be mapped are still under debate, and the analysis of the functional risk of surgery is currently limited to neurological examination. This work aimed to investigate the neurosurgical outcome (extent of resection, EOR) and functional impact of giant insular gliomas resection, focusing on neuropsychological and Quality of Life (QoL) outcomes. METHODS: In our retrospective analysis, we included all patients admitted in a five-year period with a radiological diagnosis of giant insular glioma. A transcortical approach was adopted in all cases. Resections were pursued up to functional boundaries defined intraoperatively by brain mapping techniques. We examined clinical, radiological, and intra-operative factors possibly affecting EOR and postoperative neurological, neuropsychological, and Quality of Life (QoL) outcomes. RESULTS: We finally enrolled 95 patients in the analysis. Mean EOR was 92.3%. A Gross Total Resection (GTR) was obtained in 70 cases (73.7%). Five patients reported permanent morbidity (aphasia in 3, 3.2%, and superior quadrantanopia in 2, 2.1%). Suboptimal EOR associated with poor seizures control postoperatively. Extensive intraoperative mapping (inclusive of cognitive, visual, and haptic functions) decreased long-term neurological, neuropsychological, and QoL morbidity and increased EOR. Tumor infiltration of deep perforators (vessels arising either medial to lenticulostriate arteries through the anterior perforated substance or from the anterior choroidal artery) associated with a higher chance of postoperative ischemia in consonant areas, with the persistence of new-onset motor deficits 1-month post-op, and with minor EOR. Ischemic insults in eloquent sites represented the leading factor for long-term neurological and neuropsychological morbidity. CONCLUSION: In giant insular gliomas, the use of a transcortical approach with extensive brain mapping under awake anesthesia ensures broad insular exposure and extension of the surgical resection preserving patients' functional integrity. The relation between tumor mass and deep perforators predicts perioperative ischemic insults, the most relevant risk factor for long-term and permanent postoperative morbidity.

Negative motor responses to direct electrical stimulation: Behavioral assessment hides different effects on muscles.

A negative motor response (NMR) is defined as the inability to continue voluntary movements without losing consciousness when direct electrical stimulation (DES) is applied during awake neurosurgery. While visual inspection is most commonly used to define an NMR, the actual effect of stimulation on muscle activity has been neglected by recent neurosurgical literature. We show that behavioral assessment of NMRs hides different site-dependent effects on muscles as revealed by electromyography (EMG), describing ten cases of brain tumor patients undergoing awake neurosurgery while performing a hand-object manipulation task. DES-induced NMRs were assessed behaviorally and related to the underlying electromyographic recording. Quantitative analysis of motor unit recruitment and regularity between phasic muscle contractions was computed. We show that similar NMRs classified based on behavioral criteria can be associated with suppression, increased recruitment or mixed effects on ongoing hand muscles. In some cases, suppression of hand muscle activity is associated with involuntary recruitment of muscles not involved in the task. Interestingly, stimulation of behaviorally defined "negative areas" across the frontal and parietal lobes elicits different electromyographic patterns, depending on the stimulation site. This study provides novel preliminary background as to the heterogeneous profile of muscle activity during NMRs. In fact, EMG monitoring paired with behavioral assessment can distinguish between NMRs that, despite similarity on behavioral inspection, are different in their related EMG, possibly underlying different neural substrates. The identification of different circuits hidden in similar NMRs may become relevant when planning the extension of resection.

Clinical Pearls and Methods for Intraoperative Motor Mapping.

Resection of brain tumors involving motor areas and pathways requires the identification and preservation of various cortical and subcortical structures involved in motor control at the time of the procedure, in order to maintain the patient's full motor capacities. The use of brain mapping techniques has now been integrated into clinical practice for many years, as they help the surgeon to identify the neural structures involved in motor functions. A common definition of motor function, as well as knowledge of its neural organization, has been continuously evolving, underlining the need for implementing intraoperative strategies at the time of the procedure. Similarly, mapping strategies have been subjected to continuous changes, enhancing the likelihood of preservation of full motor capacities. As a general rule, the motor mapping strategy should be as flexible as possible and adapted strictly to the individual patient and clinical context of the tumor. In this work, we present an overview of current knowledge of motor organization, indications for motor mapping, available motor mapping, and monitoring strategies, as well as their advantages and limitations. The use of motor mapping improves resection and outcomes in patients harboring tumors involving motor areas and pathways, and should be considered the gold standard in the resection of this type of tumor.

Surgery for Glioblastoma in Elderly Patients.

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

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

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