Brain Stem Glioma Recurrence: Exploring the Therapeutic Frontiers.

Gliomas of the brainstem represent a small percentage of central nervous system gliomas in adults. Due to the proximity of the tumor to critical structures, radical surgery is highly challenging and limited to selected cases. In addition, postoperative treatments, which become exclusive to non-operable patients, do not guarantee satisfactory disease control, making the progression of the disease inevitable. Currently, there is a lack of therapeutic options to control tumor growth after the diagnosis of recurrence. The rarity of these tumors, their distinct behavioral characteristics, and the limited availability of tumor tissue necessary for the development of prognostic and predictive biomarkers contribute to the absence of a standardized approach for treating recurrent brainstem gliomas. A salvage radiotherapy (RT) retreatment could represent a promising approach for recurrent brainstem gliomas. However, to date, it has been mainly evaluated in pediatric cases, with few experiences available to assess the most appropriate RT dose, safety, and clinical responses in adult patients. This comprehensive review aims to identify instances of adult patients with recurrent brainstem gliomas subjected to a secondary course of RT, with a specific focus on the analysis of treatment-related toxicity and outcomes. Through this investigation, we endeavor to contribute valuable insights into the viability and efficacy of salvage RT retreatment in managing recurrent brainstem gliomas in the adult population.

Machine learning allows expert level classification of intraoperative motor evoked potentials during neurosurgical procedures.

OBJECTIVE: To develop and evaluate machine learning (ML) approaches for muscle identification using intraoperative motor evoked potentials (MEPs), and to compare their performance to human experts. BACKGROUND: There is an unseized opportunity to apply ML analytic techniques to the world of intraoperative neuromonitoring (IOM). MEPs are the ideal candidates given the importance of their correct interpretation during a surgical operation to the brain or the spine. In this work, we develop and test a set of different ML models for muscle identification using intraoperative MEPs and compare their performance to human experts. In addition, we provide a review of the available literature on current ML applications to IOM data in neurosurgery. METHODS: We trained and tested five different ML classifiers on a MEP database developed from six different muscles in patients who underwent brain or spinal cord surgery. MEPs were obtained by both transcranial (TES) and direct cortical stimulation (DCS) protocols. The models were evaluated within a single patient and on previously unseen patients, considering signals from TES and DCS both independently and mixed. Ten expert neurophysiologists classified a set of 50 randomly selected MEPs, and their performance was compared to the best performing model. RESULTS: A total of 25.423 MEPs were included in the study. Random Forest proved to be the best performing model with 99 % accuracy in the single patient dataset task and a 78 %-94 % accuracy range on previously unseen patients. The model performance was maximized by representing MEPs as a set of features typically employed in signal processing compared to traditional neurophysiological parameters. The classification ability of the Random Forest model between six different muscles and across different MEP acquisition modalities (79 %) significantly exceeded that of human experts (mean 48 %). CONCLUSIONS: Carefully selected ML models proved to have reliable capacity of extracting meaningful information to classify intraoperative MEPs using a limited number of features, proving robustness across patients and signal acquisition modalities, outperforming human experts, and with the potential to act as decision support systems to the IOM team. Such encouraging results lay the path to further explore the underlying nature of clinically important signals, with the aim to continue to produce useful applications to make surgeries safer and more efficient.

The Cerebral Aqueduct Compliance: A Simple Morphometric Model.

BACKGROUND AND OBJECTIVES: This work aimed to identify different configurations of the adytum of the cerebral aqueduct suggesting its safe neuroendoscopic navigation. This concept is intimately connected to the physiological aqueductal dilatability or compliance, which is relatively ignored in the literature. A better knowledge of the extent of physiological aqueductal dilatability might better define the ideal diameter and safer features of dedicated flexible endoscopes. METHODS: The study includes 45 patients operated on using a flexible scope with a 3.9-mm diameter, where the structural elements of the adytum of the cerebral aqueduct are clearly visible. Patients were grouped according to the pathology (colloid cyst/normal anatomy, intraventricular hemorrhage, tetraventricular obstructive hydrocephalus, normal pressure hydrocephalus, and distal membranous aqueductal stenosis). A simple geometrical scheme was applied to the endoscopic anatomy of the aqueductal adytum in relation to the posterior commissure to measure its pathologic deformations. Eventual damages to the aqueduct walls caused by the endoscope were also reported. RESULTS: Proceeding from normal anatomy to hydrocephalic condition, the ratio between the commissure and the aqueductal access area progressively decreases, while the vertex angle increases. Interestingly, the entity of the ependymal damages due to the passage of the endoscope correlates with such measures. CONCLUSION: The cerebral aqueduct, excluding atrophic processes, is provided with a certain degree of dilatability, which we estimate to be around a diameter of 4 mm. This represents the maximum size for a flexible neuroendoscope for a safe aqueductal neuronavigation. The schematic model of the aqueductal adytum as a triangle defines 3 different aqueductal patterns and can be helpful when an intraoperative decision on whether to navigate the aqueduct must be taken.

Decoding the puzzle: A multidisciplinary systematic review of adult brainstem glioma.

Adult brainstem gliomas (BSGs) are a group of rare central nervous system tumors with varying prognoses and controversial standard treatment strategies. To provide an overview of current trends, a systematic review using the PRISMA guidelines, Class of evidence (CE) and strength of recommendation (SR), was conducted. The review identified 27 studies. Surgery was found to have a positive impact on survival, particularly for focal lesions with CE II SR C. Stereotactic image-guided biopsy was recommended when resective surgery was not feasible with CE II and SR B. The role of systemic treatments remains unclear. Eight studies provided molecular biology data. This review gathers crucial literature on diagnosis and management of adult BSGs. It provides evidence-based guidance with updated recommendations for diagnosing and treating, taking into account recent molecular and genetic advancements. The importance of brain biopsy is emphasized to optimize treatment using emerging genetic-molecular findings and explore potential targeted therapies.

Autologous anti-GD2 CAR T cells efficiently target primary human glioblastoma.

Glioblastoma (GBM) remains a deadly tumor. Treatment with chemo-radiotherapy and corticosteroids is known to impair the functionality of lymphocytes, potentially compromising the development of autologous CAR T cell therapies. We here generated pre-clinical investigations of autologous anti-GD2 CAR T cells tested against 2D and 3D models of GBM primary cells. We detected a robust antitumor effect, highlighting the feasibility of developing an autologous anti-GD2 CAR T cell-based therapy for GBM patients.

H3 K27M mutation in rosette-forming glioneuronal tumors: a potential diagnostic pitfall.

According to the fifth edition of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS), diffuse midline glioma H3 K27-altered is a grade 4 infiltrative glioma that arises from midline anatomical structures and is characterized by the loss of H3 K27me3 and co-occurring H3 K27M mutation or EZHIP overexpression. However, the H3 K27M mutation has also been observed in circumscribed gliomas and glioneuronal tumors arising in midline anatomical structures, which may result in diagnostic pitfalls.Rosette-forming glioneuronal tumor (RGNT) is a CNS WHO grade 1 neoplasm that histologically features neurocytic and glial components and originates in midline anatomical structures.This study aimed to assess whether RGNTs, similar to other midline tumors, may exhibit immunohistochemical loss of H3 K27me3 and harbor the H3 K27M mutation.All seven analyzed RGNTs displayed immunohistochemical loss of H3 K27me3 in all tumor cells or H3 K27me3 mosaic immunostaining. In one case, H3 K27me3 loss was associated with the H3 K27M mutation, whereas the other six cases did not exhibit any H3 mutations or EZHIP overexpression. During a follow-up period of 23 months, the H3 K27M-mutant case remained unchanged in size despite partial resection, indicating that the H3 mutation may not confer higher biological aggressiveness to RGNT.The immunohistochemical loss of H3 K27me3 co-occurring with the H3 K27M mutation may result in the potential misdiagnosis of RGNT, especially in cases of small biopsy specimens consisting of only the glial component.

Surgical Management of Adult Brainstem Gliomas: A Systematic Review and Meta-Analysis.

The present review aims to investigate the survival and functional outcomes in adult high-grade brainstem gliomas (BGSs) by comparing data from resective surgery and biopsy. MEDLINE, EMBASE and Cochrane Library were screened to conduct a systematic review of the literature, according to the PRISMA statement. Analysis was limited to articles including patients older than 18 years of age and those published from 1990 to September 2022. Case reports, review articles, meta-analyses, abstracts, reports of aggregated data, and reports on multimodal therapy where surgery was not the primary treatment were excluded. The ROBINS-I tool was applied to evaluate the risk of bias. Six studies were ultimately considered for the meta-analysis. The resective group was composed of 213 subjects and the bioptic group comprised 125. The analysis demonstrated a survival benefit in those patients in which an extensive resection was possible (STR HR 0.59 (95% CI 0.42, 0.82)) (GTR HR 0.63 (95% CI 0.43, 0.92)). Although surgical resection is associated with increased survival, the significantly higher complication rate makes it difficult to recommend surgery instead of biopsy for BSGs. Future investigations combining volumetric data and molecular profiles could add important data to better define the proper indication between resection and biopsy.

Endoscopic trans-Magendie foramen biopsy of the superior medullary velum: Technical note.

BACKGROUND: Surgery of the fourth ventricle is challenging due to the presence of several surrounding delicate structures. Traditional approaches do not offer an easy visualization of these areas, especially those on the roof. Thanks to the most recent developments in neurosurgical endoscopy, it is possible to access the fourth ventricle via physiological pathways, avoiding unnecessary stress or damage to the nervous and vascular structures. METHODS: We present the case of a patient with a lesion at the lingula-superior medullary velum, and an history of surgically resected lung and pancreatic adenocarcinomas. An endoscopic biopsy of the lesion through the foramen of Magendie was performed. The few reports on this endoscopic approach were also critically reviewed. RESULTS: The retrograde endoscopic exploration through a suboccipital, trans-Magendie foramen approach using a flexible endoscope allowed the clear visualization of the superior medullary velum and the possibility to obtain diagnostic biopsies of the lesion with a minimally invasive technique. CONCLUSIONS: The trans-Magendie navigation with a flexible endoscope is a safe and elegant technique to approach lesions located in any point of the fourth ventricle, particularly in its rostral portion.

Long-term effects of bilateral subthalamic nucleus deep brain stimulation on gait disorders in Parkinson's disease: a clinical-instrumental study.

OBJECTIVE: To assess the long-term effects of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on gait in a cohort of advanced Parkinson's Disease (PD) patients. METHODS: This observational study included consecutive PD patients treated with bilateral STN-DBS. Different stimulation and drug treatment conditions were assessed: on-stimulation/off-medication, off-stimulation/off-medication, and on-stimulation/on-medication. Each patient performed the instrumented Timed Up and Go test (iTUG). The instrumental evaluation of walking ability was carried out with a wearable inertial sensor containing a three-dimensional (3D) accelerometer, gyroscope, and magnetometer. This device could provide 3D linear acceleration, angular velocity, and magnetic field vector. Disease motor severity was evaluated with the total score and subscores of the Unified Parkinson Disease Rating Scale part III. RESULTS: Twenty-five PD patients with a 5-years median follow-up after surgery (range 3-7) were included (18 men; mean disease duration at surgery 10.44 ± 4.62 years; mean age at surgery 58.40 ± 5.73 years). Both stimulation and medication reduced the total duration of the iTUG and most of its different phases, suggesting a long-term beneficial effect on gait after surgery. However, comparing the two treatments, dopaminergic therapy had a more marked effect in all test phases. STN-DBS alone reduced total iTUG duration, sit-to-stand, and second turn phases duration, while it had a lower effect on stand-to-sit, first turn, forward walking, and walking backward phases duration. CONCLUSIONS: This study highlighted that in the long-term after surgery, STN-DBS may contribute to gait and postural control improvement when used together with dopamine replacement therapy, which still shows a substantial beneficial effect.

Clinical Characteristics of Poor-Grade Aneurysmal Subarachnoid Hemorrhage Treatment.

Background The initial clinical status after aneurysm rupture, whether primary or secondary, determines the final outcome. The most common cause of patient deterioration is a high Hunt and Hess (HH) score, which correlates closely with a high mortality rate. Poor-grade aneurysmal subarachnoid hemorrhage (SAH) is determined as an HH score 4 or 5. The aim of this study was to evaluate the clinical characteristics of poor graded aneurysmal SAH at our institution. Patients and Methods During the 5-year period, 415 patients with intracranial aneurysm were admitted to our institution. Patients with poor-grade aneurysmal SAH accounted 31.08% ( n = 132) of the total number of ruptured aneurysms. Interventional treatment was predominantly in the form of surgery, whereas conservative treatment included medication and external ventricular drainage. Final outcome was assessed with a modified Rankin score (mRs). Statistical analysis was performed using SPSS version 23.0 with a significance level set to 5% (α = 0.05). Results The majority of patients (57.6%) were in the age range from 51 to 69 years. Twenty-five patients (18.9%) had an HH score of 4, whereas 107 patients (81.1%) had an HH score of 5. Depending on the location, the majority of patients ( n = 43) had an aneurysm on the medial cerebral artery (MCA). The final aneurysm occlusion was performed in 71 patients, of whom 94.36% were treated surgically. A positive outcome (mRs 0-4) was found in 49.25% of patients who underwent primarily surgical, treatment with a mortality of 42.3%. Although the outcome was better in patients with an HH score 4, both groups benefited from surgical treatment. Conclusion Poor-grade aneurismal SAH is a condition of the middle and older age, with most patients with an HH 5 score and deep comatose state. There was better outcome in patients with an HH score of 4 compared to an HH score of 5 and both groups benefited from surgical treatment, which resulted in a positive outcome in almost 50% of surgically treated patients.

Interplay between speech and gait variables in Parkinson's disease patients treated with subthalamic nucleus deep brain stimulation: A long-term instrumental assessment.

OBJECTIVE: To evaluate correlations between speech and gait parameters in the long term and under different medication and subthalamic nucleus deep brain stimulation (STN-DBS) conditions in a cohort of advanced Parkinson's disease (PD) patients. METHODS: This observational study included consecutive PD patients treated with bilateral STN-DBS. Axial symptoms were evaluated using a standardized clinical-instrumental approach. Speech and gait were assessed by perceptual and acoustic analyses and by the instrumented Timed Up and Go (iTUG) test, respectively. Disease motor severity was evaluated with the total score and subscores of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III. Different stimulation and drug treatment conditions were assessed: on-stimulation/off-medication, off-stimulation/off-medication, and on-stimulation/on-medication. RESULTS: Twenty-five PD patients with a 5-year median follow-up after surgery (range 3-7 years) were included (18 males; disease duration at surgery: 10.44 [SD 4.62] years; age at surgery: 58.40 [SD 5.73] years). In the off-stimulation/off-medication and on-stimulation/on-medication conditions, patients who spoke louder had also the greater acceleration of the trunk during gait; whereas in the on-stimulation/on-medication condition only, patients with the poorer voice quality were also the worst to perform the sit to stand and gait phases of the iTUG. Conversely, patients with the higher speech rate performed well in the turning and walking phases of the iTUG. CONCLUSIONS: This study underlines the presence of different correlations between treatment effects of speech and gait parameters in PD patients treated with bilateral STN-DBS. This may allow us to better understand the common pathophysiological basis of these alterations and to develop a more specific and tailored rehabilitation approach for axial signs after surgery.

The extent of resection of T2-flair hyperintense area for eloquent glioblastomas: outcomes analysis between awake and general anesthesia patients.

BACKGROUND: Maximum safe resection for eloquent areas glioblastomas (GBMs) is the greatest tumor resection achievable without causing neurological deficits. This study aims to assess, through quantitative volumetric analysis, the outcomes of patients with eloquent areas GBMs and correlate the extent of resection (EOR), based on MRI T1-contrast enhanced (CE) and T2- fluid-attenuated inversion recovery (FLAIR) sequences, with patient outcomes and overall survival. METHODS: We prospectively collected and analyzed patients with a diagnosis of primary GBM located in an eloquent area operated between January 2012 and April 2018. We examined 295 consecutive patients' records with GBM and identified 82 eloquent GBMs who met inclusion criteria. We stratified our patients by type of treatment-awake surgery (AS) and general anesthesia (GA) craniotomies. The kind of treatment was correlated with EOR, focusing on exeresis over the limit of the contrast-enhanced signal intensity, including both T1-CE and T2-FLAIR MRI signal alterations. RESULTS: The overall mean EOR value was higher in AS than in GA on T1-CE (P value: 0.010) and T2-Flair MRI images (P value: 0.007). Also, patients who had at least 30% of T2-FLAIR signal resection (EOR≥30%) had a significantly lower risk of death and recurrence (P value: 0.020), independent of residual T1-CE tumor volume. CONCLUSIONS: Extensive T2-Flair resection and AS improve overall survival and reduce risk of recurrence while simultaneously minimizing surgical and medical complications among patients with GBMs in eloquent areas.

Longitudinal Neuropsychological Assessment of Symptomatic Edema after Subthalamic Nucleus Deep Brain Stimulation Surgery: A Case Series Study.

Severe non-infectious or non-haemorrhagic brain edema surrounding the electrode represents a rare complication of subthalamic nucleus deep brain stimulation (STN-DBS) surgery. The aim of this study is to report three patients with advanced Parkinson's Disease (PD) who developed symptomatic brain edema after STN-DBS surgery treated with intravenous steroids with a specific profile of reversible cognitive alterations. Patients were both assessed with a comprehensive neuropsychological battery including attention, memory, visuo-spatial and executive tasks. They were also briefly assessed for emotional and behavioural alterations, and for possible limitations in the activities of daily living. Normative data for an Italian population were available for all neuropsychological tests. The patients were firstly assessed before the surgery (baseline) as soon as they became symptomatic for the post-surgery edema and a few more times in follow-up up to ten months. In all patients we observed the resolution of cognitive deficits within six months after surgery with the corresponding reabsorption of edema at brain CT scans. The appearance of post-DBS edema is a fairly frequent and clinically benign event. However, in some rare cases it can be very marked and lead to important clinical-albeit transient-disturbances. These events can compromise, at least from a psychological point of view, the delicate path of patients who undergo DBS and can prolong the post-operative hospital stay. In this setting it could be helpful to perform a brain CT scan in 2-3 days with the aim of detecting the early appearance of edema and treating it before it can constitute a relevant clinical problem.

Freezing of Gait in Parkinson's Disease Patients Treated with Bilateral Subthalamic Nucleus Deep Brain Stimulation: A Long-Term Overview.

Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment in advanced Parkinson's Disease (PD). However, the effects of STN-DBS on freezing of gait (FOG) are still debated, particularly in the long-term follow-up (≥5-years). The main aim of the current study is to evaluate the long-term effects of STN-DBS on FOG. Twenty STN-DBS treated PD patients were included. Each patient was assessed before surgery through a detailed neurological evaluation, including FOG score, and revaluated in the long-term (median follow-up: 5-years) in different stimulation and drug conditions. In the long term follow-up, FOG score significantly worsened in the off-stimulation/off-medication condition compared with the pre-operative off-medication assessment (z = -1.930; p = 0.05) but not in the on-stimulation/off-medication (z = -0.357; p = 0.721). There was also a significant improvement of FOG at long-term assessment by comparing on-stimulation/off-medication and off-stimulation/off-medication conditions (z = -2.944; p = 0.003). These results highlight the possible beneficial long-term effects of STN-DBS on FOG.

Spinal hemangioblastomas: analysis of surgical outcome and prognostic factors.

The prognostic factors for surgically removed spinal hemangioblastomas, the impact of VHL disease on outcome, and the role of intraoperative neuromonitoring are still not completely clear. The aim of this study was to review our experience with spinal hemangioblastomas in order to assess potential predictors of neurological outcome after surgery. All cases of spinal hemangioblastomas removed at two Italian academic institutions from 1985 to 2020 were reviewed. Data about clinical presentation and symptom duration, diagnosis of VHL, surgical approach, use of IONM, duration of hospital stay, follow-up, and modified McCormick grade before and after surgery were extracted. Sixty-one patients (31 F, 30 M) underwent 69 surgeries to remove 74 spinal hemangioblastomas (37 cervical, 32 thoracic, 5 lumbar). Improvement was found in 32.3% of cases, neurological condition remained stable in 51.6% of cases, and deteriorated in 16.1% of patients. A worsening trend in VHL patients and an improvement trend in non-VHL patients were detected, despite the lack of statistical significance. Laminotomy and use of IONM were found to be associated with better outcome, although no association was found between surgery without IONM and worse outcome. In most cases, patients affected by spinal hemangioblastomas can expect a good long-term outcome. In our experience, laminotomy seems to be associated with better outcome compared to laminectomy. While its absence is not associated with worse outcome, IONM seems to be associated with a better neurological outcome. Our study suggests that the more impaired the preoperative neurological condition, the worse the outcome.

GD2 CAR T cells against human glioblastoma.

Glioblastoma is the most malignant primary brain tumor and is still in need of effective medical treatment. We isolated patient-derived glioblastoma cells showing high GD2 antigen expression representing a potential target for CAR T strategy. Data highlighted a robust GD2 CAR antitumor potential in 2D and 3D glioblastoma models associated with a significant and CAR T-restricted increase of selected cytokines. Interestingly, immunosuppressant TGF ß1, expressed in all co-cultures, did not influence antitumor activity. The orthotopic NOD/SCID models using primary glioblastoma cells reproduced human histopathological features. Considering still-conflicting data on the delivery route for targeting brain tumors, we compared intracerebral versus intravenous CAR T injections. We report that the intracerebral route significantly increased the length of survival time in a dose-dependent manner, without any side effects. Collectively, the proposed anti-GD2 CAR can counteract human glioblastoma potentially opening a new therapeutic option for a still incurable cancer.

Hemangioblastoma with Contrast-Enhanced Cystic Wall: When the Surgical Rule Must Not Be Respected.

OBJECTIVE: The purpose of this paper is to describe the variation of surgical plan and technique required in a rare subset of hemangioblastomas compared with the accepted general strategy. The established rule in hemangioblastoma surgery is to avoid cyst wall removal, as it is not neoplastic, and it will not recur if mural nodule is completely removed. However, the wall of the associated cyst is occasionally enhanced by gadolinium on preoperative magnetic resonance imaging. METHODS: We present the case of a patient with a hemangioblastoma that was progressively compressed by a growing cyst, with the final appearance of a contrast-enhanced cyst wall. We collected similar cases reported in the literature. RESULTS: Our study points out the need for a tailored preoperative strategy, the usefulness of intraoperative fluorescent dyes, and the crucial role of frozen section histopathologic analysis to confirm diagnosis and optimize treatment. CONCLUSIONS: When a hemangioblastoma is associated with a contrast-enhanced cyst, care must be taken to intraoperatively confirm the presence of neoplastic cells and eventually remove the neoplastic cyst wall to reduce the risk of recurrence.