Mechanisms and therapeutic implications of hypermutation in gliomas.

A high tumour mutational burden (hypermutation) is observed in some gliomas1-5; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.

Somatic PIK3CA Mutations in Sporadic Cerebral Cavernous Malformations.

BACKGROUND: Cerebral cavernous malformations (CCMs) are common sporadic and inherited vascular malformations of the central nervous system. Although familial CCMs are linked to loss-of-function mutations in KRIT1 (CCM1), CCM2, or PDCD10 (CCM3), the genetic cause of sporadic CCMs, representing 80% of cases, remains incompletely understood. METHODS: We developed two mouse models harboring mutations identified in human meningiomas with the use of the prostaglandin D2 synthase (PGDS) promoter. We performed targeted DNA sequencing of surgically resected CCMs from patients and confirmed our findings by droplet digital polymerase-chain-reaction analysis. RESULTS: We found that in mice expressing one of two common genetic drivers of meningioma - Pik3ca H1047R or AKT1 E17K - in PGDS-positive cells, a spectrum of typical CCMs develops (in 22% and 11% of the mice, respectively) instead of meningiomas, which prompted us to analyze tissue samples from sporadic CCMs from 88 patients. We detected somatic activating PIK3CA and AKT1 mutations in 39% and 1%, respectively, of lesion tissue from the patients. Only 10% of lesions harbored mutations in the CCM genes. We analyzed lesions induced by the activating mutations Pik3ca H1074R and AKT1 E17K in mice and identified the PGDS-expressing pericyte as the probable cell of origin. CONCLUSIONS: In tissue samples from sporadic CCMs, mutations in PIK3CA were represented to a greater extent than mutations in any other gene. The contribution of somatic mutations in the genes that cause familial CCMs was comparatively small. (Funded by the Fondation ARC pour la Recherche contre le Cancer and others.).

Northeast Atlantic elasmobranch community on the move: Functional reorganization in response to climate change.

While spatial distribution shifts have been documented in many marine fishes under global change, the responses of elasmobranchs have rarely been studied, which may have led to an underestimation of their potential additional threats. Given their irreplaceable role in ecosystems and their high extinction risk, we used a 24-year time series (1997-2020) of scientific bottom trawl surveys to examine the effects of climate change on the spatial distribution of nine elasmobranch species within Northeast Atlantic waters. Using a hierarchical modeling of species communities, belonging to the joint species distribution models, we found that suitable habitats for four species increased on average by a factor of 1.6 and, for six species, shifted north-eastwards and/or to deeper waters over the past two decades. By integrating species traits, we showed changes in habitat suitability led to changes in the elasmobranchs trait composition. Moreover, communities shifted to deeper waters and their mean trophic level decreased. We also note an increase in the mean community size at maturity concurrent with a decrease in fecundity. Because skates and sharks are functionally unique and dangerously vulnerable to both climate change and fishing, we advocate for urgent considerations of species traits in management measures. Their use would make it better to identify species whose loss could have irreversible impacts in face of the myriad of anthropogenic threats.

Defining benchmark outcomes for mesial temporal lobe epilepsy surgery: A global multicenter analysis of 1119 cases.

OBJECTIVE: Benchmarking has been proposed to reflect surgical quality and represents the highest standard reference values for desirable results. We sought to determine benchmark outcomes in patients after surgery for drug-resistant mesial temporal lobe epilepsy (MTLE). METHODS: This retrospective multicenter study included patients who underwent MTLE surgery at 19 expert centers on five continents. Benchmarks were defined for 15 endpoints covering surgery and epilepsy outcome at discharge, 1 year after surgery, and the last available follow-up. Patients were risk-stratified by applying outcome-relevant comorbidities, and benchmarks were calculated for low-risk ("benchmark") cases. Respective measures were derived from the median value at each center, and the 75th percentile was considered the benchmark cutoff. RESULTS: A total of 1119 patients with a mean age (range) of 36.7 (1-74) years and a male-to-female ratio of 1:1.1 were included. Most patients (59.2%) underwent anterior temporal lobe resection with amygdalohippocampectomy. The overall rate of complications or neurological deficits was 14.4%, with no in-hospital death. After risk stratification, 377 (33.7%) benchmark cases of 1119 patients were identified, representing 13.6%-72.9% of cases per center and leaving 742 patients in the high-risk cohort. Benchmark cutoffs for any complication, clinically apparent stroke, and reoperation rate at discharge were ≤24.6%, ≤.5%, and ≤3.9%, respectively. A favorable seizure outcome (defined as International League Against Epilepsy class I and II) was reached in 83.6% at 1 year and 79.0% at the last follow-up in benchmark cases, leading to benchmark cutoffs of ≥75.2% (1-year follow-up) and ≥69.5% (mean follow-up of 39.0 months). SIGNIFICANCE: This study presents internationally applicable benchmark outcomes for the efficacy and safety of MTLE surgery. It may allow for comparison between centers, patient registries, and novel surgical and interventional techniques.

Safety and practicality study of using an exoskeleton in acute neurosurgery patients.

INTRODUCTION: Early mobilization is key in neurologically impaired persons, limiting complications and improving long-term recovery. Self-balanced exoskeletons are used in rehabilitation departments to help patients stand and walk. We report the first case series of exoskeleton use in acute neurosurgery and intensive care patients, evaluating safety, clinical feasibility and patients' satisfaction. METHODS: We report a retrospective observational study including individuals hospitalized in the neurosurgical intensive care and neurosurgery departments. We included patients with a medical prescription for an exoskeleton session, and who met no contraindication. Patients benefited from standing sessions using a self-balanced exoskeleton (Atalante, Wandercraft, France). Patients and sessions data were collected. Safety, feasibility and adherence were evaluated. RESULTS: Seventeen patients were scheduled for 70 standing sessions, of which 27 (39%) were completed. They were typically hospitalized for intracranial hemorrhage (74%) and presented with unilateral motor impairments, able to stand but with very insufficient weight shifting to the hemiplegic limb, requiring support (MRC 36.2 ± 3.70, SPB 2.0 ± 1.3, SPD 0.7 ± 0.5). The average duration of standing sessions was 16 ± 9 min. The only side effect was orthostatic hypotension (18.5%), which resolved with returning to seating position. The most frequent reason for not completing a session was understaffing (75%). All patients were satisfied and expressed a desire to repeat it. CONCLUSIONS: Physiotherapy using the exoskeleton is safe and feasible in the acute neurosurgery setting, although it requires adaptation from the staff to organize the sessions. An efficacy study is ongoing to evaluate the benefits for the patients.

Repeated blood-brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial.

BACKGROUND: Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB) can be used to open the blood-brain barrier. We aimed to assess the safety and pharmacokinetics of LIPU-MB to enhance the delivery of albumin-bound paclitaxel to the peritumoural brain of patients with recurrent glioblastoma. METHODS: We conducted a dose-escalation phase 1 clinical trial in adults (aged ≥18 years) with recurrent glioblastoma, a tumour diameter of 70 mm or smaller, and a Karnofsky performance status of at least 70. A nine-emitter ultrasound device was implanted into a skull window after tumour resection. LIPU-MB with intravenous albumin-bound paclitaxel infusion was done every 3 weeks for up to six cycles. Six dose levels of albumin-bound paclitaxel (40 mg/m2, 80 mg/m2, 135 mg/m2, 175 mg/m2, 215 mg/m2, and 260 mg/m2) were evaluated. The primary endpoint was dose-limiting toxicity occurring during the first cycle of sonication and albumin-bound paclitaxel chemotherapy. Safety was assessed in all treated patients. Analyses were done in the per-protocol population. Blood-brain barrier opening was investigated by MRI before and after sonication. We also did pharmacokinetic analyses of LIPU-MB in a subgroup of patients from the current study and a subgroup of patients who received carboplatin as part of a similar trial (NCT03744026). This study is registered with ClinicalTrials.gov, NCT04528680, and a phase 2 trial is currently open for accrual. FINDINGS: 17 patients (nine men and eight women) were enrolled between Oct 29, 2020, and Feb 21, 2022. As of data cutoff on Sept 6, 2022, median follow-up was 11·89 months (IQR 11·12-12·78). One patient was treated per dose level of albumin-bound paclitaxel for levels 1 to 5 (40-215 mg/m2), and 12 patients were treated at dose level 6 (260 mg/m2). A total of 68 cycles of LIPU-MB-based blood-brain barrier opening were done (median 3 cycles per patient [range 2-6]). At a dose of 260 mg/m2, encephalopathy (grade 3) occurred in one (8%) of 12 patients during the first cycle (considered a dose-limiting toxicity), and in one other patient during the second cycle (grade 2). In both cases, the toxicity resolved and treatment continued at a lower dose of albumin-bound paclitaxel, with a dose of 175 mg/m2 in the case of the grade 3 encephalopathy, and to 215 mg/m2 in the case of the grade 2 encephalopathy. Grade 2 peripheral neuropathy was observed in one patient during the third cycle of 260 mg/m2 albumin-bound paclitaxel. No progressive neurological deficits attributed to LIPU-MB were observed. LIPU-MB-based blood-brain barrier opening was most commonly associated with immediate yet transient grade 1-2 headache (12 [71%] of 17 patients). The most common grade 3-4 treatment-emergent adverse events were neutropenia (eight [47%]), leukopenia (five [29%]), and hypertension (five [29%]). No treatment-related deaths occurred during the study. Imaging analysis showed blood-brain barrier opening in the brain regions targeted by LIPU-MB, which diminished over the first 1 h after sonication. Pharmacokinetic analyses showed that LIPU-MB led to increases in the mean brain parenchymal concentrations of albumin-bound paclitaxel (from 0·037 µM [95% CI 0·022-0·063] in non-sonicated brain to 0·139 µM [0·083-0·232] in sonicated brain [3·7-times increase], p<0·0001) and carboplatin (from 0·991 µM [0·562-1·747] in non-sonicated brain to 5·878 µM [3·462-9·980] µM in sonicated brain [5·9-times increase], p=0·0001). INTERPRETATION: LIPU-MB using a skull-implantable ultrasound device transiently opens the blood-brain barrier allowing for safe, repeated penetration of cytotoxic drugs into the brain. This study has prompted a subsequent phase 2 study combining LIPU-MB with albumin-bound paclitaxel plus carboplatin (NCT04528680), which is ongoing. FUNDING: National Institutes of Health and National Cancer Institute, Moceri Family Foundation, and the Panattoni family.

Unveiling the enigma of the blood-brain barrier in glioblastoma: current advances from preclinical and clinical studies.

PURPOSE OF REVIEW: Glioblastoma (GBM), the most prevalent primary brain malignancy in adults, poses significant challenges in terms of treatment. Current therapeutic strategies for GBM patients involve maximal safe resection, followed by radiotherapy with concurrent and adjuvant temozolomide. However, despite this multimodal approach for GBM, the prognosis of GBM patients remains dismal because of their inherent primary and secondary resistances to treatments. RECENT FINDINGS: Several molecular and cellular mechanisms, including the presence of the blood-brain barrier (BBB), contribute to these resistances. The BBB, comprising multiple layers surrounding brain vessels, acts as a barrier limiting effective drug delivery to the brain. Invasive and noninvasive tools to deliver drugs and pharmaceutical formulations locally or systemically are continuously evolving to overcome the BBB in GBM toward improving drug bioavailability in the brain and reducing systemic toxicities. SUMMARY: Preliminary studies utilizing these approaches have demonstrated promising results in terms of safety and signals of efficacy during early-phase clinical trials. However, further work through additional clinical trials is necessary to evaluate the potential clinical benefits for GBM patients.

A threshold for mitotic activity and post-surgical residual volume defines distinct prognostic groups for astrocytoma IDH-mutant.

AIMS: The distinction between CNS WHO grade 2 and grade 3 is instrumental in choosing between observational follow-up and adjuvant treatment for resected astrocytomas IDH-mutant. However, the criteria of CNS WHO grade 2 vs 3 have not been updated since the pre-IDH era. METHODS: Maximal mitotic activity in consecutive high-power fields corresponding to 3 mm2 was examined for 118 lower-grade astrocytomas IDH-mutant. The prognostic value for time-to-treatment (TTT) and overall survival (OS) of mitotic activity and other putative prognostic factors (including age, performance status, pre-surgical tumour volume, multilobar involvement, post-surgical residual tumour volume and midline involvement) was assessed for tumours with ATRX loss and the absence of CDKN2A homozygous deletion or CDK4 amplification, contrast enhancement, histological necrosis and microvascular proliferation. RESULTS: Seventy-one per cent of the samples had <6 mitoses per 3 mm2 . Mitotic activity, residual volume and multilobar involvement were independent prognostic factors of TTT. The threshold of ≥6 mitoses per 3 mm2 identified patients with a shorter TTT (median 18.5 months). A residual volume ≥1 cm3 also identified patients with a shorter TTT (median 24.5 months). The group defined by <6 mitoses per 3 mm2 and a residual volume <1 cm3 had the longest TTT (median 73 months) and OS (100% survival at 7 years). These findings were confirmed in a validation cohort of 52 tumours. CONCLUSIONS: Mitotic activity and post-surgical residual volume can be combined to evaluate the prognosis for patients with resected astrocytomas IDH-mutant. Patients with <6 mitoses per 3 mm2 and a residual volume <1 cm3 were the best candidates for observational follow-up.

Corticosteroid treatment for refractory intracranial hypertension: a rescue therapy in patients with severe traumatic brain injury with contusional lesions-a feedback.

INTRODUCTION: Refractory intracranial hypertension (rICH) is a severe complication among patients with severe traumatic brain injury (sTBI). Medical treatment may be insufficient, and in some cases, the only viable treatment option is decompressive hemicraniectomy. The assessment of a corticosteroid therapy against vasogenic edema secondary to severe brain injuries seems interesting to prevent this surgery in sTBI patients with rICH caused by contusional areas. METHODS: This is a monocentric retrospective observational study including all consecutive sTBI patients with contusion injuries and a rICH requiring cerebrospinal fluid drainage with external ventricular drainage between November 2013 and January 2018. Patient inclusion criterium was a therapeutic index load (TIL; an indirect measure of TBI severity) > 7. Intracranial pressure (ICP) and TIL were assessed before and 48 h after corticosteroid therapy (CTC). Then, we divided the population into two groups according to the evolution of the TIL: responders and non-responders to corticosteroid therapy. RESULTS: During the study period, 512 patients were hospitalized for sTBI, and among them, 44 (8.6%) with rICH were included. They received 240 mg per day [120 mg, 240 mg] of Solu-Medrol for 2 days [1; 3], 3 days after the sTBI. The average ICP in patients with rICH before the CTC bolus was 21 mmHg [19; 23]. After the CTC bolus, the ICP fell significantly to less than 15 mmHg (p < 0.0001) for at least 7 days. The TIL decreased significantly the day after the CTC bolus and until day 2. Among these 44 patients, 68% were included in the responder group (n = 30). DISCUSSION: Short and systemic corticosteroid therapy in patients with refractory intracranial hypertension secondary to severe traumatic brain injury seems to be a potentially useful and efficient treatment for lowering intracranial pressure and decreasing the need for more invasive surgeries.

Effects of Low-Intensity Pulsed Ultrasound-Induced Blood-Brain Barrier Opening in P301S Mice Modeling Alzheimer's Disease Tauopathies.

Alzheimer's disease (AD) is the leading cause of dementia. No treatments have led to clinically meaningful impacts. A major obstacle for peripherally administered therapeutics targeting the central nervous system is related to the blood-brain barrier (BBB). Ultrasounds associated with microbubbles have been shown to transiently and safely open the BBB. In AD mouse models, the sole BBB opening with no adjunct drugs may be sufficient to reduce lesions and mitigate cognitive decline. However, these therapeutic effects are for now mainly assessed in preclinical mouse models of amyloidosis and remain less documented in tau lesions. The aim of the present study was therefore to evaluate the effects of repeated BBB opening using low-intensity pulsed ultrasounds (LIPU) in tau transgenic P301S mice with two main readouts: tau-positive lesions and microglial cells. Our results show that LIPU-induced BBB opening does not decrease tau pathology and may even potentiate the accumulation of pathological tau in selected brain regions. In addition, LIPU-BBB opening in P301S mice strongly reduced microglia densities in brain parenchyma, suggesting an anti-inflammatory action. These results provide a baseline for future studies using LIPU-BBB opening, such as adjunct drug therapies, in animal models and in AD patients.

Safety of radiosurgery concurrent with systemic therapy (chemotherapy, targeted therapy, and/or immunotherapy) in brain metastases: a systematic review.

Stereotactic radiosurgery (SRS) is a standard option for brain metastases (BM). There is lack of consensus when patients have a systemic treatment, if a washout is necessary. The aim of this review is to analyze the toxicity of SRS when it is concurrent with chemotherapies, immunotherapy, and/or targeted therapies. From Medline and Embase databases, we searched for English literature published up to April 2020 according to the PRISMA guidelines, using for key words the list of the main systemic therapies currently in use And "radiosurgery," "SRS," "GKRS," "Gamma Knife," "toxicity," "ARE," "radiation necrosis," "safety," "brain metastases." Studies reporting safety or toxicity with SRS concurrent with systemic treatment for BM were included. Of 852 abstracts recorded, 77 were included. The main cancers were melanoma, lung, breast, and renal carcinoma. These studies cumulate 6384 patients. The median SRS dose prescription was 20 Gy [12-30] .For some, they compared a concurrent arm with a non-concurrent or a SRS-alone arm. There were no skin toxicities, no clearly increased rate of bleeding, or radiation necrosis with significant clinical impact. SRS combined with systemic therapy appears to be safe, allowing the continuation of treatment when brain SRS is considered.

Brain Biopsy for Neurological Diseases of Unknown Etiology in Critically Ill Patients: Feasibility, Safety, and Diagnostic Yield.

OBJECTIVES: Brain biopsy is a useful surgical procedure in the management of patients with suspected neoplastic lesions. Its role in neurologic diseases of unknown etiology remains controversial, especially in ICU patients. This study was undertaken to determine the feasibility, safety, and the diagnostic yield of brain biopsy in critically ill patients with neurologic diseases of unknown etiology. We also aimed to compare these endpoints to those of non-ICU patients who underwent a brain biopsy in the same clinical context. DESIGN: Monocenter, retrospective, observational cohort study. SETTING: A French tertiary center. PATIENTS: All adult patients with neurologic diseases of unknown etiology under mechanical ventilation undergoing in-ICU brain biopsy between January 2008 and October 2020 were compared with a cohort of non-ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 2,207 brain-biopsied patients during the study period, 234 biopsies were performed for neurologic diseases of unknown etiology, including 29 who were mechanically ventilated and 205 who were not ICU patients. Specific histological diagnosis and final diagnosis rates were 62.1% and 75.9%, respectively, leading to therapeutic management modification in 62.1% of cases. Meningitis on prebiopsy cerebrospinal fluid analysis was the sole predictor of obtaining a final diagnosis (2.3 [1.4-3.8]; p = 0.02). ICU patients who experienced therapeutic management modification after the biopsy had longer survival (p = 0.03). The grade 1 to 4 (mild to severe) complication rates were: 24.1%, 3.5%, 0%, and 6.9%, respectively. Biopsy-related mortality was significantly higher in ICU patients compared with non-ICU patients (6.9% vs 0%; p = 0.02). Hematological malignancy was associated with biopsy-related mortality (1.5 [1.01-2.6]; p = 0.04). CONCLUSIONS: Brain biopsy in critically ill patients with neurologic disease of unknown etiology is associated with high diagnostic yield, therapeutic modifications and postbiopsy survival advantage. Safety profile seems acceptable in most patients. The benefit/risk ratio of brain biopsy in this population should be carefully weighted.

Roles and outcomes of stereotactic biopsy for adult patients with brainstem lesion.

PURPOSE: This study aimed to assess the benefit-risk ratio by determining diagnostic yield and safety of brainstem biopsies in adult patients. The secondary objectives were (i) to compare brainstem biopsy safety and postbiopsy patients' outcomes and survival with those of patients biopsied for a brain or cerebellar lesion, and (ii) to assess the impact of brainstem biopsy on final diagnosis and further therapeutic management. METHODS: Among 1784 stereotactic biopsies performed in adult patients at a tertiary center between April 2009 and October 2020, we retrospectively examined 50 consecutive brainstem biopsies. We compared variables regarding diagnostic yield, safety and post-biopsy outcomes between brainstem biopsy patients and brain/cerebellum biopsy patients. RESULTS: Brainstem biopsy led to a diagnosis in 86% of patients (94.6% in patients with suspected tumor). Lesion contrast enhancement on imaging was the sole predictor of obtaining a diagnosis. Rates of symptomatic complications and mortality were significantly higher in brainstem biopsy patients compared to brain/cerebellum biopsy patients (20% vs 0%; p < 0.001 and 6% vs 0%; p = 0.01, respectively). Transfrontal trajectory and prebiopsy swallowing disorders were predictors of brainstem biopsy-related symptomatic complications. Brainstem biopsy findings led to diagnostic change in 22% of patients. CONCLUSIONS: Stereotactic biopsy in adult patients with brainstem lesion has a high diagnostic yield. Although stereotactic brainstem biopsy is associated with more functional and fatal complications than biopsies targeting the brain/cerebellum, its safety profile appears acceptable. Thus, the benefit-risk ratio of stereotactic biopsy in patients with brainstem lesion is favorable but should nevertheless be carefully weighted on a case-by-case basis.

Outpatient stereotactic brain biopsies.

Outpatient neurosurgery is rising popularity leading to patients' satisfaction and cost-savings. Although several North-American teams have shown the safety of outpatient stereotactic brain biopsies, few data from other countries with different health care systems are available. We therefore conducted a feasibility and safety study on the outpatient stereotactic brain biopsies. We prospectively examined all the consecutive stereotactic brain biopsies performed in an outpatient setting at our tertiary medical center, between June 2018 and September 2020. Among the 437 patients who underwent stereotactic brain biopsy during the study period, 40 (9.2%) patients were enrolled for an outpatient management. The sex ratio was 1 and the median age on biopsy day was 55 [41-66] years. The median distance from patients' home to hospital was 17 km [3-47]. 95% of patients had pre-biopsy ASA score of 1 or 2 and mRs equal to 2 or less. The rate of same-day discharge was 100%. No patient experienced post-biopsy symptomatic complication necessitating readmission within the month following the biopsy. One patient (2.5%) resorted to an unplanned consultation. Histological findings obtained from brain biopsy led to a diagnosis in all patients; the most frequently found were neoplastic lesions (77.5%). Stereotactic brain biopsies can therefore be safely achieved on an outpatient setting in carefully selected patients. This process could be more widely adopted in other neurosurgical centers, without affecting the quality of patient's health care and safety. In this article, we propose management guidelines and pre-biopsy checklist for performing ambulatory stereotactic brain biopsies.

Anterior interhemispheric approach for anterior fossa dural arteriovenous fistulas.

Anterior fossa dural arteriovenous fistulas (AF-DAVF) usually display a cortical venous drainage and are therefore at risk for rupture. Microsurgery is traditionally considered in many centers as the first-line treatment since endovascular treatment (EVT) entails a lower cure rate and significant ophthalmic risks. The anterior interhemispheric approach (AIA), originally described by Mayfrank in 1996, seems to offer the effectiveness of microsurgery while limiting the risks related to subfrontal craniotomy. The objective of this study was to analyze the surgical outcomes of patients who underwent this surgical approach for the treatment of AF-DAVF. We hereby describe our 10 years' experience of patients treated for an AF-DAVF with this technique in our institution and retrospectively analyzed our results. In addition, we describe our operative technique and its specificities. Eleven patients with AF-DAVF were included in our study. The definitive cure of the fistula was confirmed in all cases with postoperative cerebral angiography. All patients had a good neurological outcome and no major complication occurred. Brain retractors were never used during surgery, the frontal sinus was never opened neither, and anosmia was never observed after surgery. Anterior interhemispheric approach seems to be safe and effective to treat AF-DAVF with lower risks than other surgical approaches. This technique could be more widely considered when facing such midline vascular lesion.

Spine metastasis in patients with prostate cancer: Survival prognosis assessment.

BACKGROUND: Patients presenting spine metastasis (SpM) from prostate cancer (PC) form a heterogeneous population, through this study, we aimed to clarify and update their prognostic assessment. METHODS: The patient data used in this study was obtained from a French national multicenter database of patients treated for PC with SpM between 2014 and 2017. A total of 72 patients and 365 SpM cases were diagnosed. RESULTS: The median overall survival time for all patients following the event of SpM was 28.8 months. First, we identified three significant survival prognostic factors of PC patients with SpM: good Eastern Cooperative Oncology Group/World Health Organization personnel status (Status 0 hazard ratio [HR]: 0.031, 95% confidence interval [CI]: 0.008-0.127; p < .0001) or (Status 1 HR: 0.163, 95% CI: 0.068-0.393; p < .0001) and SpM radiotherapy (HR: 2.923, 95% CI: 1.059-8.069; p < .0001). Secondly, the presence of osteolytic lesions of the spine (vs. osteoblastic) was found to represent an independent prognosis factor for longer survival [HR: 0.424, 95% CI: 0.216-0.830; p = .01]. Other factors including the number of SpM, surgery, extraspinal metastasis, synchrone metastasis, metastasis-free survival, and SpM recurrence were not identified as being prognostically relevant to the survival of patients with PC. CONCLUSION: Survival and our ability to estimate it in patients presenting PC with SpM have improved significantly. Therefore, we advocate the relevance of updating SpM prognostic scoring algorithms by incorporating data regarding the timeline of PC as well as the presence of osteolytic SpM to conceive treatments that are adapted to each patient.

Blood-brain barrier opening with low intensity pulsed ultrasound for immune modulation and immune therapeutic delivery to CNS tumors.

INTRODUCTION: Opening of the blood-brain barrier (BBB) by pulsed low intensity ultrasound has been developed during the last decade and is now recognized as a safe technique to transiently and repeatedly open the BBB. This non- or minimally invasive technique allows for a targeted and uniform dispersal of a wide range of therapeutic substances throughout the brain, including immune cells and antibodies. METHODS: In this review article, we summarize pre-clinical studies that have used BBB-opening by pulsed low intensity ultrasound to enhance the delivery of immune therapeutics and effector cell populations, as well as several recent clinical studies that have been initiated. Based on this analysis, we propose immune therapeutic strategies that are most likely to benefit from this strategy. The literature review and trial data research were performed using Medline/Pubmed databases and clinical trial registry www.clinicaltrials.gov . The reference lists of all included articles were searched for additional studies. RESULTS: A wide range of immune therapeutic agents, including small molecular weight drugs, antibodies or NK cells, have been safely and efficiently delivered to the brain with pulsed low intensity ultrasound in preclinical models, and both tumor control and increased survival have been demonstrated in different types of brain tumor models in rodents. Ultrasound-induced BBB disruption may also stimulate innate and cellular immune responses. CONCLUSIONS: Ultrasound BBB opening has just recently entered clinical trials with encouraging results, and the association of this strategy with immune therapeutics creates a new field of brain tumor treatment.

Clinical characteristics and long-term surgical outcome of spinal myxopapillary ependymoma: a French cohort of 101 patients.

PURPOSE: Myxopapillary ependymoma (MPE) is the most frequent tumor affecting the medullary conus. The surgical therapeutic management is still debated and only few studies have focused on the postoperative clinical outcome of patients. This study aimed to demonstrate long-term postoperative outcome and to assess the predictive factors of recurrence as well as the clinical evolution of these patients. METHODS: From 1984 to 2019, in four French centers, 101 adult patients diagnosed with MPE were retrospectively included. RESULTS: Median age at surgery was 39 years. Median tumor size was 50 mm and lesions were multifocal in 13% of patients. All patients benefited from surgery and one patient received postoperative radiotherapy. Gross total resection was obtained in 75% of cases. Sixteen percent of patients presented recurrence after a median follow-up of 70 months. Progression free survival at 5 and 10 years were respectively estimated at 83% and 79%. After multivariable analysis, sacral localization, and subtotal resection were shown to be independently associated with tumor recurrence. 85% of the patients had a favorable evolution concerning pain. 12% of the patients presented a postoperative deterioration of sphincter function and 4% of motor function. CONCLUSION: Surgery alone is an acceptable option for MPE patients. Patients with sacral location or incomplete resection are at high risk of recurrence and should be carefully monitored.

Teaching brain imaging through a drawing method may improve learning in medical students.

OBJECTIVES: Brain imaging is particularly difficult to learn and to teach. This study aimed to evaluate the performance of teaching brain imaging through drawing method in medical faculty students. METHODS: We conducted a prospective, interventional, randomized, single-blind study in third-year voluntary medical students between December 2016 and June 2019. Eighty medical students received a theoretical training on brain imaging interpretation and were subsequently randomized into two groups ("teaching through drawing" and "standard teaching"). An initial evaluation was carried out to assess the students' basic level. Three teaching and training sessions were spread over 2 months in each group. One month after the third teaching session, students were evaluated by an examiner who was blind to the student's group. The same comprehensive evaluation grid has been used for the initial and final students' evaluations to give an objective score out of 20 points. Students' scores were compared between groups using the t test and effect sizes were measured using Cohen's d. RESULTS: Students' mean age was 21.1 years old. In total, 61.3% were female. Regarding initial evaluation, scores did not differ significantly between both groups (10.1 ± 2.0 versus 9.9 ± 1.9, p = 0.65), thus confirming the homogeneity of the students' basic level. The scores obtained from the final evaluation were significantly higher for the "teaching through drawing" students than for the "standard teaching" students (14.7 ± 2.7 vs 13.2 ± 2.0, p = 0.009, Cohen's d = 0.62). CONCLUSIONS: This study provides class II evidence that the method of drawing alone can improve brain imaging comprehension and analysis in medical faculty students. KEY POINTS: • The method of drawing can improve brain imaging analysis in medical faculty students. • A large majority of students were satisfied by the method of brain imaging teaching through drawing.

Outpatient vagus nerve stimulation surgery in patients with drug-resistant epilepsy with severe intellectual disability.

PURPOSE: Vagus nerve stimulation (VNS) implantation is increasingly proposed in outpatient procedure. Some epilepsy syndromes are associated with severe neurodevelopmental disabilities (intellectual disability, autism) and often motor or sensory handicaps, making ambulatory surgery more complex. METHODS: We prospectively assessed the feasibility and safety of outpatient VNS implantation in 26 adult patients with drug-resistant epilepsy with severe intellectual disability between December 2017 and October 2020. RESULTS: The male-to-female ratio was 0.9 and the mean age on surgery day was 23.1 years. Seventeen patients (65.4%) suffered from epileptic encephalopathy, 7 (26.9%) from cryptogenic or genetic generalized epilepsy, and 2 (7.7%) from severe multifocal epilepsy. Postoperatively, all patients were discharged the day of surgery. No patient was admitted to a hospital or have consulted within one month due to postoperative complications. There was no surgery-related complication during patients' follow-up. CONCLUSION: Our study highlights the safety and feasibility of VNS surgery in an outpatient setting for patients with severe intellectual disability. We report detailed protocol and preoperative checklist to optimize outpatient VNS surgery in these not able-bodied patients. Severe disabilities or epilepsy-associated handicaps should not be an exclusion criterion when considering ambulatory VNS implantation.