B rain metastases are a significant source of illness and death among cancer patients 8 and will eventually develop in about 20%-40% of patients with a primary extracranial neoplasm. 9 The intent of current optimal case management remains mostly palliative. Resection has been shown to improve neurological symptoms, improve functional independence, and increase survival times. 19 However, surgery alone is associated with a 46%-59% rate of local recurrence, presumably because Early Gamma Knife stereotactic radiosurgery to the tumor bed of resected brain metastasis for improved local control Object. Optimal case management after surgical removal of brain metastasis remains controversial. Although postoperative whole-brain radiation therapy (WBRT) has been shown to prevent local recurrence and decrease deaths, this modality can substantially decrease neurocognitive function and quality of life. Stereotactic radiosurgery (SRS) can theoretically achieve the same level of local control with fewer side effects, although studies conclusively demonstrating such outcomes are lacking. To assess the effectiveness and safety profile of tumor bed SRS after resection of brain metastasis, the authors performed a retrospective analysis of 110 patients who had received such treatment at the Centre Hospitalier Universitaire de Sherbrooke. They designed the study to identify risk factors for local recurrence and placed special emphasis on factors that could potentially be addressed.Methods. Patients who had received treatment from 2004 through 2013 were included if they had undergone surgical removal of 1 or more brain metastases and if the tumor bed was treated by SRS regardless of the extent of resection or prior WBRT. All cases were retrospectively analyzed for patient and tumor-specific factors, treatment protocol, adverse outcomes, cavity outcomes, and survival for as long as follow-up was available. Univariate and multivariate Cox regression analyses were performed to identify risk factors for local recurrence and predictors of increased survival times.Results. Median patient age at first SRS treatment was 58 years (range 37-84 years). The most frequently diagnosed primary tumor was non-small cell lung cancer. The rate of gross-total resection was 81%. The median Karnofsky Performance Scale score was 90%. Tumor bed SRS was performed at a median of 3 weeks after surgery. Median follow-up and survival times were 10 and 11 months, respectively. Actuarial local control of the cavity at 12 months was 73%; median time to recurrence was 6 months. According to multivariate analysis, risk factors for recurrence were a longer surgery-to-SRS delay (HR 1.625, p = 0.003) and a lower maximum radiation dose delivered to the cavity (HR 0.817, p = 0.006). Factors not associated with increased recurrence were subtotal or piecemeal resections, prior WBRT, histology of the primary tumor, and larger cavity volume. No factors predictive of survival were identified. Symptomatic radiation-induced enhancement occurred in 6% of patients and leptomeninge...

Deep brain stimulation (DBS) is a neuromodulatory treatment used in patients with drug-resistant epilepsy (DRE). The primary goal of this systematic review and metaanalysis is to describe recent advancements in the field of DBS for epilepsy, to compare the results of published trials, and to clarify the clinical utility of DBS in DRE. A systematic literature search was performed by two independent authors. Forty-four articles were included in the meta-analysis (23 for anterior thalamic nucleus [ANT], 8 for centromedian thalamic nucleus [CMT], and 13 for hippocampus) with a total of 527 patients. The mean seizure reduction after stimulation of the ANT, CMT, and hippocampus in our meta-analysis was 60.8%, 73.4%, and 67.8%, respectively. DBS is an effective and safe therapy in patients with DRE. Based on the results of randomized controlled trials and larger clinical series, the best evidence exists for DBS of the anterior thalamic nucleus. Further randomized trials are required to clarify the role of CMT and hippocampal stimulation. Our analysis suggests more efficient deep brain stimulation of ANT for focal seizures, wider use of CMT for generalized seizures, and hippocampal DBS for temporal lobe seizures. Factors associated with clinical outcome after DBS for epilepsy are electrode location, stimulation parameters, type of epilepsy, and longer time of stimulation. Recent advancements in anatomical targeting, functional neuroimaging, responsive neurostimulation, and sensing of local field potentials could potentially lead to improved outcomes after DBS for epilepsy and reduced sudden, unexpected death of patients with epilepsy. Biomarkers are needed for successful patient selection, targeting of electrodes and optimization of stimulation parameters.

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BackgroundChronic subdural hematoma (CSDH) is one of the most frequent reason for cranial neurosurgical consultation. There is no widely accepted medical treatment for this condition. Herein, we present the protocol for the Tranexamic Acid (TXA) in Chronic Subdural Hematomas (TRACS) trial aiming at determining whether TXA can increase the rate of CSDH resolution following conservative management, lower the number of required surgical procedures and decrease the rate of CSDH recurrence following surgical evacuation.MethodsTRACS is a multicenter, double-blind, randomized, parallel-design, placebo-controlled, phase IIB study designed to provide preliminary efficacy data as well as feasibility, safety and incidence data required to plan a larger definitive phase III trial.Consecutive patients presenting with a diagnosis of chronic subdural hematoma will be screened for eligibility. Exclusion criteria include: specific risk factors for thromboembolic disease, anticoagulant use or contraindication to TXA. A total of 130 patients will be randomized to receive either 750 mg of TXA daily or placebo until complete radiological resolution of the CSDH or for a maximum of 20 weeks. CSDH volume will be measured on serial computed tomography (CT) scanning. Cognitive function tests, quality of life questionnaires as well as functional autonomy assessments will be performed at enrollment, at 10 weeks following randomization and at 3 months following treatment cessation. During the treatment period, patients will undergo standard CSDH management with surgery being performed at the discretion of the treating physician. If surgery is performed, the CSDH and its outer membrane will be sampled for in vitro analysis.The primary outcome is the rate of CSDH resolution by 20 weeks without intervening unplanned surgical procedure. Secondary outcomes include: CSDH volume, incidence of surgical evacuation procedures, CSDH recurrence, cognitive functions, functional autonomy, quality of life, incidence of complications and length of hospital stay. Planned subgroup analyses will be performed for conservatively versus surgically managed subjects and highly versus poorly vascularized CSDH.DiscussionCSDH is a frequent morbidity for which an effective medical treatment has yet to be discovered. The TRACS trial will be the first prospective study of TXA for CSDH.Trial registrationNCT ID: NCT02568124.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1358-5) contains supplementary material, which is available to authorized users.

Stereotactic radiosurgery (SRS) offers a high degree of tumor control for benign meningiomas. However, radiosurgery can occasionally incite edema or exacerbate pre-existing peri-tumoral edema. The current study investigates the incidence, timing, and extent of edema around parasagittal or parafalcine meningiomas following SRS. A retrospective multicenter review was undertaken through participating centers in the International Gamma Knife Research Foundation (previously the North American Gamma Knife Consortium or NAGKC). All included patients had a parafalcine or parasagittal meningioma and a minimum of 6 months follow up. The median follow up was 19.6 months (6-158 months). Extent of new or worsening edema was quantitatively analyzed using volumetric analysis; edema indices were longitudinally computed following radiosurgery. Analysis was performed to identify prognostic factors for new or worsening edema. A cohort of 212 patients comprised of 51.9 % (n = 110) females, 40.1 % upfront SRS and 59.9 % underwent adjuvant SRS for post-surgical residual tumor. The median tumor volume at SRS was 5.2 ml. Venous sinus compression or invasion was demonstrated in 25 % (n = 53). The median marginal dose was 14 Gy (8-20 Gy). Tumor volume control was determined in 77.4 % (n = 164 out of 212 patients). Tumor edema progressed and then regressed in 33 % (n = 70), was stable or regressed in 52.8 % (n = 112), and progressively worsened in 5.2 % (n = 11). Tumor location, tumor volume, venous sinus invasion, margin, and maximal dose were found to be significantly related to post-SRS edema in multivariate analysis. SRS affords a high degree of tumor control for patients with parasagittal or parafalcine meningiomas. Nevertheless, SRS can lead to worsening peritumoral edema in a subset of patients such as those with larger tumors (>10 cc) and venous sinus invasion/compression. Long-term follow up is required to detect and appropriately manage post-SRS edema.

A BS TRACT: Background: In patients with medically refractory essential tremor, unilateral magnetic resonanceguided focused ultrasound thalamotomy can improve contralateral tremor. However, this procedure does not address ipsilateral symptoms. Objective: The objective of the current study was to determine whether bilateral thalamotomies can be performed with an acceptable safety profile where benefits outweigh adverse effects. Methods: We conducted a prospective, single-arm, single-blinded phase 2 trial of second-side magnetic resonance-guided focused ultrasound thalamotomy in patients with essential tremor. Patients were followed for 3 months. The primary outcome was the change in quality of life relative to baseline, as well as the answer to the question "Given what you know now, would you treat the second side again?". Secondary outcomes included tremor, gait, speech, and adverse effects. Results: Ten patients were analyzed. The study met both primary outcomes, with the intervention resulting in clinically significant improvement in quality of life at 3 months (mean Quality of Life in Essential Tremor score difference, 19.7; 95%CI,; P = 0.004) and all patients reporting that they would elect to receive the secondside treatment again. Tremor significantly improved in all patients. Seven experienced mild adverse effects, including 2 with transient gait impairment and a fall, 1 with dysarthria and dysphagia, and 1 with mild dysphagia persisting at 3 months.

Although the mechanisms that regulate folding and maturation of newly synthesized G protein-coupled receptors are crucial for their function, they remain poorly characterized. By yeast two-hybrid screening, we have isolated ANKRD13C, a protein of unknown function, as an interacting partner for the DP receptor for prostaglandin D 2 . In the present study we report the characterization of this novel protein as a regulator of DP biogenesis and trafficking in the biosynthetic pathway. Colocalization by confocal microscopy with an endoplasmic reticulum (ER) marker, subcellular fractionation experiments, and demonstration of the interaction between ANKRD13C and the cytoplasmic C terminus of DP suggest that ANKRD13C is a protein associated with the cytosolic side of ER membranes. Co-expression of ANKRD13C with DP initially increased receptor protein levels, whereas siRNAmediated knockdown of endogenous ANKRD13C decreased them. Pulse-chase experiments indicated that ANKRD13C can promote the biogenesis of DP by inhibiting the degradation of newly synthesized receptors. However, a prolonged interaction between ANKRD13C and DP resulted in ER retention of misfolded/unassembled forms of the receptor and to their proteasome-mediated degradation. ANKRD13C also regulated the expression of other GPCRs tested (CRTH2, thromboxane A 2 (TP␣), and ␤2-adrenergic receptor), whereas it did not affect the expression of green fluorescent protein, GRK2 (G proteincoupled receptor kinase 2), and VSVG (vesicular stomatitis virus glycoprotein), showing specificity toward G proteincoupled receptors. Altogether, these results suggest that ANKRD13C acts as a molecular chaperone for G proteincoupled receptors, regulating their biogenesis and exit from the ER.As the largest family of membrane receptors, G proteincoupled receptors (GPCRs) 4 mediate physiological responses to a vast array of cellular mediators such as hormones, neurotransmitters, lipids, nucleotides, peptides, ions, and photons. To be fully functional, GPCRs need to be delivered to the plasma membrane in a ligand-responsive and signaling-competent form. The synthesis and maturation of these receptors require a complex combination of processes that include protein folding, posttranslational modifications, and transport through distinct cellular compartments of the secretory pathway (1). In recent years, GPCRs were found to interact with many proteins besides G proteins, and such interactions were shown to play important roles in receptor biogenesis and trafficking. For example, the Drosophila cyclophilin protein ninaA (neither inactivation nor afterpotential A) and its mammalian homolog, RanBP2 (Ran-binding protein 2), associate with rhodopsin and opsins, respectively. They have been characterized as chaperones that can facilitate receptor folding and are essential for efficient localization of opsins at the cell surface (2-4). The receptor-activity-modifying proteins represent another example of GPCR-interacting proteins implicated in the trafficking and functionality of receptors....

Silent corticotroph staining pituitary adenoma (SCA) represents an uncommon subset of Non-Functioning adenomas (NFAs), hypothesized to be more locally aggressive. In this retrospective multicenter study, we investigate the safety and effectiveness of Stereotactic Radiosurgery (SRS) in patients with SCA compared with other non-SCA NFA’s. Eight centers participating in the International Gamma-Knife Research Foundation (IGKRF) contributed to this study. Outcomes of 50 patients with confirmed SCAs and 307 patients with confirmed non-SCA NFA’s treated with SRS were evaluated. Groups were matched. SCA was characterized by a lack of clinical evidence of Cushing disease, yet with positive immunostaining for corticotroph. Median age was 55.2 years (13.7–87). All patients underwent at least one trans-sphenoidal tumor resection prior to SRS. SRS parameters were comparable as well. Median follow-up 40 months (6–163). Overall tumor control rate (TCR) 91.2% (n = 280). In the SCA group, TCR were 82% (n = 41) versus 94.1% (n = 289) for the control-NFA (p = 0.0065). The SCA group showed a significantly higher incidence of new post-SRS visual deficit (p < 0.0001) assigned to tumor progression and growth, and post-SRS weakness and fatigue (p < 0.0001). In univariate and multivariate analysis, only the status of silent corticotroph staining (p = 0.005, p = 0.009 respectively) and margin dose (p < 0.0005, p = 0.0037 respectively) significantly influenced progression rate. A margin dose of ≥17 Gy was noted to influence the adenoma progression rate in the entire cohort (p = 0.003). Silent corticotroph staining represents an independent factor for adenoma progression and hypopituitarism after SRS. A higher margin dose may convey a greater chance of TCR.