Local delivery of hrBMP4 as an anticancer therapy in patients with recurrent glioblastoma: a first-in-human phase 1 dose escalation trial.

BACKGROUND: This Phase 1 study evaluates the intra- and peritumoral administration by convection enhanced delivery (CED) of human recombinant Bone Morphogenetic Protein 4 (hrBMP4) - an inhibitory regulator of cancer stem cells (CSCs) - in recurrent glioblastoma. METHODS: In a 3 + 3 dose escalation design, over four to six days, fifteen recurrent glioblastoma patients received, by CED, one of five doses of hrBMP4 ranging from 0·5 to 18 mg. Patients were followed by periodic physical, neurological, blood testing, magnetic resonance imaging (MRI) and quality of life evaluations. The primary objective of this first-in-human study was to determine the safety, dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of hrBMP4. Secondary objectives were to assess potential efficacy and systemic exposure to hrBMP4 upon intracerebral infusion. RESULTS: Intra- and peritumoral infusion of hrBMP4 was safe and well-tolerated. We observed no serious adverse events related to this drug. Neither MTD nor DLT were reached. Three patients had increased hrBMP4 serum levels at the end of infusion, which normalized within 4 weeks, without sign of toxicity. One patient showed partial response and two patients a complete (local) tumor response, which was maintained until the most recent follow-up, 57 and 30 months post-hrBMP4. Tumor growth was inhibited in areas permeated by hrBMP4. CONCLUSION: Local delivery of hrBMP4 in and around recurring glioblastoma is safe and well-tolerated. Three patients responded to the treatment. A complete response and long-term survival occurred in two of them. This warrants further clinical studies on this novel treatment targeting glioblastoma CSCs. TRIAL REGISTRATION: ClinicaTrials.gov identifier: NCT02869243.

Prevention of Post-Operative Pain after Elective Brain Surgery: A Meta-Analysis of Randomized Controlled Trials.

Background and Objective: To analyze the effects of several drug for pain prevention in adults undergoing craniotomy for elective brain surgery. Material and Methods: A systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The inclusion criteria were limited to randomized controlled trials (RCTs) that evaluated the effectiveness of pharmacological treatments for preventing post-operative pain in adults (aged 18 years or older) undergoing craniotomies. The main outcome measures were represented by the mean differences in validated pain intensity scales administered at 6 h, 12 h, 24 h and 48 h post-operatively. The pooled estimates were calculated using random forest models. The risk of bias was evaluated using the RoB2 revised tool, and the certainty of evidence was assessed according to the GRADE guidelines. Results: In total, 3359 records were identified through databases and registers' searching. After study selection, 29 studies and 2376 patients were included in the meta-analysis. The overall risk of bias was low in 78.5% of the studies included. The pooled estimates of the following drug classes were provided: NSAIDs, acetaminophen, local anesthetics and steroids for scalp infiltration and scalp block, gabapentinoids and agonists of adrenal receptors. Conclusions: High-certainty evidence suggests that NSAIDs and acetaminophen may have a moderate effect on reducing post-craniotomy pain 24 h after surgery compared to control and that ropivacaine scalp block may have a bigger impact on reducing post-craniotomy pain 6 h after surgery compared to control. Moderate-certainty evidence indicates that NSAIDs may have a more remarkable effect on reducing post-craniotomy pain 12 h after surgery compared to control. No moderate-to-high-certainty evidence indicates effective treatments for post-craniotomy pain prevention 48 h after surgery.

Robot assisted laser-interstitial thermal therapy with iSYS1 and Visualase: how I do it.

BACKGROUND: Laser-interstitial thermal therapy (LITT) is an ablative treatment based on a surgically implanted laser-emitting catheter to induce a focal ablation of the pathological tissue. The main indications in neurosurgery are primary brain tumors, metastases, radiation necrosis, and pediatric brain tumors. Several approaches have been proposed to implant the laser-emitting catheter, both in frameless and frame-based conditions. METHODS: We report our approach for Robot assisted laser-interstitial thermal therapy of brain lesions with iSYS1 and Visualase (Medtronic). CONCLUSIONS: iSYS1 represents a significant adjunct to LITT procedures and may be safely implemented in routine laser-catheter positioning.

Neurosurgical tools to extend tumor resection in hemispheric low-grade gliomas: conventional and contrast enhanced ultrasonography.

PURPOSE: Pediatric low-grade gliomas (LGGs) are the most frequent solid tumor in childhood. Based on an increasing number of literature reports, maximal safe resection is recommended as the first line of treatment whenever possible. However, distinguishing tumor tissue from the surrounding normal brain is often challenging with infiltrating neoplasms, even with the assistance of intraoperative, microscopic and conventional neuronavigation systems. Therefore, any technique that enhances the detection and visualization of LGGs intraoperatively is certainly desirable. METHODS: In this paper, we reviewed the role of intraoperative conventional ultrasound and contrast-enhanced ultrasound (CEUS) as a tool for extending tumor resection in LGGs. Moreover, our experience with this technology is reported and discussed. RESULTS: Both B-mode and CEUS are helpful in highlighting LGGs, detecting tumor margins and providing additional information such as vascularization, thus improving the safety of a more radical resection. CONCLUSIONS: Although the full potentialities of the method are yet to be explored, intraoperative ultrasound is a promising tool in oncologic surgery and LGG surgery.

Pediatric Hemispheric High-Grade Gliomas and H3.3-G34 Mutation: A Review of the Literature on Biological Features and New Therapeutic Strategies.

Pediatric high-grade glioma (pHGG) encompasses a wide range of gliomas with different genomic, epigenomic, and transcriptomic features. Almost 50% of pHGGs present a mutation in genes coding for histone 3, including the subtype harboring the H3.3-G34 mutation. In this context, histone mutations are frequently associated with mutations in TP53 and ATRX, along with PDGFRA and NOTCH2NL amplifications. Moreover, the H3.3-G34 histone mutation induces epigenetic changes in immune-related genes and exerts modulatory functions on the microenvironment. Also, the functionality of the blood-brain barrier (BBB) has an impact on treatment response. The prognosis remains poor with conventional treatments, thus eliciting the investigation of additional and alternative therapies. Promising molecular targets include PDGFRA amplification, BRAF mutation, EGFR amplification, NF1 loss, and IDH mutation. Considering that pHGGs harboring the H3.3-G34R mutation appear to be more susceptible to immunotherapies (ITs), different options have been recently explored, including immune checkpoint inhibitors, antibody mediated IT, and Car-T cells. This review aims to summarize the knowledge concerning cancer biology and cancer-immune cell interaction in this set of pediatric gliomas, with a focus on possible therapeutic options.

Practical assessment of preoperative functional mapping techniques: navigated transcranial magnetic stimulation and functional magnetic resonance imaging.

Preoperative brain mapping is vital to improve the outcome of patients with tumors located in eloquent areas. While functional magnetic resonance imaging (fMRI) remains the most commonly used preoperative mapping technique, navigated transcranial magnetic stimulation (nTMS) has recently been proposed as a new preoperative method for the clinical and surgical management of such patients. This study aims at evaluating the impact of nTMS as a routine examination and its ultimate contribution to patient outcome. We performed a preliminary prospective study on eight patients harboring a cerebral lesion in eloquent motor areas. Each patient underwent preoperative cortical brain mapping via both fMRI and nTMS; then, we assessed the reliability of both methods by comparing them with intraoperative mapping by direct cortical stimulation (DCS). This study suggests that nTMS was more accurate than fMRI in detecting the true cortical motor area when compared with DCS data, with a mean of deviation ± confidence interval (CI) of 8.47 ± 4.6 mm between nTMS and DCS and of 12.9 ± 5.7 mm between fMRI and DCS (p < 0.05). The results indicated that within the limits of our statistical sample, nTMS was found to be a useful, reliable, and non-invasive option for preoperative planning as well as for the identification of the motor strip; in addition, it usually has short processing times and is very well tolerated by patients, thereby increasing their compliance and possibly improving surgical outcome.

Craniotomy vs. craniectomy for posterior fossa tumors: a prospective study to evaluate complications after surgery.

BACKGROUND: Posterior fossa surgery traditionally implies permanent bone removal. Although suboccipital craniectomy offers an excellent exposure, it could lead to complications. Thus, some authors proposed craniotomy as a valuable alternative to craniectomy. In the present study we compare postoperative complications after craniotomy or craniectomy for posterior fossa surgery. METHODS: We prospectively collected data for a consecutive series of patients who underwent either posterior fossa craniotomy or craniectomy for tumor resection. We divided patients into two groups based on the surgical procedure performed and safety, complication rates and length of hospitalization were analyzed. Craniotomies were performed with Control-Depth-Attachment(®) drill and chisel, while we did craniectomies with perforator and rongeurs. RESULTS: One-hundred-fifty-two patients were included in the study (craniotomy n =100, craniectomy n =52). We detected no dural damage after bone removal in both groups. The total complication rate related to the technique itself was 7 % for the craniotomy group and 32.6 % for the craniectomy group (<0.0001). Pseudomeningocele occurred in 4 % vs. 19.2 % (p =0.0009), CSF leak in 2 % vs. 11.5 % (p =0.006) and wound infection in 1 % vs. 1.9 % (p =0.33), respectively. Post-operative hydrocephalus, a multi-factorial complication which could affect our results, was also calculated and occurred in 4 % of the craniotomy vs. 9.6 % of the craniectomy group (p =0.08). The mean length of in-hospital stay was 9.3 days for the craniotomy group and 11.8 days for the craniectomy group (p =0.10). CONCLUSIONS: The present study suggests that fashioning a suboccipital craniotomy is as effective and safe as performing a craniectomy; both procedures showed similar results in preserving dural integrity, while post-operative complications were fewer when a suboccipital craniotomy was performed.

Different states of stemness of glioblastoma stem cells sustain glioblastoma subtypes indicating novel clinical biomarkers and high-efficacy customized therapies.

BACKGROUND: Glioblastoma (GBM) is the most malignant among gliomas with an inevitable lethal outcome. The elucidation of the physiology and regulation of this tumor is mandatory to unravel novel target and effective therapeutics. Emerging concepts show that the minor subset of glioblastoma stem cells (GSCs) accounts for tumorigenicity, representing the true target for innovative therapies in GBM. METHODS: Here, we isolated and established functionally stable and steadily expanding GSCs lines from a large cohort of GBM patients. The molecular, functional and antigenic landscape of GBM tissues and their derivative GSCs was highlited in a side-by-side comprehensive genomic and transcriptomic characterization by ANOVA and Fisher's exact tests. GSCs' physio-pathological hallmarks were delineated by comparing over time in vitro and in vivo their expansion, self-renewal and tumorigenic ability with hierarchical linear models for repeated measurements and Kaplan-Meier method. Candidate biomarkers performance in discriminating GBM patients' classification emerged by classification tree and patients' survival analysis. RESULTS: Here, distinct biomarker signatures together with aberrant functional programs were shown to stratify GBM patients as well as their sibling GSCs population into TCGA clusters. Of importance, GSCs cells were demonstrated to fully resemble over time the molecular features of their patient of origin. Furthermore, we pointed out the existence of distinct GSCs subsets within GBM classification, inherently endowed with different self-renewal and tumorigenic potential. Particularly, classical GSCs were identified by more undifferentiated biological hallmarks, enhanced expansion and clonal capacity as compared to the more mature, relatively slow-propagating mesenchymal and proneural cells, likely endowed with a higher potential for infiltration either ex vivo or in vivo. Importantly, the combination of DCX and EGFR markers, selectively enriched among GSCs pools, almost exactly predicted GBM patients' clusters together with their survival and drug response. CONCLUSIONS: In this study we report that an inherent enrichment of distinct GSCs pools underpin the functional inter-cluster variances displayed by GBM patients. We uncover two selectively represented novel functional biomarkers capable of discriminating GBM patients' stratification, survival and drug response, setting the stage for the determination of patient-tailored diagnostic and prognostic strategies and, mostly, for the design of appropriate, patient-selective treatment protocols.

Growth factor independence underpins a paroxysmal, aggressive Wnt5aHigh/EphA2Low phenotype in glioblastoma stem cells, conducive to experimental combinatorial therapy.

BACKGROUND: Glioblastoma multiforme (GBM) is an incurable tumor, with a median survival rate of only 14-15 months. Along with heterogeneity and unregulated growth, a central matter in dealing with GBMs is cell invasiveness. Thus, improving prognosis requires finding new agents to inhibit key multiple pathways, even simultaneously. A subset of GBM stem-like cells (GSCs) may account for tumorigenicity, representing, through their pathways, the proper cellular target in the therapeutics of glioblastomas. GSCs cells are routinely enriched and expanded due to continuous exposure to specific growth factors, which might alter some of their intrinsic characteristic and hide therapeutically relevant traits. METHODS: By removing exogenous growth factors stimulation, here we isolated and characterized a subset of GSCs with a "mitogen-independent" phenotype (I-GSCs) from patient's tumor specimens. Differential side-by-side comparative functional and molecular analyses were performed either in vitro or in vivo on these cells versus their classical growth factor (GF)-dependent counterpart (D-GSCs) as well as their tissue of origin. This was performed to pinpoint the inherent GSCs' critical regulators, with particular emphasis on those involved in spreading and tumorigenic potential. Transcriptomic fingerprints were pointed out by ANOVA with Benjamini-Hochberg False Discovery Rate (FDR) and association of copy number alterations or somatic mutations was determined by comparing each subgroup with a two-tailed Fisher's exact test. The combined effects of interacting in vitro and in vivo with two emerging GSCs' key regulators, such as Wnt5a and EphA2, were then predicted under in vivo experimental settings that are conducive to clinical applications. In vivo comparisons were carried out in mouse-human xenografts GBM model by a hierarchical linear model for repeated measurements and Dunnett's multiple comparison test with the distribution of survival compared by Kaplan-Meier method. RESULTS: Here, we assessed that a subset of GSCs from high-grade gliomas is self-sufficient in the activation of regulatory growth signaling. Furthermore, while constitutively present within the same GBM tissue, these GF-independent GSCs cells were endowed with a distinctive functional and molecular repertoire, defined by highly aggressive Wnt5aHigh/EphA2Low profile, as opposed to Wnt5aLow/EphA2High expression in sibling D-GSCs. Regardless of their GBM subtype of origin, I-GSCs, are endowed with a raised in vivo tumorigenic potential than matched D-GSCs, which were fast-growing ex-vivo but less lethal and invasive in vivo. Also, the malignant I-GSCs' transcriptomic fingerprint faithfully mirrored the original tumor, bringing into evidence key regulators of invasiveness, angiogenesis and immuno-modulators, which became candidates for glioma diagnostic/prognostic markers and therapeutic targets. Particularly, simultaneously counteracting the activity of the tissue invasive mediator Wnt5a and EphA2 tyrosine kinase receptor addictively hindered GSCs' tumorigenic and invasive ability, thus increasing survival. CONCLUSION: We show how the preservation of a mitogen-independent phenotype in GSCs plays a central role in determining the exacerbated tumorigenic and high mobility features distinctive of GBM. The exploitation of the I-GSCs' peculiar features shown here offers new ways to identify novel, GSCs-specific effectors, whose modulation can be used in order to identify novel, potential molecular therapeutic targets. Furthermore, we show how the combined use of PepA, the anti-Wnt5a drug, and of ephrinA1-Fc to can hinder GSCs' lethality in a clinically relevant xenogeneic in vivo model thus being conducive to perspective, novel combinatorial clinical application.

Epirubicin exhibits potent anti-tumor activity in an animal model of malignant glioma when administered via controlled-release polymers.

Epirubicin (EPI) has strong cytotoxic activity that makes it a potential candidate for the treatment of malignant gliomas. To minimize toxicity and increase CNS penetration, EPI was incorporated into biodegradable polymers, and its in vitro and in vivo properties were studied. 9L, F98, C6, U251, and EMT-6 cell lines were treated with EPI in vitro and cell viability was measured. Toxicity of EPI/polycarboxyphenoxypropane-sebacic-acid (pCPP:SA) polymers was tested in vivo using F344 rats intracranially implanted with EPI polymers (2-50% by weight). The efficacy of 50% EPI:pCPP:SA polymers was determined in F344 rats intracranially challenged with 9L and treated either simultaneously or 5 days after tumor implantation. The efficacy of 50% EPI:pCCP:SA polymers administered on Day 5 in combination with oral TMZ was determined in rats intracranially challenged with 9L gliosarcoma. EPI was cytotoxic in all cell lines used in vitro. Intracranial implantation of the EPI polymers in rats generated neither local nor systemic toxicity. Animals receiving intracranial EPI on Day 5 had 50% long-term survivors (LTS), which was superior to local EPI delivered on Day 0 (LTS = 12.5%). Animals receiving intracranial EPI in combination with oral TMZ had 75% LTS whereas no other group had LTS. In those EPI treated animals that died before the controls there was evidence of intracranial hemorrhage. Systemic epirubicin resulted in high toxicity levels and early deaths in all the experiments. EPI polymers, alone or in combination with oral TMZ, is an effective therapeutic modality against experimental 9L gliosarcoma.

Image-Guided Biopsy of Intracranial Lesions with a Small Robotic Device (iSYS1): A Prospective, Exploratory Pilot Study.

BACKGROUND: Robotic technologies have been used in the neurosurgical operating rooms for the last 30 yr. They have been adopted for several stereotactic applications and, particularly, image-guided biopsy of intracranial lesions which are not amenable for open surgical resection. OBJECTIVE: To assess feasibility, safety, accuracy, and diagnostic yield of robot-assisted frameless stereotactic brain biopsy with a recently introduced miniaturized device (iSYS1; Interventional Systems Medizintechnik GmbH, Kitzbühel, Austria), fixed to the Mayfield headholder by a jointed arm. METHODS: Clinical and surgical data of all patients undergoing frameless stereotactic biopsies using the iSYS1 robotized system from October 2016 to December 2017 have been prospectively collected and analyzed. Facial surface registration has been adopted for optical neuronavigation. RESULTS: Thirty-nine patients were included in the study. Neither mortality nor morbidity related to the surgical procedure performed with the robot was recorded. Diagnostic tissue samples were obtained in 38 out of 39 procedures (diagnostic yield per procedure was 97.4%). All patients received a definitive histological diagnosis. Mean target error was 1.06 mm (median 1 mm, range 0.1-4 mm). CONCLUSION: The frameless robotic iSYS1-assisted biopsy technique was determined to be feasible, safe, and accurate procedure; moreover, the diagnostic yield was high. The surface matching registration method with computed tomography as the reference image set did not negatively affect the accuracy of the procedure.

A novel robot-guided minimally invasive technique for brain tumor biopsies.

OBJECTIVEAs decisions regarding tumor diagnosis and subsequent treatment are increasingly based on molecular pathology, the frequency of brain biopsies is increasing. Robotic devices overcome limitations of frame-based and frameless techniques in terms of accuracy and usability. The aim of the present study was to present a novel, minimally invasive, robot-guided biopsy technique and compare the results with those of standard burr hole biopsy.METHODSA tubular minimally invasive instrument set was custom-designed for the iSYS-1 robot-guided biopsies. Feasibility, accuracy, duration, and outcome were compared in a consecutive series of 66 cases of robot-guided stereotactic biopsies between the minimally invasive (32 patients) and standard (34 patients) procedures.RESULTSApplication of the minimally invasive instrument set was feasible in all patients. Compared with the standard burr hole technique, accuracy was significantly higher both at entry (median 1.5 mm [range 0.2-3.2 mm] vs 1.7 mm [range 0.8-5.1 mm], p = 0.008) and at target (median 1.5 mm [range 0.4-3.4 mm] vs 2.0 mm [range 0.8-3.9 mm], p = 0.019). The incision-to-suture time was significantly shorter (median 30 minutes [range 15-50 minutes] vs 37.5 minutes [range 25-105 minutes], p < 0.001). The skin incision was significantly shorter (median 16.3 mm [range 12.7-23.4 mm] vs 28.4 mm [range 20-42.2 mm], p = 0.002). A diagnostic tissue sample was obtained in all cases.CONCLUSIONSApplication of the novel instrument set was feasible in all patients. According to the authors' data, the minimally invasive robot-guidance procedure can significantly improve accuracy, reduce operating time, and improve the cosmetic result of stereotactic biopsies.

Brain Tectal Tumors: A Flexible Approach.

BACKGROUND AND IMPORTANCE: Mesencephalic tectal gliomas represent a subset of midbrain tumors, which are more frequent in children than in adults. They usually become symptomatic when causing hydrocephalus by occluding the aqueduct. Because of their slow progression, due to their benign histology, they are characterized by a relatively good prognosis, although hydrocephalus might jeopardize patients' prognosis. Treatment is usually represented by cerebrospinal fluid diversion associated or not with biopsy. CLINICAL PRESENTATION: We report 2 illustrative cases of tectal gliomas in adults where endoscopic third ventriculostomy (ETV) and simultaneous endoscopic biopsy were obtained during the same operation by means of a single burr hole with a flexible endoscope. CONCLUSION: We recommend using this overlooked neurosurgical tool for such cases, since it allows the surgeon to safely perform an ETV, then judge whether biopsy can be done or not, without harming the patient, and possibly achieving an important piece of information (histopathological diagnosis) to manage this subset of oncological patients.

Ultrasound guided mini-invasive tailored approach and intraoperative neurophysiological monitoring: a synergistic strategy for the removal of tumors near the motor cortex. A preliminary experience.

BACKGROUND: The aim of this paper was to evaluate the synergic strategy comprising intraoperative neurophysiological monitoring and ultrasound sonography in terms of clinical motor scores and extent of resection. METHODS: Patients harboring tumors in close relationship with the motor cortex were operated on with image-guided mini-invasive approach and multimodal neurophysiological monitoring. The peculiarity is the partial exposure of the motor cortex and the limited electrophysiological mapping used to search for negative spots. Multimodal neurophysiological monitoring comprised the electrocortical stimulation, somatosensory evoked potentials, motor evoked potentials and subcortical stimulation. Ultrasound sonography guided the tumor removal. The post-op clinical motor scores and the extent of resection were assessed. RESULTS: Twelve patients were operated on with the combined approach and were further analyzed. Six had high grade gliomas, 1 anaplastic astrocytoma, 1 oligodendroglioma, 1 pilocytic astrocytoma and three had metastasis. One out of 12 had a worsening of the motor scores at the last follow-up. The mean extent of resection was 90% ranging from 60% to 100%, but in 9 out of 12 patients, it reached or exceeded 90%. CONCLUSIONS: The synergic strategy comprising intraoperative multimodal neurophysiological monitoring and the ultrasound sonography is feasible in all surgeries. Data are promising in terms of both clinical motor scores and extent of resection. This strategy represents an alternative approach to the treatment of supratentorial tumors, although further studies are necessary to confirm the long-term efficacy of this procedure.

Piezoelectric Surgery for Dorsal Spine.

BACKGROUND: Laminoplasty and laminectomy are 2 common surgical procedures used in treating degenerative and neoplastic diseases of the spinal canal. Routinely used instruments, such as the Kerrison rongeur and high-speed drill, can result in potentially serious complications, such as dural injury and thermal and mechanical damage to neurovascular structures. We adopted piezoelectric bone surgery, which permits a selective cut of mineralized tissues, to perform posterior procedures on the thoracic spine, where the relationship between bone and the spinal cord is critical. The aim of this article was to evaluate the use of piezoelectric surgery for performing dorsal spine laminectomy and laminoplasty. METHODS: The Mectron piezosurgery device was developed for cutting bone with microvibrations that are created by the piezoelectric effect. This instrument allows a safe and precise bone cut, and it is characterized by no heat generation, thus avoiding thermal injury to bone and soft tissues. We used this device to perform 8 laminoplasties for tumors of the dorsal spine and 2 laminectomies for thoracic spinal stenosis in 10 patients. RESULTS: There were no procedure-related intraoperative complications, such as dural injury or damage to neural structures. CONCLUSIONS: The piezoelectric device showed excellent results in terms of safety and precise bone cutting properties when performing posterior surgical procedures in the dorsal spine, where thermal injury produced by the conventionally used drill may damage the spinal cord closer to bony elements.

Advanced Ultrasound Imaging in Glioma Surgery: Beyond Gray-Scale B-mode.

Introduction: Glioma surgery is aimed at obtaining maximal safe tumor resection while preserving or improving patient's neurological status. For this reason, there is growing interest for intra-operative imaging in neuro-oncological surgery. Intra-operative ultrasound (ioUS) provides the surgeon with real-time, anatomical and functional information. Despite this, in neurosurgery ioUS mainly relies only on gray-scale brightness mode (B-mode). Many other ultrasound imaging modalities, such as Fusion Imaging with pre-operative acquired magnetic resonance imaging (MRI), Doppler modes, Contrast Enhanced Ultrasound (CEUS), and elastosonography have been developed and have been extensively used in other organs. Although these modalities offer valuable real-time intra-operative information, so far their usage during neurosurgical procedures is still limited. Purpose: To present an US-based multimodal approach for image-guidance in glioma surgery, highlighting the different features of advanced US modalities: fusion imaging with pre-operative acquired MRI for Virtual Navigation, B-mode, Doppler (power-, color-, spectral-), CEUS, and elastosonography. Methods: We describe, in a step-by-step fashion, the applications of the most relevant advanced US modalities during different stages of surgery and their implications for surgical decision-making. Each US modality is illustrated from a technical standpoint and its application during glioma surgery is discussed. Results: B-mode offers dynamic morphological information, which can be further implemented with fusion imaging to improve image understanding and orientation. Doppler imaging permits to evaluate anatomy and function of the vascular tree. CEUS allows to perform a real-time angiosonography, providing valuable information in regards of parenchyma and tumor vascularization and perfusion. This facilitates tumor detection and surgical strategy, also allowing to characterize tumor grade and to identify residual tumor. Elastosonography is a promising tool able to better define tumor margins, parenchymal infiltration, tumor consistency and permitting differentiation of high grade and low grade lesions. Conclusions: Multimodal ioUS represents a valuable tool for glioma surgery being highly informative, rapid, repeatable, and real-time. It is able to differentiate low grade from high grade tumors and to provide the surgeon with relevant information for surgical decision-making. ioUS could be integrated with other intra-operative imaging and functional approaches in a synergistic manner to offer the best image guidance for each patient.

Local delivery of temozolomide by biodegradable polymers is superior to oral administration in a rodent glioma model.

PURPOSE: Dose-limiting adverse effects of thrombocytopenia and leukopenia prevent augmentation of current temozolomide (TMZ) dosing protocols; therefore, we hypothesized that the direct intracranial delivery of TMZ would lead to improved efficacy in an animal model of malignant glioma in an animal model. METHODS: Temozolomide was incorporated into biodegradable polymers and the active drug was released over 80 h. Intracranial toxicity was assessed in F344 rats and a maximally tolerated dose was not achieved. RESULTS: In vivo drug biodistribution demonstrated that intracranial concentrations of TMZ increased threefold compared with orally delivered TMZ. In a rodent glioma model, animals treated with a single TMZ polymer (50% w/w) had a median survival of 28 days (P < 0.001 vs. controls, P < 0.001 vs. oral treatment), whereas animals treated with oral TMZ had a median survival of 22 days compared to control animals (median survival of 13 days). Animals treated with two TMZ polymers (50% w/w) had a median survival of 92 days (P < 0.001 vs. controls, P < 0.001 vs. oral treatment). The percentage of long-term survivors (LTS) for groups receiving intracranial TMZ ranged from 25 to 37.5%; there were no LTS with oral TMZ treatment. Animals treated with radiation therapy (XRT) and intracranial TMZ (median survival not reached, LTS = 87.5%) demonstrated improved survival compared to those with intracranial TMZ alone (median survival, 41 days; LTS = 37.5%), or oral TMZ and XRT (median survival, 43 days, LTS = 38.9%). CONCLUSIONS: The survival of tumor-bearing animals was improved with local delivery of TMZ compared with systemic administration. XRT in combination with intracranial TMZ did not cause additional toxicity and prolonged the survival even further.

The semisitting position: analysis of the risks and surgical outcomes in a contemporary series of 425 adult patients undergoing cranial surgery.

OBJECTIVE The objective of this study was to analyze the incidence of the primary complications related to positioning or surgery and their impact on neurological outcome in a consecutive series of patients undergoing elective surgery in the semisitting position. METHODS The authors prospectively collected and retrospectively analyzed data from adult patients undergoing elective surgery in the semisitting position for a cranial disease. Patients were managed perioperatively according to a standard institutional protocol, a standardized stepwise positioning, and surgical maneuvers to decrease the risk of venous air embolism (VAE) and other complications. Intraoperative and postoperative complications were recorded. Neurointensive care unit (NICU) length of stay (LOS) and hospital LOS were the intermediate endpoints. Neurological outcome was the primary endpoint as determined by the modified Rankin scale (mRS) score at 6 months after surgery. RESULTS Four hundred twenty-five patients were included in the analysis. VAE occurred in 90 cases (21%) and it made no significant statistical difference in NICU LOS, hospital LOS, and neurological outcome. No complication was directly related to the semisitting position, although 46 patients (11%) experienced at least 1 surgery-related complication and NICU LOS and hospital LOS were significantly prolonged in this group. Neurological outcome was significantly worse for patients with complications (p < 0.0001). CONCLUSIONS Even in the presence of intraoperative VAE, the semisitting position was not related to an increased risk of postoperative deficits and can represent a safe additional option for the benefit of specific surgical and patient needs.

Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-like Cells.

Brain invasion by glioblastoma determines prognosis, recurrence, and lethality in patients, but no master factor coordinating the invasive properties of glioblastoma has been identified. Here we report evidence favoring such a role for the noncanonical WNT family member Wnt5a. We found the most invasive gliomas to be characterized by Wnt5a overexpression, which correlated with poor prognosis and also discriminated infiltrating mesenchymal glioblastoma from poorly motile proneural and classical glioblastoma. Indeed, Wnt5a overexpression associated with tumor-promoting stem-like characteristics (TPC) in defining the character of highly infiltrating mesenchymal glioblastoma cells (Wnt5aHigh). Inhibiting Wnt5a in mesenchymal glioblastoma TPC suppressed their infiltrating capability. Conversely, enforcing high levels of Wnt5a activated an infiltrative, mesenchymal-like program in classical glioblastoma TPC and Wnt5aLow mesenchymal TPC. In intracranial mouse xenograft models of glioblastoma, inhibiting Wnt5a activity blocked brain invasion and increased host survival. Overall, our results highlight Wnt5a as a master regulator of brain invasion, specifically TPC, and they provide a therapeutic rationale to target it in patients with glioblastoma. Cancer Res; 77(4); 996-1007. ©2016 AACR.

Lysis of intracerebral hematoma with stereotactically implanted tissue plasminogen activator polymers in a rabbit model.

OBJECT: Currently no adequate surgical treatment exists for spontaneous intracerebral hemorrhage (ICH). Implantable polymers can be used effectively to deliver therapeutic agents to the local site of the pathological process, thus reducing adverse systemic effects. The authors report the use of stereotactically implanted polymers loaded with tissue plasminogen activator (tPA) to induce lysis of ICH in a rabbit model. METHODS: Ethylene vinyl acetate (EVAc) polymers were loaded with bovine serum albumin (BSA) only or with BSA plus tPA. In vitro pharmacokinetic (three polymers) and thrombolysis (12 polymers) studies were performed. For the in vivo study, 12 rabbits were fixed in a stereotactic frame, and 0.2 ml of clotted autologous blood was injected into the right frontal lobe parenchyma. After 20 minutes, control BSA polymers were stereotactically implanted at the hemorrhage site in six rabbits, and experimental BSA plus tPA polymers were implanted in six rabbits. Animals were killed at 3 days, and blood clot volume was assessed. The pharmacokinetic study showed release of 146 ng of tPA over 3 days. The tPA activity correlated with in vitro thrombolysis. In the in vivo study, the six animals treated with tPA polymers had a mean (+/- standard error of the mean [SEM]) thrombus volume of 1.43 +/- 0.29 mm3 at 3 days, whereas the six animals treated with blank (BSA-only) polymers had a mean (+/- SEM) thrombus volume of 19.99 +/- 3.74 mm3 (p < 0.001). CONCLUSIONS: Ethylene vinyl acetate polymers release tPA over the course of 3 days. Stereotactic implantation of tPA-loaded EVAc polymers significantly reduced ICH volume. Polymers loaded with tPA may be useful clinically for lysis of ICH without the side effects of systemic administration of tPA.