Multimodality Structural and Functional Monitoring in Brain Tumor Surgery: The Role of IONM and IOUS.

Brain tumor surgery represents the pinnacle of technical and technological advances in the neurosurgery. The goal remains optimized extent of resection with preservation of neurological function. The benefit of a multimodal structural and functional intra-operative monitoring approach is to improve the ability of the surgeon to achieve the goal of optimized surgical resection. Despite significant technological advances, challenges in defining tumor and functional neural tissue interface remain a significant barrier. The opportunity to address this challenge, however, presents us with an exciting path ahead.

Intraoperative comparison between strain elastography and pre-operative MRI features in high-grade gliomas using fusion imaging: a pilot study.

OBJECTIVE: To compare the elastographic patterns of high-grade gliomas (HGGs) solid portions and those of adjacent healthy brain parenchyma, on intraoperative ultrasound, with magnetic resonance image (MRI) characteristics. METHODS: Clinical records and images of HGGs patients, operated between June and December 2018, were retrospectively reviewed. Fusion images were used to compare preoperative gadolinium-enhanced T1-weighted MRI/fluid-attenuated inversion recovery images (Gd-T1 MRI/FLAIR) to intraoperative strain elastography (SE). FLAIR/Gd-T1 MRI images were used to define: enhancement patterns (absent/whole lesion/peripheral) and lesions' characteristics (primary and secondary pattern, further subdivided in solid/necrotic/cystic/infiltrating). HGGs SE patterns were categorized as homogeneous/inhomogeneous, while lesions' primary and secondary patterns as stiff/intermediate/elastic. The SE motive of neighboring healthy brain parenchyma was defined similarly. RESULTS: 18 patients (M:F, 11:7; mean age: 53 years) harboring 14 glioblastomas (77.8%, GBMs) and 4 anaplastic astrocytomas (22.2%, AAs) were compared. GBMs typically enhanced peripherally and had a primary necrotic pattern (78.6% and 64.3%, respectively), while AAs did not enhance and were solid (75% both) at T1-Gd MRI and FLAIR images. At SE AAs had a homogeneous stiff primary pattern, whereas the majority of GBMs primary patterns were heterogeneous (85.7%) and intermediate (78.6%). CONCLUSIONS: Three major SE patterns defined HGGs and adjacent healthy brain parenchyma. SE patterns varied accordingly to HGG histotypes and Gd-T1 MRI/FLAIR characteristics.

Ultrasound-Guided Mechanical High-Intensity Focused Ultrasound (Histotripsy) Through an Acoustically Permeable Polyolefin-Based Cranioplasty Device.

Histotripsy is a non-thermal focused ultrasound therapy in development for the non-invasive ablation of cancerous tumors. Intracranial histotripsy has been limited by significant pressure attenuation through the skull, requiring large, complex array transducers to overcome this effect. OBJECTIVE: Recently, a biocompatible, polyolefin-based cranioplasty device was developed to allow ultrasound (US) transmission into the intracranial space with minimal distortion. In this study, we investigated the in vitro feasibility of applying US-guided histotripsy procedures across the prosthesis. METHODS: Pressure waveforms and beam profiles were collected for single- and multi-element histotripsy transducers. Then, high-speed optical images of the bubble cloud with and without the prosthesis were collected in water and tissue-mimicking agarose gel phantoms. Finally, red blood cell (RBC) tissue phantom and excised brain tissue experiments were completed to test the ablative efficacy across the prosthesis. RESULTS: Single element tests revealed increased pressure loss with increasing transducer frequency and increasing transducer-to-prosthesis angle. Array transducer measurements at 1 MHz showed average pressure losses of >50% across the prosthesis. Aberration correction recovered up to 18% of the pressure lost, and high-speed optical imaging in water, agarose gels, and RBC phantoms demonstrated that histotripsy bubble clouds could be generated across the prosthesis at pulse repetition frequencies of 50-500 Hz. Histologic analysis revealed a complete breakdown of brain tissue treated across the prosthesis. Conclusion & Significance: Overall, the results of this study demonstrate that the cranial prosthesis may be used as an acoustic window through which intracranial histotripsy can be applied under US guidance without the need for large transcranial array transducers.

The Immunomodulatory Effects of Fluorescein-Mediated Sonodynamic Treatment Lead to Systemic and Intratumoral Depletion of Myeloid-Derived Suppressor Cells in a Preclinical Malignant Glioma Model.

Fluorescein-mediated sonodynamic therapy (FL-SDT) is an extremely promising approach for glioma treatment, resulting from the combination of low-intensity focused ultrasound (FUS) with a sonosensitizer. In the present study, we evaluated the efficacy and immunomodulation of SDT with fluorescein as the sonosensitizer in immunocompetent GL261 glioma mice for the first time. In vitro studies demonstrated that the exposure of GL261 cells to FL-SDT induced immunogenic cell death and relevant upregulation of MHC class I, CD80 and CD86 expression. In vivo studies were then performed to treat GL261 glioma-bearing mice with FL-SDT, fluorescein alone, or FUS alone. Perturbation of the glioma-associated macrophage subset within the immune microenvironment was induced by all the treatments. Notably, a relevant depletion of myeloid-derived suppressor cells (MDSCs) and concomitant robust infiltration of CD8+ T cells were observed in the SDT-FL-treated mice, resulting in a significant radiological delay in glioma progression and a consequent improvement in survival. Tumor control and improved survival were also observed in mice treated with FL alone (median survival 41.5 days, p > 0.0001 compared to untreated mice), reflecting considerable modulation of the immune microenvironment. Interestingly, a high circulating lymphocyte-to-monocyte ratio and a very low proportion of MDSCs were predictive of better survival in FL- and FL-SDT-treated mice than in untreated and FUS-treated mice, in which elevated monocyte and MDSC frequencies correlated with worse survival. The immunostimulatory potential of FL-SDT treatment and the profound modulation of most immunosuppressive components within the microenvironment encouraged the exploration of the combination of FL-SDT with immunotherapeutic strategies.

Theranostics in the vasculature: bioeffects of ultrasound and microbubbles to induce vascular shutdown.

Ultrasound-triggered microbubbles destruction leading to vascular shutdown have resulted in preclinical studies in tumor growth delay or inhibition, lesion formation, radio-sensitization and modulation of the immune micro-environment. Antivascular ultrasound aims to be developed as a focal, targeted, non-invasive, mechanical and non-thermal treatment, alone or in combination with other treatments, and this review positions these treatments among the wider therapeutic ultrasound domain. Antivascular effects have been reported for a wide range of ultrasound exposure conditions, and evidence points to a prominent role of cavitation as the main mechanism. At relatively low peak negative acoustic pressure, predominantly non-inertial cavitation is most likely induced, while higher peak negative pressures lead to inertial cavitation and bubbles collapse. Resulting bioeffects start with inflammation and/or loose opening of the endothelial lining of the vessel. The latter causes vascular access of tissue factor, leading to platelet aggregation, and consequent clotting. Alternatively, endothelium damage exposes subendothelial collagen layer, leading to rapid adhesion and aggregation of platelets and clotting. In a pilot clinical trial, a prevalence of tumor response was observed in patients receiving ultrasound-triggered microbubble destruction along with transarterial radioembolization. Two ongoing clinical trials are assessing the effectiveness of ultrasound-stimulated microbubble treatment to enhance radiation effects in cancer patients. Clinical translation of antivascular ultrasound/microbubble approach may thus be forthcoming.

Role of Advanced Hemodynamic Ultrasound Evaluation in the Differential Diagnosis of Middle Cerebral Artery Stenosis: Introducing Morphological Criteria.

OBJECTIVE: The aim of the work described here was to determine the possible impact of the new technique advanced hemodynamic ultrasound evaluation (AHUSE) in identification of severe intracranial stenosis. Transcranial Doppler (TCD) and transcranial color-coded Doppler (TCCD) provide reliable velocimetric data, the indirect analysis of which allows us to obtain information on the patency of vessels and assumed stenosis range. However, very tight stenoses (>95%) cannot be detected with velocimetric criteria because of spectrum drops and the absence of high velocities, so that the right curve of the Spencer equation cannot be solved. Likewise, high velocities are not detected when analyzing morphologically long stenosis. Furthermore, the current classifications based on velocimetric criteria do not provide any categorization on stenoses with multiple acceleration points (MAPs). METHODS: With this Technical Note we aim to introduce, in addition to velocimetric criteria, more morphological criteria based on TCCD with the algorithm of AHUSE to optimize the characterization of intracranial stenosis (IS). TCCD-AHUSE relies on intensity-based next-generation techniques and can be used to identify IS with MAPs and simultaneously perform a morphological assessment of the stenosis length. RESULTS: We introduce a new technical ultrasound (U) approach that we tested in a sample of four different types of stenoses combining velocimetric data and AHUSE using Esaote Microvascularization (MicroV) technique to the M1 tract of the middle cerebral artery (MCA). CONCLUSION: The authors believe that a multiparametric evaluation is more sensitive and supports the clinician by introducing the morphological concept, not just the velocimetric concept, to differentiate the IS pattern of MCA. The potential for developing a diagnostic/prognostic algorithm is discussed.

Surface Cranial Ultrasound: The Natural Heir to X-Ray for the Screening of Skull Deformities in Infants.

PURPOSE: Volumetric tomography (3D-CT) is currently considered the gold standard for the diagnosis of craniosynostosis, but its use as the first-line examination for cranial deformities is a topic of debate, because of skull X-ray radiation and low sensitivity and specificity. Cranial ultrasound is an emerging noninvasive radiation-free alternative, but its diagnostic accuracy still needs confirmation. MATERIALS AND METHODS: The present prospective study included 350 infants with skull deformities, who underwent cranial ultrasound as the first-line examination, followed by 3D-CT if the echography results was positive or unclear. If the results were negative, infants underwent physical treatment and follow-up. To evaluate ultrasound reliability, we focused on cases that underwent both the index test and the gold standard and performed a double-blind comparison of the echography and 3D-CT results. RESULTS: Ultrasound documented patent sutures in 293 infants and 9 had inconclusive results. The 293 ultrasound-negative infants were followed clinically: all improved, except 28 that underwent 3D-CT. In all of these cases, 3D-CT confirmed the ultrasonography results (no false negatives). 48 infants showed premature suture closure and underwent 3D-CT: 47 were confirmed (true positive), 1 was false positive. The sensitivity was 100%, the specificity was 99.7%, the positive and negative predictive values were 97.9% and 100%, respectively, the accuracy was 99.7%, and the diagnostic test evaluation was conclusive. CONCLUSION: The study documented the high sensitivity and specificity of echography for the diagnosis of craniosynostosis in a referral center, with better results being achieved before 6 months of age. Major limitations are the loss of diagnostic significance as the child grows and the learning curve needed. The advantages are avoidance of radiation and chance to evaluate the brain at the same time.

Ultrasound Elastography in Neurosurgery: Current Applications and Future Perspectives.

BACKGROUND: Similar to clinical palpation, Ultrasound elastography (USE) helps distinguish between tissues by providing information on their elasticity. While it has been widely explored and has been applied to many body organs, USE has not been studied as extensively for application in neurosurgery. The current systematic review was performed to identify articles related to the use of interoperative USE in neurosurgery. METHODS: Search included MEDLINE(R) database. Only original peer-reviewed full-text articles were included. No language or publication year restrictions were imposed. Two independent reviewers assessed the search results for relevance. The identified articles were screened by title, abstract, and full-text review. RESULTS: Seventeen articles were included in the qualitative analysis and 13 articles were related to oncology, epilepsy (n = 3), and spine (n = 1). In oncology, USE was found useful in defining tumor stiffness, aiding surgical planning, detecting residual tumors, discriminating between tumor and brain tissue, and differentiating between different tumors. In epilepsy, USE could improve the detection of epileptogenic foci, thereby enhancing the prospect of complete and safe resection. The application in spinal surgery was limited to demonstrating that a compressed spinal cord is stiffer than the decompressed one. CONCLUSIONS: USE was found to be a safe, quick, portable, and economic tool that was a useful intraoperative adjunct to provide information corresponding to a variety of neurosurgical diseases, at different stages of surgery. This review describes the current intraoperative neurosurgical applications of USE, the concept of elasticity, and different USE modalities as well as the technical challenges, limitations, and possible future implications.

A High-Fidelity Agar-Based Phantom for Ultrasonography-Guided Brain Biopsy Simulation: A Novel Training Prototype with Visual Feedback.

OBJECTIVE: A novel agar-based phantom was developed and assessed for ultrasonography (USG)-guided brain biopsy training. The phantom provides visual cues combined with sonologic cues, allowing multimodal training. Impact of multimodal training is evaluated through pretraining and posttraining trials. METHODS: Twenty-five participants were divided based on experience with USG-based procedures into familiar (≥3 procedures performed in the past) (n = 14) and unfamiliar (<3 procedures performed) (n = 11). Agar phantoms with an opaque top and transparent middle layer were constructed in transparent glass bowls, each having 12 embedded targets. Participants underwent 2 supervised trials of USG-guided biopsy with aluminum foil covering the glass bowls, eliminating visual cues. Between 2 trials, participants underwent unsupervised self-training on a phantom without foil cover, providing visual cues. Performance was measured through insonation efficiency (EfI), biopsy efficiency (EfB), efficiency score (Ef), error score (Er), and performance score (PS). Scores were compared between and within the 2 groups before and after training. Impact of the self-training session on subjective comfort levels with the procedure was assessed through feedback forms. RESULTS: Familiars had better pretraining EfB, Ef, Er, and PS (P < 0.001) compared with unfamiliars. After training, both performed similarly on all metrics. After training, familiars improved only in EfI (P = 0.001), with the unfamiliars showing significance in all metrics except EfI. CONCLUSIONS: Simulation and phantom-based models can never supplant training through supervised skill application in vivo but our model supplements training by enabling technical skill acquisition, especially for beginners in USG-guided brain biopsy.

Multiparametric Intraoperative Ultrasound in Oncological Neurosurgery: A Pictorial Essay.

Intraoperative ultrasound (ioUS) is increasingly used in current neurosurgical practice. This is mainly explained by its affordability, handiness, multimodal real-time nature, and overall by its image spatial and temporal resolution. Identification of lesion and potential residue, analysis of the vascularization pattern, and characterization of the nature of the mass are only some of the advantages that ioUS offers to guide safe and efficient tumor resection. Technological advances in ioUS allow to achieve both structural and functional imaging. B-mode provides high-resolution visualization of the lesion and of its boundaries and relationships. Pioneering modes, such as contrast-enhanced ultrasound (CEUS), ultrasensitive Doppler, and elastosonography, are tools with great potential in characterizing different functional aspects of the lesion in a qualitative and quantitative manner. As already happening for many organs and pathologies, the combined use of different US modalities offers new insights in a multiparametric fashion. In this study, we present the potential of our multiparametric approach for ioUS during neuro-oncological surgery. In this effort, we provide a pictorial essay focusing on the most frequent pathologies: low- and high-grade gliomas, meningiomas, and brain metastases.

Ultrasounds induce blood-brain barrier opening across a sonolucent polyolefin plate in an in vitro isolated brain preparation.

The blood-brain barrier (BBB) represents a major obstacle to the delivery of drugs to the central nervous system. The combined use of low-intensity pulsed ultrasound waves and intravascular microbubbles (MB) represents a promising solution to this issue, allowing reversible disruption of the barrier. In this study, we evaluate the feasibility of BBB opening through a biocompatible, polyolefin-based plate in an in vitro whole brain model. Twelve in vitro guinea pig brains were employed; brains were insonated using a planar transducer with or without interposing the polyolefin plate during arterial infusion of MB. Circulating MBs were visualized with an ultrasonographic device with a linear probe. BBB permeabilization was assessed by quantifying at confocal microscopy the extravasation of FITC-albumin perfused after each treatment. US-treated brains displayed BBB permeabilization exclusively in the volume under the US beam; no significant differences were observed between brains insonated with or without the polyolefin plate. Control brains not perfused with MB did not show signs of FITC-albumin extravasation. Our preclinical study suggests that polyolefin cranial plate could be implanted as a skull replacement to maintain craniotomic windows and perform post-surgical repeated BBB opening with ultrasound guidance to deliver therapeutic agents to the central nervous system.

Cranial sonolucent prosthesis: a window of opportunity for neuro-oncology (and neuro-surgery).

INTRODUCTION: Ultrasound (US) is a versatile technology, able to provide a real-time and multiparametric intraoperative imaging, and a promising way to treat neuro-oncological patients outside the operating room. Anyhow, its potential is limited both in imaging and therapeutic purposes by the existence of the bone shielding. To enhance the spectrum of uses, our group has designed a dedicated US-translucent cranial prosthesis. Herein, we provide the proof of concept of a long-term US-based follow-up and a potential bedside therapeutic exploitation of US. METHODS: The prosthesis was first implanted in a cadaveric specimen to record any issue related to the cranioplasty procedure. Hence, the device was implanted in a patient undergoing surgery for a multi-recurrent anaplastic oligodendroglioma. US multiparametric scans through the device were acquired at 3, 6, 9, and 30 months after the procedure. RESULTS: The prosthesis could be modeled and implanted through ordinary instruments, with no concerns over safety and feasibility. Trans-prosthesis multiparametric US imaging was feasible, with image quality comparable to intraoperative US. Long-term follow-up in an outpatient setting was possible with no adverse events. Trans-prosthesis mechanical interaction with microbubbles was also feasible during follow-up. CONCLUSIONS: This report provides the first proof of concept for a potential breakthrough in the management of neuro-oncological patients. Indeed, through the implantation of an artificial acoustic window, the road is set to employ US both for a more dynamic long-term follow-up, and for US-guided therapeutic applications.

Artificial intelligence-enhanced intraoperative neurosurgical workflow: current knowledge and future perspectives.

INTRODUCTION: Artificial intelligence (AI) and machine learning (ML) augment decision-making processes and productivity by supporting surgeons over a range of clinical activities: from diagnosis and preoperative planning to intraoperative surgical assistance. We reviewed the literature to identify current AI platforms applied to neurosurgical perioperative and intraoperative settings and describe their role in multiple subspecialties. EVIDENCE ACQUISITION: A systematic review of the literature was conducted following the PRISMA guidelines. PubMed, EMBASE, and Scopus databases were searched from inception to December 31st, 2020. Original articles were included if they: presented AI platforms implemented in perioperative, intraoperative settings and reported ML models' performance metrics. Due to the heterogeneity in neurosurgical applications, a qualitative synthesis was deemed appropriate. The risk of bias and applicability of predicted outcomes were assessed using the PROBAST tool. EVIDENCE SYNTHESIS: Forty-one articles were included. All studies evaluated a supervised learning algorithm. A total of 10 ML models were described; the most frequent were neural networks (N.=15) and tree-based models (N.=13). Overall, the risk of bias was medium-high, but applicability was considered positive for all studies. Articles were grouped into four categories according to the subspecialty of interest: neuro-oncology, spine, functional and other. For each category, different prediction tasks were identified. CONCLUSIONS: In this review, we summarize the state-of-art applications of AI for the intraoperative augmentation of neurosurgical workflows across multiple subspecialties. ML models may boost surgical team performances by reducing human errors and providing patient-tailored surgical plans, but further and higher-quality studies need to be conducted.

Hybrid Workshops During the COVID-19 Pandemic-Dawn of a New Era in Neurosurgical Learning Platforms.

BACKGROUND: During the COVID-19 pandemic, disruption of surgical hands-on training has hampered the skills acquisition by budding neurosurgeons. Online and virtual classrooms have not been able to substitute the hands-on experience and learning via direct interaction with senior colleagues. To overcome these challenges, we organized a hybrid workshop where simulation-based learning modules, and direct and virtual interaction with surgeons during live surgeries or didactic lectures were utilized to help delegates in understanding the nuances of neurosurgery. METHODS: A 3-day hybrid workshop was held in March 2021, which was attended by 133 delegates. A structured questionnaire was utilized to record their feedback. RESULTS: An overwhelming majority of the respondents (94.1%, n = 64) found hybrid conferences to be better than an online conference. Most of the respondents (88.3%, n = 60) rated the utility of direct face-to-face interaction to be more satisfying as compared with online interaction with faculty during a webinar. Again, many the respondents (86.8%, n = 59) believed that similar hybrid events will be the new normal given the current situation of COVID-19 pandemic. A large majority (88.2%, n = 60) of the respondents reported that they will prefer a hybrid event over an online conference. CONCLUSIONS: In this era of the COVID-19 pandemic, "hybrid" microneurosurgery workshops offer unique opportunities to enhance surgical skills acquisition by hands-on simulation-based learning and observing live surgical demonstrations, apart from 2-way interactions with experts under one roof. This may be a stepping stone for what lies ahead in the future of neurosurgical training.

Sonodynamic therapy for gliomas.

INTRODUCTION: Glioma remains incurable and a life limiting disease with an urgent need for effective therapies. Sonodynamic therapy (SDT) involves systemic delivery of non-toxic chemical agents (sonosensitizers) that accumulate in tumor cells or environment and are subsequently activated by exposure to low-frequency ultrasound to become cytotoxic agents. Herein, we discuss proposed mechanisms of action of SDT and provide recommendation for future research and clinical applications of SDT for gliomas. METHODS: Review of literature of SDT in glioma cell cultures and animal models published in Pubmed/MEDLINE before January, 2021. RESULTS: Different porphyrin and xanthene derivatives have proven to be effective sonosensitizers. Generation of reactive oxygen species and free radicals from water pyrolysis or sonosensitizers, or physical destabilization of cell membrane, have been identified as mechanisms of SDT leading to cell death. Numerous studies across glioma cell lines using various sonosensitizers and ultrasound parameters have documented tumoricidal effects of SDT. Studies in small animal glioma xenograft models have also consistently documented that SDT is associated with improved tumor control and longer survival of animals treated with SDT while avoiding damage of surrounding brain. There are no clinical trials completed to date regarding safety and efficacy of SDT in patients harboring gliomas, but some are beginning. CONCLUSIONS: Pre-clinical studies cell cultures and animal models indicate that SDT is a promising treatment approach for gliomas. Further studies should define optimal sonication parameters and sonosensitizers for gliomas. Clinical trials of SDT in patients harboring gliomas and other malignant brain tumors are currently underway.

Development of and Gathering Validity Evidence for a Theoretical Test in Contrast-Enhanced Ultrasound.

Contrast-enhanced ultrasound (CEUS) is an imaging modality applied in a broad field of medical specialties for diagnostic uses, guidance during biopsy procedures and ablation therapies and sonoporation therapy. Appropriate training and assessment of theoretical and practical competencies are recommended before practicing CEUS, but no validated assessment tools exist. This study was aimed at developing a theoretical multiple-choice question-based test for core CEUS competencies and gathering validity evidence for the test. An expert team developed the test via a Delphi process. The test was administered to medical doctors with varying CEUS experience, and the results were used to evaluate test items, internal-consistency reliability, ability to distinguish between different proficiency levels and to establish a pass/fail score. Validity evidence was gathered according to Messick's framework. The final test with 47 test items could distinguish between operators with and without CEUS experience with acceptable reliability. The pass/fail score led to considerable risk of false positives and negatives. The test may be used as an entry test before learning practical CEUS competencies but is not recommended for certification purposes because of the risk of false positives and negatives.

From Focused Ultrasound Tumor Ablation to Brain Blood Barrier Opening for High Grade Glioma: A Systematic Review.

BACKGROUND: Focused Ultrasound (FUS) is gaining a therapeutic role in neuro-oncology considering its novelty and non-invasiveness. Multiple pre-clinical studies show the efficacy of FUS mediated ablation and Blood-Brain Barrier (BBB) opening in high-grade glioma (HGG), but there is still poor evidence in humans, mainly aimed towards assessing FUS safety. METHODS: With this systematic review our aim is, firstly, to summarize how FUS is proposed for human HGG treatment. Secondly, we focus on future perspectives and new therapeutic options. Using PRISMA 2020 guidelines, we reviewed case series and trials with description of patient characteristics, pre- and post-operative treatments and FUS outcomes. We considered nine case series (five about tumor ablation and four about BBB opening) with FUS-treated HGG patients between 1991 and 2021. RESULTS: Sixty-eight patients were considered in total, mostly males (67.6%), with a mean age of 50.5 ± 15.3 years old. Major complication rates were found in the tumor ablation group (26.1%). FUS has been rarely applied for direct tumoral ablation in human HGG patients with controversial results, but at the best of current studies, FUS-mediated BBB opening is showing good results with very low complication rates, paving the way for a new reliable technique to improve local chemotherapy delivery and antitumoral immune response. CONCLUSIONS: FUS can become a complementary technique to surgical resection and standard radiochemotherapy in recurrent HGG. Ongoing trials could provide in the near future more data on FUS-mediated BBB opening impact on progression-free survival, overall survival and potential drug-delivery capacities.

Intracranial Sonodynamic Therapy With 5-Aminolevulinic Acid and Sodium Fluorescein: Safety Study in a Porcine Model.

BACKGROUND: Sonodynamic therapy (SDT) is an emerging ultrasound-based treatment modality for malignant gliomas which combines ultrasound with sonosensitizers to produce a localized cytotoxic and modulatory effect. Tumor-specificity of the treatment is achieved by the selective extravasation and accumulation of sonosensitizers in the tumor-bearing regions. The aim of this study is to demonstrate the safety of low-intensity ultrasonic irradiation of healthy brain tissue after the administration of FDA-approved sonosensitizers used for SDT in experimental studies in an in vivo large animal model. METHODS: In vivo safety of fluorescein (Na-Fl)- and 5 aminolevulinic acid (5-ALA)-mediated low-intensity ultrasound irradiation of healthy brain parenchyma was assessed in two sets of four healthy swine brains, using the magnetic resonance imaging (MRI)-guided Insightec ExAblate 4000 220 kHz system. After administration of the sonosensitizers, a wide fronto-parietal craniotomy was performed in pig skulls to allow transmission of ultrasonic beams. Sonication was performed on different spots within the thalamus and periventricular white matter with continuous thermal monitoring. Sonication-related effects were investigated with MRI and histological analysis. RESULTS: Post-treatment MRI images acquired within one hour following the last sonication, on day one, and day seven did not visualize any sign of brain damage. On histopathology, no signs of necrosis or apoptosis attributable to the ultrasonic treatments were shown in target areas. CONCLUSIONS: The results of the present study suggest that either Na-FL or 5-ALA-mediated sonodynamic therapies under MRI-guidance with the current acoustic parameters are safe towards healthy brain tissue in a large in vivo model. These results further support growing interest in clinical translation of sonodynamic therapy for intracranial gliomas and other brain tumors.

The "STARS-CASCADE" Study: Virtual Reality Simulation as a New Training Approach in Vascular Neurosurgery.

OBJECTIVE: Surgical clipping has become a relatively rare procedure in comparison to endovascular exclusion of cerebral aneurysms. Consequently, there is a declining number of cases where young neurosurgeons can practice clipping. For this reason, we investigated the application of a new 3-dimensional (3D) simulation and rehearsal device, Surgical Theater, in vascular neurosurgery. METHODS: We analyzed data of 20 patients who underwent surgical aneurysm clipping. In 10 cases, Surgical Theater was used to perform the preoperative 3D planning (CASCADE group), while traditional imaging was used in the other cases (control group). Preoperative 3D simulation was performed by 4 expert and 3 junior neurosurgeons (1 fellow, 2 residents). During postoperative debriefings, expert surgeons explained the different aspects of the operation to their younger colleagues in an interactive way using the simulator. Questionnaires were given to the surgeons to get qualitative feedback about the simulator, and the junior surgeons' performance at simulator was also analyzed. RESULTS: There were no differences in surgery outcomes, complications, and surgical duration (P > 0.05) between the 2 groups. Senior neurosurgeons performed similarly when operating at the simulator as compared with in the operating room, while junior neurosurgeons improved their performance at the simulator after the debriefing session (P < 0.005). CONCLUSIONS: Surgical Theater proved to be realistic in replicating vascular neurosurgery scenarios for rehearsal and simulation purposes. Moreover, it was shown to be useful for didactic purposes, allowing young neurosurgeons to take full advantage and learn from senior colleagues to become familiar with this demanding neurosurgical subspecialty.