The role of preoperative [11C]methionine PET in defining tumor-related epilepsy and predicting short-term postoperative seizure control in temporal lobe low-grade gliomas.

OBJECTIVE: Surgery is the mainstay of treatment for low-grade glioma (LGG)-related epilepsy. However, the goal of achieving both oncological radical resection and seizure freedom can be challenging. PET with [11C]methionine (MET) has been recently introduced in clinical practice for the management of patients with LGGs, not only to monitor the response to treatments, but also as a preoperative tool to define the metabolic tumor extent and to predict tumor grading, type, and prognosis. Still, its role in defining tumor-related epilepsy and postoperative seizure outcomes is limited. The aim of this preliminary study was to investigate the role of MET PET in defining preoperative seizure characteristics and short-term postoperative seizure control in a cohort of patients with newly diagnosed temporal lobe low-grade gliomas (tLGGs). METHODS: Patients with newly diagnosed and histologically proven temporal lobe grade 2/3 gliomas (2021 WHO CNS tumor classification) who underwent resection at the authors' institution between July 2011 and March 2021 were included in this retrospective study. MET PET images were acquired, fused with MRI scans, and qualitatively and semiquantitatively analyzed. Any eventual PET/MRI involvement of the temporomesial area, seizure characteristics, and 1-year seizure outcomes were reported. RESULTS: A total of 52 patients with tLGGs met the inclusion criteria. MET PET was positive in 41 (79%) patients, with a median metabolic tumor volume of 14.56 cm3 (interquartile range [IQR] 6.5-28.2 cm3). The median maximum and mean tumor-to-background ratio (TBRmax, TBRmean) were 2.24 (IQR 1.58-2.86) and 1.53 (IQR 1.37-1.70), respectively. The metabolic tumor volume was found to be related to the presence of seizures at disease onset, but only in noncodeleted tumors (p = 0.014). Regarding patients with uncontrolled seizures at surgery, only the temporomesial area PET involvement showed a statistical correlation both in the univariate (p = 0.058) and in the multivariate analysis (p = 0.030). At 1-year follow-up, seizure control was correlated with MET PET-derived semiquantitative data. Particularly, higher TBRmax (p = 0.0192) and TBRmean (p = 0.0128) values were statistically related to uncontrolled seizures 1 year after surgery. CONCLUSIONS: This preliminary study suggests that MET PET may be used as a preoperative tool to define seizure characteristics and outcomes in patients with tLGGs. These findings need to be further validated in larger series with longer epileptological follow-ups.

Supramaximal resection: retrospective study on IDH-wildtype Glioblastomas based on the new RANO-Resect classification.

BACKGROUND: The prognostic value of the extent of resection in the management of Glioblastoma is a long-debated topic, recently widened by the 2022 RANO-Resect Classification, which advocates for the resection of the non-enhancing disease surrounding the main core of tumors (supramaximal resection, SUPR) to achieve additional survival benefits. We conducted a retrospective analysis to corroborate the role of SUPR by the RANO-Resect Classification in a single center, homogenous cohort of patients. METHODS: Records of patients operated for WHO-2021 Glioblastomas at our institution between 2007 and 2018 were retrospectively reviewed; volumetric data of resected lesions were computed and classified by RANO-Resect criteria. Survival and correlation analyses were conducted excluding patients below near-total resection. RESULTS: 117 patients met the inclusion criteria, encompassing 45 near-total resections (NTR), 31 complete resections (CR), and 41 SUPR. Median progression-free and overall survival were 11 and 15 months for NTR, 13 and 17 months or CR, 20 and 24 months for SUPR, respectively (p < 0.001), with inverse correlation observed between survival and FLAIR residual volume (r -0.28). SUPR was not significantly associated with larger preoperative volumes or higher rates of postoperative deficits, although it was less associated with preoperative neurological deficits (OR 3.37, p = 0.003). The impact of SUPR on OS varied between MGMT unmethylated (HR 0.606, p = 0.044) and methylated (HR 0.273, p = 0.002) patient groups. CONCLUSIONS: Results of the present study support the validity of supramaximal resection by the new RANO-Resect classification, also highlighting a possible surgical difference between tumors with methylated and unmethylated MGMT promoter.

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.

Predictive Factors of Long-Term Neurologic Outcome and Progression-Free Survival in Intramedullary Spinal Cord Tumors: A 10-year Single-Center Cohort Study and Review of the Literature.

BACKGROUND: Intramedullary spinal cord tumors (IMSCTs) are a rare subgroup of neoplasms, encompassing both benign, slow-growing masses, and malignant lesions; radical surgical excision represents the cornerstone of treatment for such pathologies regardless of histopathology, which, on the other hand, is a known predictor of survival and neurologic outcome postsurgery. The present study aims to investigate the relevance of other factors in predicting survival and long-term functional outcomes. METHODS: We conducted a review of current literature on functional outcomes of IMSCTs, as well as a 10-years prospective analysis of a wide cohort of patients with diagnosis of IMSCTs who underwent surgical resection at our institution. RESULTS: Our series encompasses 60 patients with IMSCTS, among which 36 ependymomas, 6 cavernous angiomas, 5 hemangioblastomas, 6 WHO Grade I-IV astrocytomas, 3 intramedullary spinal metastases and 4 miscellaneous tumors. GTR was achieved in 76,67% of patients, with high preoperative McCormick grade, syringomyelia and changes at neurophysiologic monitoring being the strongest predictors at multivariate analysis (P = 0.0027, P = 0.0017 and P = 0.001 respectively). CONCLUSIONS: Consistently with literature, preoperative neurologic function is the most important factor predicting long-term functional outcome (0.17, CI 0.069-0.57 with P = 0.0018), advocating for early surgery in the management of IMSCTs, whereas late complications such as myelopathy and neuropathic pain were present regardless of preoperative function.

Minimally invasive microsurgical decompression of the lumbar spine using a novel robotised digital microscope: A preliminary experience.

BACKGROUND: The operative microscope (OM) represents, to date, the standard for neurosurgical procedures. However, new technologies have been proposed during the latest years to overcome its limitations, from high-quality exoscopes to complex robotised visualisation systems. We report our preliminary experience with a novel digital robotised microscope, the BHS RoboticScope (RS), for minimally invasive spinal surgery. METHODS: We employed the RS in five consecutive patients who underwent bilateral lumbar spine decompression through a monolateral approach. Patient outcomes, device technical characteristics and the surgeon's personal perspectives have been evaluated. RESULTS: No complications occurred. All procedures were concluded without switching to the microscope. Image quality, lightning, depth perception and freedom of movement were judged satisfactory as compared to the standard microscope. CONCLUSION: The easy maneuverability and the high quality of pictures provided by the RS device improve the surgeon's comfort in deep fields, representing an effective option for minimally invasive spinal procedures.

Radiosurgery of limited brain metastases from primary solid tumor: results of the randomized phase III trial (NCT02355613) comparing treatments executed with a specialized or a C-arm linac-based platform.

BACKGROUND: Comparative prospective data regarding different radiosurgery (SRS) modalities for treating brain metastases (BMs) from solid tumors are not available. To investigate with a single institute phase III randomized trial whether SRS executed with linac (Arm-B) is superior to a dedicated multi-source gamma-ray stereotactic platform (Arm-A). METHODS: Adults patients with 1-4 BMs from solid tumors up to 30 mm in maximum diameter were randomly assigned to arms A and B. The primary endpoint was cumulative incidence of symptomatic (grade 2-3) radionecrosis (CIRN). Secondary endpoints were local progression cumulative incidence (CILP), distant brain failure, disease-free survival (DFS), and overall survival (OS). RESULTS: A total of 251 patients were randomly assigned to Arm-A (121) or Arm-B (130). The 1-year RN cumulative incidence was 6.7% in whole cohort, 3.8% (95% CI 1.9-7.4%) in Arm-B, and 9.3% (95% CI 6.2-13.8%) in the Arm-A (p = 0.43). CIRN was influenced by target volume irradiated only for the Arm-A (p << 0.001; HR 1.36 [95% CI 1.25-1.48]). Symptomatic RN occurred in 56 cases at a median time of 10.3 months (range 1.15-54.8 months), 27 in the Arm-B at a median time of 15.9 months (range 4.9-54.8 months), and 29 in the Arm-A at a median time of 6.9 months (1.2-32.3 months), without statistically significant differences between the two arms. No statistically significant differences were recorded between the two arms in CILP, BDF, DFS or OS. The mean beam-on time to deliver SRS was 49.0 ± 36.2 min in Arm-A, and 3.1 ± 1.6 min in Arm-B. CONCLUSIONS: Given the technical differences between the treatment platforms investigated in this single-institution study, linac-based SRS (Arm-B) did not lead to significantly lower grade 2-3 RN rates versus the multi-source gamma-ray system (Arm-A) in a population of patients with limited brain metastases of small volume. No significant difference in local control was observed between both arms. For Arm-B, the treatment delivery time was significantly lower than for Arm-A. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02355613.

Multimodal Treatments for Brain Metastases from Renal Cell Carcinoma: Results of a Multicentric Retrospective Study.

The aim of this study was to evaluate the clinical outcomes of a large series of brain metastatic renal cell carcinoma (BMRCC) patients treated in three Italian centers. METHODS: A total of 120 BMRCC patients with a total of 176 lesions treated were evaluated. Patients received surgery plus postoperative HSRS, single-fraction SRS, or hypofractionated SRS (HSRS). Local control (LC), brain distant failure (BDF), overall survival (OS), toxicities, and prognostic factors were assessed. RESULTS: The median follow-up time was 77 months (range 16-235 months). Surgery plus HSRS was performed in 23 (19.2%) cases, along with SRS in 82 (68.3%) and HSRS in 15 (12.5%). Seventy-seven (64.2%) patients received systemic therapy. The main total dose and fractionation used were 20-24 Gy in single fraction or 32-30 Gy in 4-5 daily fractions. Median LC time and 6 month and 1, 2 and 3 year LC rates were nr, 100%, 95.7% ± 1.8%, 93.4% ± 2.4%, and 93.4% ± 2.4%. Median BDF time and 6 month and 1, 2 and 3 year BDF rates were n.r., 11.9% ± 3.1%, 25.1% ± 4.5%, 38.7% ± 5.5%, and 44.4% ± 6.3%, respectively. Median OS time and 6 month and 1, 2 and 3 year OS rates were 16 months (95% CI: 12-22), 80% ± 3.6%, 58.3% ± 4.5%, 30.9% ± 4.3%, and 16.9% ± 3.6, respectively. No severe neurological toxicities occurred. Patients with a favorable/intermediate IMDC score, a higher RCC-GPA score, an early occurrence of BMs from primary diagnosis, absence of EC metastases, and a combined local treatment (surgery plus adjuvant HSRS) had a better outcome. CONCLUSIONS: SRS/HSRS is proven to be an effective local treatment for BMRCC. A careful evaluation of prognostic factors is a valid step to manage the optimal therapeutic strategy for BMRCC patients.

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.

Sonodynamic Therapy for the Treatment of Intracranial Gliomas.

High-grade gliomas are the most common and aggressive malignant primary brain tumors. Current therapeutic schemes include a combination of surgical resection, radiotherapy and chemotherapy; even if major advances have been achieved in Progression Free Survival and Overall Survival for patients harboring high-grade gliomas, prognosis still remains poor; hence, new therapeutic options for malignant gliomas are currently researched. Sonodynamic Therapy (SDT) has proven to be a promising treatment combining the effects of low-intensity ultrasound waves with various sound-sensitive compounds, whose activation leads to increased immunogenicity of tumor cells, increased apoptotic rates and decreased angiogenetic potential. In addition, this therapeutic technique only exerts its cytotoxic effects on tumor cells, while both ultrasound waves and sensitizing compound are non-toxic per se. This review summarizes the present knowledge regarding mechanisms of action of SDT and currently available sonosensitizers and focuses on the preclinical and clinical studies that have investigated its efficacy on malignant gliomas. To date, preclinical studies implying various sonosensitizers and different treatment protocols all seem to confirm the anti-tumoral properties of SDT, while first clinical trials will soon start recruiting patients. Accordingly, it is crucial to conduct further investigations regarding the clinical applications of SDT as a therapeutic option in the management of intracranial gliomas.

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-CT-MADE" Study: Advanced Rehearsal and Intraoperative Navigation for Skull Base Tumors.

BACKGROUND: Skull base meningiomas represent a challenge for neurosurgeons, and the procedures are typically performed by experienced neurosurgeons, thus limiting resident training. A new simulation and rehearsal device can be used as an aid for senior surgeons during these operations and serve as a training tool for junior surgeons. METHODS: Forty patients harboring an anterior/middle fossa meningioma were recruited. Surgical Theater, a rehearsal/simulation platform, was used for preoperative planning and intraoperative 3D navigation on 20 patients (CT-MADE group), while the remaining (control group) underwent a traditional navigation. Qualitative comparisons between the 2 groups were made with regard to surgical procedure and patient outcome. Satisfaction questionnaires were completed by expert neurosurgeons and residents to assess the overall usefulness of the platform. Furthermore, the surface of the simulated craniotomy performed during the planning was compared with the one actually performed during surgery in order to evaluate the reliability of the planning. RESULTS: No differences between the 2 groups were found (surgery duration: P = 0.4; visual impairment: P = 0.56). Both residents and senior neurosurgeons enjoyed using the platform for intraoperative navigation and planning; simulated craniotomies were significantly smaller as compared with the real ones (P = 0.009), probably because it was not intuitive to depict the exact margins of the operculum with the platform. CONCLUSION: Surgical Theater helped residents to improve their anatomic and procedural comprehension and was deemed as a useful aid to safely perform some demanding neurosurgical procedures, by both senior and junior surgeons.