Preliminary Validation of FoRCaSco: A New Grading System for Cerebral and Cerebellar Cavernomas.

OBJECTIVE: Surgical indications for cerebral cavernous malformations (CCMs) remain significantly center- and surgeon-dependent; available grading systems are potentially limited, as they do not include epileptologic and radiologic data. Several experienced authors proposed a new grading system for CCM and the first group of patients capable of providing its statistical validation was analyzed. METHODS: A retrospective series of 289 CCMs diagnosed between 2008 and 2021 was collected in a shared anonymous database among 9 centers. The new grading system ranges from -1 to 10. For each patient with cortical and cerebellar cavernous malformations the grading system was applied, and a retrospective outcome analysis was performed. We proposed a score of 4 as a cutoff for surgical indication. RESULTS: Operated patients with a score ≥4 were grouped with non-operated patients with a score <4, as they constituted the group that received correct treatment according to the new grading system. Patients with a score ≥4, who underwent surgery and had an improved outcome, were compared to patients with a score ≥4 who were not operated (P = 0.04), and to patients with a score <4 who underwent surgery (P < 0.001). CONCLUSIONS: This preliminary statistical analysis demonstrated that this new grading would be applicable in surgical reality. The cutoff score of 4 correctly separated the patients who could benefit from surgical intervention from those who would not. The outcome analysis showed that the treated patients in whom the grading system has been correctly applied have a better outcome than those in whom the grading system has not been applied.

Minimally Invasive Subfrontal Approach: How to Make it Safe and Effective from the Olfactory Groove to the Mesial Temporal Lobe.

BACKGROUND: Different surgical approaches have been developed to manage lesions of the anterior and middle skull base areas. Frontal, pterional, bifrontal, and fronto-orbito-zygomatic approaches are traditionally used to reach these regions. With advancements in the neurosurgical field, skull opening should be simple and as minimally invasive as possible, tailored on the surgical corridor to the target. The supraorbital approach and the "keyhole" concept have been introduced and popularized by Axel Perneczky starting from 1998 and are now considered a part of everyday practice. The extended possibilities of this surgical route, considering the reachable targets and surgical limits, are described and systematically analyzed, including a description of the salient surgical anatomy, presenting different illustrative cases. METHODS AND RESULTS: Different illustrative cases are presented and discussed to underline the potentials and limits of the minimally invasive subfrontal approach (MISFA) and the possibilities to tailoring the craniotomy on the basis of the targets: extra-axial lesions with different localizations (anterior roof of the orbit, olfactory groove, tuberculum sellae, medial third of the sphenoid wing, anterior and posterior clinoid process), deeper intra-axial lesions (gyrus rectus, medial temporal lobe-uncus-amygdala-anterior hippocampus), and vascular lesions (anterior communicating aneurysm). Each case has been preoperatively planned considering the anatomical and radiologic features and using virtual simulation software to tailor the best possible corridor to reach the surgical target. CONCLUSIONS: The MISFA is a safe multicorridor approach that can be used efficiently to manage lesions of the anterior and middle skull base areas with extremely low approach-related morbidity.

An international call for a new grading system for cerebral and cerebellar cavernomas.

Surgical indications for cerebral cavernous malformations remain significantly center- and surgeon-dependent. Available grading systems are potentially limited, as they do not include epileptological and radiological data. A novel grading system is proposed for supratentorial and cerebellar cavernomas: it considers neuroradiological features (bleeding, increase in size), neurological status (focal deficits and seizures), location of the lesion and age of the patient. The score ranges from -1 to 10; furthermore, surgery should be considered when a score of 4 or higher is present. Based on neuroradiological characteristics, 0 points are assigned if the CCM is stable in size at different neuroradiological controls, 1 point if there is an increase in volume during follow-up, 2 points if intra- or extra-lesional bleeding <1 cm is present and 3 points if the CCM produced a hematoma >1 cm. Regarding focal neurological deficits, 0 points are assigned if absent and 2 points if present. For seizures, 0 points are assigned if absent, 1 point if present, but controlled by medications, and 2 points if drug resistant. We considered the site of the CCM, and in case of deep-seated lesions in a critical area (basal ganglia, thalamus) 1 point (-1) is subtracted, while for subcortical or deep cerebellar lesions 0 points are assigned, for CCMs in a cortical critical area 1 point is assigned and in case of lesions in cortical not in critical area or superficial cerebellar area, 2 points are assigned. As far as age is concerned, 0 points are assigned for patients older than 50 years and 1 point for patients younger than 50. In conclusion, a novel grading for surgical decision making in cerebral cavernomas, based on the experience of selected neurosurgeons, basic scientists, and patients, is suggested with the aim of further improving and standardizing the treatment of CCMs. The aim of this paper was also to call for both retrospective and prospective multicenter studies with the aim of testing the efficacy of the grading system in different centers.

Post-operative management of brain metastases: GRADE-based clinical practice recommendations on behalf of the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

PURPOSE: To perform a systematic review of the current level of evidence on post-operative management following brain metastasectomy (namely: adjuvant stereotactic radiosurgery, whole brain radiotherapy or observation), and to propose a GRADE-based dedicated recommendation to inform Radiation Oncologists' clinical practice. METHODS: A panel of expert Radiation Oncologists from the Italian Association of Radiotherapy and Clinical Oncology had defined the search question per the PICO methodology. Electronic databases were independently screened; the Preferred Reporting Items for Systematic Reviews and Meta-Analyses was adopted. The individual and pooled hazard ratios with 95% confidence intervals (CI), as well as the pooled risk ratio (RR) were calculated using a fixed- or random-effects model. RESULTS: Eight full-texts were retrieved: six retrospective studies and two randomized clinical trials. Outcomes of benefit and damage were analyzed for SRS + observation (PICO A) and SRS + WBRT. SRS allowed for increased rates of local control when compared to both observation and WBRT, while evidence was less conclusive for distant brain control, leptomeningeal disease control and overall survival. In the SRS, the incidence of severe radionecrosis was higher as compared to WBRT, despite neurocognitive deterioration rates were lower. Overall, SRS seems to favorably compare with observation and whole brain RT, despite the level of evidence for the recommendation was low and very low, respectively. CONCLUSION: Despite low level of evidence, the panel concluded that the risk/benefit ratio probably favors adjuvant SRS as compared to the observation and whole brain RT as adjuvant treatments following brain metastasectomy (5 votes/5 participants, 100% attendance).

Posttraumatic Vertebral Arteriovenous Fistula: A Lifeline from Tetraplegia?

BACKGROUND: Vertebral artery (VA) rupture is a rare condition that occurs about in 0.5% of cervical trauma. The management of our case was complicated by a spinal epidural hematoma (SEH) leading to worsening neurologic deficits. Only 1 similar case has been reported before in the literature. CASE DESCRIPTION: We report the case of a 37-year-old victim of a serious car accident. Shortly after admission to the emergency department, she developed weakness in all 4 limbs and sensory deficit below T6 level. Cervical spine computed tomography scan revealed an SEH from C1 to T3. Computed tomography angiography scan showed rupture of the left VA at C3 level, with a posttraumatic vertebral arteriovenous fistula at the same level, draining in the epidural venous plexus and to the right jugular internal vein. Immediately after embolization of the left VA, we performed a cervical decompression from C2 to C7. Three months after surgery the patient had a full recovery. CONCLUSIONS: No guidelines exist to treat this situation. We propose consequential steps to treat a posttraumatic cervical SEH with evidence of VA rupture.

Surgical Management of Brain Cavernous Malformations.

Surgical removal of accessible lesions is the only direct therapeutic approach for cerebral cavernous malformations (CCMs). The approach should be carefully evaluated according to clinical, anatomical, and neuroradiological assessment in order to both select the patient and avoid complications. In selected cases, a quantitative anatomical study with a preoperative simulation of surgery could be used to plan the operation. Neuronavigation, ultrasound, and neurophysiologic monitoring are generally required respectively to locate the CCMs and to avoid critical areas. The chapter describes all the possible surgical approaches for supratentorial, infratentorial, deep seated and brain stem CCMs. In any case before performing surgery, the physicians should always consider the benign nature of the lesions and the absolute necessity to avoid not only neurological deficits, but also a neuropsychological impairment that could affect the quality of life of the patients.

High-Definition 3-Dimensional Exoscope for 5-ALA Glioma Surgery: 3-Dimensional Operative Video.

A 54-yr-old man presented with the radiological recurrence of a glioblastoma at the level of the left anterior cingulate gyrus, 46 mo after first surgery, which had been complicated by bone flap infection. Due to the relatively small recurrence, the long survival, and the good neurological status, surgery was warranted. A new, high-definition (4 K) and 3-dimensional exoscope (ORBEYE; Sony Olympus Medical Solutions Inc, Tokyo, Japan) was used during the surgical approach and throughout tumor removal, which was aided by five-aminolevulinic acid (5-ALA) derived fluorescence. The postoperative course was characterized by supplementary motor area syndrome, which quickly improved, leading to a discharge home 1 wk after surgery. Histological examination confirmed a wild-type (WT) IDH1/2, MGMT (DNA repair enzyme O6-methylguanine-DNA methyltransferase) methylated glioblastoma with a proliferative index focally as high as 20%. He is now being considered for a second-line treatment. As recently reported for spinal surgery,1 we believe this technology has significant potential for its small dimension (which can provide optimal positioning even in ergonomically challenging positions), ease of movement, and image quality, including 5-ALA fluorescence. The patient's consent was obtained for publication.

Second line treatment of recurrent glioblastoma with sunitinib: results of a phase II study and systematic review of literature.

INTRODUCTION: Second line treatment of recurrent or progressive glioblastoma multiforme (GBM) is not standardized. Anti-angiogenic strategies with tyrosine-kinase inhibitors have been tested with conflicting results. We tested the association of sunitinib plus irinotecan (CPT-11) in a phase II trial in terms of response rate (RR) and 6-months progression-free survival (6-PFS). We also reviewed the clinical evidence from all the trials with sunitinib in this setting published to date and summarized it in a meta-analysis. EVIDENCE ACQUISITION: Patients with GBM recurrent or progressive after surgery and standard chemo-radiotherapy were treated with sunitinib 37.5 mg/day for 14 days + CPT-11 125 mg/sqm every 14 days in a Simon's two-stage phase II study. A summary data meta-analysis was performed to establish the 6-PFS in patients with ascertained histological diagnosis of GBM treated with sunitinib. EVIDENCE SYNTHESIS: Six patients were enrolled in the stage I of the trial and only one had a stable disease. The overall response rate was 17% and 6-PFS was not reached. Therefore, the trial was stopped early for insufficient activity. All toxicities were grade 1-2. Systematic review of the literature identified 9 studies (including the present one) for a total of 221 patients. Pooled 6-PFS was 15.1% (95% CI: 9.0-24.4). Subgroup analysis by different schedule revealed a 6-PFS of 17.5% (95% CI: 10.3-28.1) in the weekly setting which was consistent across all the studies (I2=0%, P=0.66) and a pooled 6-PFS of 12.7% (95% CI: 4.9-29.1) in the daily setting with a substantial amount of heterogeneity (I2=65%, P=0.01). CONCLUSIONS: Results of this trial and those of the systematic review indicate that, compared to conventional chemotherapy or bevacizumab, sunitinib has insufficient activity in the setting of recurrent GBM. Better patient's molecular stratification for second-line treatment in GBM is warranted.

Comparison of Allogeneic and Syngeneic Rat Glioma Models by Using MRI and Histopathologic Evaluation.

Research in neurooncology traditionally requires appropriate in vivo animal models, on which therapeutic strategies are tested before human trials are designed and proceed. Several reproducible animal experimental models, in which human physiologic conditions can be mimicked, are available for studying glioblastoma multiforme. In an ideal rat model, the tumor is of glial origin, grows in predictable and reproducible patterns, closely resembles human gliomas histopathologically, and is weakly or nonimmunogenic. In the current study, we used MRI and histopathologic evaluation to compare the most widely used allogeneic rat glioma model, C6-Wistar, with the F98-Fischer syngeneic rat glioma model in terms of percentage tumor growth or regression and growth rate. In vivo MRI demonstrated considerable variation in tumor volume and frequency between the 2 rat models despite the same stereotactic implantation technique. Faster and more reproducible glioma growth occurred in the immunoresponsive environment of the F98-Fischer model, because the immune response is minimized toward syngeneic cells. The marked inability of the C6-Wistar allogeneic system to generate a reproducible model and the episodes of spontaneous tumor regression with this system may have been due to the increased humoral and cellular immune responses after tumor implantation.

Solid lipid nanoparticles by coacervation loaded with a methotrexate prodrug: preliminary study for glioma treatment.

AIM: Methotrexate-loaded biocompatible nanoparticles were tested for preliminary efficacy in glioma treatment. MATERIALS & METHODS: Behenic acid nanoparticles, prepared by the coacervation method, were loaded with the ester prodrug didodecylmethotrexate, which was previously tested in vitro against glioblastoma human primary cultures. Nanoparticle conjugation with an ApoE mimicking chimera peptide was performed to obtain active targeting to the brain. RESULTS & CONCLUSION: Biodistribution studies in healthy rats assessed the superiority of ApoE-conjugated formulation, which was tested on an F98/Fischer glioma model. Differences were observed in tumor growth rate (measured by MRI) between control and treated rats. In vitro tests on F98 cultured cells assessed their susceptibility to treatment, with consequent apoptosis, and allowed us to explain the apoptosis observed in glioma models.

A neuro-oncologic challenge: the case of a large, aggressive, malignant meningioma of the skull base with paranasal sinus involvement.

BACKGROUND: Malignant meningiomas, rare tumors that account for approximately 1%-3% of all meningioma, have high recurrence, morbidity, and mortality rate and a particularly poor outcome. Surgical excision followed by adjuvant radiotherapy is the current approach for the treatment of these tumors. METHODS: In the case reported, the disease, characterized by a high proliferative index (Ki67 60%-70%), was treated with endoscopic surgery limited to the extracranial portion; then the patient underwent radiotherapy, on the residual tumor volume, to a total dose of 66 Gy delivered in 33 fractions (2 Gy/fraction) by helical intensity-modulated radiation therapy with image-guided radiotherapy daily checks (tomotherapy). RESULTS: Two and a half years after the treatment, the patient is alive and a partial response is maintained. The patient is healthy overall with grade I fatigue and grade II hearing loss as late toxicity (Common Terminology Criteria for Adverse Events 4.1). CONCLUSIONS: Within a multidisciplinary approach, new radiotherapy techniques confirm their effectiveness and reliability for the treatment of malignant meningioma.

Positive-charged solid lipid nanoparticles as paclitaxel drug delivery system in glioblastoma treatment.

Paclitaxel loaded solid lipid nanoparticles (SLN) of behenic acid were prepared with the coacervation technique. Generally, spherical shaped SLN with mean diameters in the range 300­600 nm were obtained. The introduction of charged molecules, such as stearylamine and glycol chitosan into the formulation allowed to obtain positive SLN with Zeta potential in the 8-20 mV range and encapsulation efficiency in the 25­90% range.Blood­brain barrier (BBB) permeability, tested in vitro through hCMEC/D3 cells monolayer, showed a significantly increase in the permeation of Coumarin-6, used as model drug, when vehicled in SLN. Positive-charged SLN do not seem to enhance permeation although stearylamine-positive SLN resulted the best permeable formulation after 24 h.Cytotoxicity studies on NO3 glioblastoma cell line demonstrated the maintenance of cytotoxic activity of all paclitaxel-loaded SLN that was always unmodified or greater compared with free drug. No difference in cytotoxicity was noted between neutral and charged SLN.Co-culture experiments with hCMEC/D3 and different glioblastoma cells evidenced that, when delivered in SLN, paclitaxel increased its cytotoxicity towards glioblastoma cells.