Neurooncology

Peginterferon alfa-2a for cystic craniopharyngioma treatment

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Peginterferon alfa-2a for cystic craniopharyngioma treatment

J.Sales-Llopis

Neurosurgery Department, General University Hospital Alicante, Spain

Craniopharyngiomas, especially their cystic forms, pose unique management challenges due to their proximity to critical neurovascular structures. Intracystic therapies offer a minimally invasive alternative to repeated surgical interventions. Over the past decade, interferon-alfa-2a/2b emerged as a viable intracystic treatment due to its anti-proliferative and immune-modulating properties, coupled with low toxicity. However, discontinuation of commercial availability prompted the search for alternatives.

Hedrich et al. describes a retrospective case series, including five patients with intracystic peginterferon alfa-2a for cystic craniopharyngioma treatment according to an innovative care protocol. After initial CP cyst aspiration, peginterferon alfa-2a was injected once per week via an Ommaya reservoir for 6 weeks followed by response assessment with MRI.

Patients’ age ranged from 4 to 54 years (four patients <12 years, one adult patient). Intracystic therapy with peginterferon alfa-2a was tolerated well by all five individuals without any major toxicities and resulted in cyst shrinkage in all of the five patients. The importance of a permeability study prior to commencing intracystic therapy became apparent in one patient who suffered from cyst leakage.

Intracystic treatment with peginterferon alfa-2a was found to be a tolerable and efficacious treatment modality in patients with cystic craniopharyngioma. This experience warrants further research with a larger number of patients with measurement of long-term efficacy and safety outcomes 1).

The authors propose peginterferon alfa-2a, a pegylated form with extended half-life and established safety profile in other indications, as a substitute, presenting a retrospective case series evaluating its feasibility and safety.

Study Design and Methodology

– Design: Retrospective case series

– Sample: 5 patients (age 4–54; 4 children, 1 adult)

– Protocol: After initial cyst aspiration, peginterferon alfa-2a was administered weekly for 6 weeks via an Ommaya reservoir.

– Follow-up: MRI for response assessment

– Pre-treatment: Permeability study was highlighted as essential following one adverse case of leakage.

🔎 Strengths:

– Innovative use of peginterferon alfa-2a to fill a therapeutic gap.

– Uniform protocol across cases.

– Clear documentation of safety and early efficacy.

– Broad age range increases generalizability.

⚠️ Limitations:

– Very small sample size (n=5) limits statistical validity.

– Retrospective nature introduces potential bias and lacks standardized outcome metrics.

– Short-term follow-up; no data on recurrence, endocrine impact, or long-term survival.

– No comparator group (e.g., standard interferon alfa-2a or surgery-only) limits interpretation of relative efficacy.

Results

– Safety: No major toxicities reported in any patient.

– Efficacy: Cyst shrinkage achieved in all five patients.

– Complication: One patient experienced leakage, underscoring the need for a permeability test.

The data supports the hypothesis that peginterferon alfa-2a is a safe and potentially effective intracystic agent in this context.

Discussion and Clinical Relevance

This study provides preliminary real-world evidence that peginterferon alfa-2a can serve as an effective intracystic treatment option for cystic craniopharyngiomas, particularly important in the wake of discontinued access to interferon alfa-2a. The lack of significant toxicity is encouraging, especially in pediatric patients.

However, due to the small number of cases and lack of long-term outcome data, the findings should be interpreted as hypothesis-generating rather than practice-changing. Further research in prospective, multi-institutional trials with larger cohorts is warranted.

Conclusion Hedrich et al. offer a promising alternative approach for managing cystic craniopharyngiomas using peginterferon alfa-2a. The treatment appears feasible, safe, and effective in the short term. Yet, the study’s limitations — particularly its size and retrospective design — mean that broader validation is essential before widespread clinical adoption.

Comparative Analysis of Intracystic Treatments

Peginterferon alfa-2a vs Bleomycin vs Radioisotopes

Feature/Agent Peginterferon alfa-2a Bleomycin Radioisotopes (e.g., P-32, Y-90)
Mechanism of Action Immunomodulatory and antiproliferative Cytotoxic antibiotic causing DNA strand breaks Beta radiation causing localized cyst wall necrosis
Dosing Protocol Weekly x6 via Ommaya Multiple instillations (e.g., 4–6 doses over weeks) Single or repeated instillation; dosimetry-based
Age Use Pediatric and adult Caution in young children due to neurotoxicity Generally avoided in children <5–6 years old
Safety Profile Excellent short-term tolerability in small series Risk of chemical meningitis, neurotoxicity Risk of CSF leak, radiation necrosis, hypothalamic damage
Key Risks Cyst leakage (1 case in 5); minimal toxicity Seizures, necrosis if drug leaks to parenchyma Radiation exposure to critical adjacent structures
Regulatory Access Off-label, emerging use Widely available Often restricted, requires radiopharmacy services
Onset of Response Gradual shrinkage over weeks Moderate to rapid Rapid but with potential delayed adverse effects
Imaging Follow-up MRI after 6 weeks MRI at regular intervals Imaging + dosimetry (CT/SPECT) required
Long-Term Data Limited (new approach, case series only) Moderate, decades of use Available, esp. from Europe, but often in outdated protocols
Procedure Requirements Ommaya reservoir; permeability test recommended Ommaya reservoir or catheter Ommaya + radiation safety protocols

Summary Recommendations

Agent Advantages Disadvantages
Peginterferon alfa-2a Favorable safety, non-cytotoxic, off-label alternative to IFN-α2a Limited experience, unclear long-term outcomes
Bleomycin Effective and accessible; longer track record Neurotoxicity risk if leakage occurs; more systemic side effects
Radioisotopes Potent and often effective with fewer instillations Technically demanding; radiation risks; contraindicated in very young children

When to Consider Each Treatment?

* Peginterferon alfa-2a → Ideal for younger children or when minimal toxicity is essential. Requires close monitoring and permeability testing. * Bleomycin → Suitable where experience exists with its use. Effective but requires caution regarding leakage and systemic toxicity. * Radioisotopes → Best reserved for specialized centers with radiation safety protocols and older pediatric or adult patients with refractory cysts.

.

🧠 Flowchart Logic

Is the patient under 5 years old?

→ Yes → ❌ Avoid radioisotopes

→ No → ✅ Radioisotopes may be considered

Is radiation facility & radiopharmacy available?

→ Yes → Consider radioisotopes

→ No → Proceed to next

Is cyst accessible with Ommaya and permeability confirmed?

→ No → ❌ Intracystic therapy not recommended

→ Yes → Proceed to next

Is neurotoxicity a major concern (e.g., very young child, hypothalamic proximity)?

→ Yes → ✅ Prefer Peginterferon alfa-2a

→ No → Proceed to next

Institutional experience with bleomycin?

→ Yes → Consider bleomycin

→ No → Consider peginterferon alfa-2a

1)

Hedrich C, Patel P, Haider L, Taylor T, Lau E, Hook R, Dorfer C, Roessler K, Stepien N, Lippolis MA, Schned H, Koeller C, Mayr L, Azizi AA, Peyrl A, Lopez BR, Lassaletta A, Bennett J, Gojo J, Bartels U. Feasibility, tolerability, and first experience of intracystic treatment with peginterferon alfa-2a in patients with cystic craniopharyngioma. Front Oncol. 2024 Jul 10;14:1401761. doi: 10.3389/fonc.2024.1401761. PMID: 39050573; PMCID: PMC11266088.

Subarachnoid hemorrhage treatment research

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He et al. aim to investigate whether Dental Pulp Stem Cells can improve early brain injury after subarachnoid hemorrhage, and explore the mechanisms. In the study, they utilized the endovascular perforation method to establish a subarachnoid hemorrhage mouse model and investigated whether DPSCs administered via tail vein injection could improve early brain injury after subarachnoid hemorrhage. Furthermore, they used hemin-stimulated HT22 cells to simulate neuronal cell injury induced by SAH and employed a co-culture approach to examine the effects of DPSCs on these cells. To gain insights into the potential mechanisms underlying the improvement of SAH-induced EBI by DPSCs, they conducted bioinformatics analysis. Finally, they further validated the findings through experiments. In vivo experiments, they found that DPSCs administration improved neurological dysfunction, reduced brain edema, and prevented neuronal apoptosis in SAH mice. Additionally, they observed a decrease in the expression level of miR-26a-5p in the cortical tissues of SAH mice, which was significantly increased following intravenous injection of DPSCs. Through bioinformatics and luciferase reporter assay, they confirmed the target relationship between miR-26a-5p and PTEN. Moreover, we demonstrated that DPSCs exerted neuroprotective effects by modulating the miR-26a-5p/PTEN/AKT pathway. The study demonstrates that DPSCs can improve EBI after SAH through the miR-26a-5p/PTEN/AKT pathway, laying a foundation for the application of DPSCs in subarachnoid hemorrhage treatment. These findings provide a theoretical basis for further investigating the therapeutic mechanisms of DPSCs and developing novel subarachnoid hemorrhage treatment research strategies 1).

Critical Review of He et al.: Investigating the Therapeutic Potential of Dental Pulp Stem Cells in Early Brain Injury After Subarachnoid Hemorrhage

Introduction

The study by He et al. explores whether Dental Pulp Stem Cells (DPSCs) can mitigate early brain injury (EBI) following subarachnoid hemorrhage (SAH) and investigates the underlying mechanisms. The authors utilize a well-established endovascular perforation method to induce SAH in mice and assess the therapeutic efficacy of DPSCs administered via tail vein injection. Additionally, in vitro experiments using hemin-stimulated HT22 cells provide mechanistic insights, particularly in relation to the miR-26a-5p/PTEN/AKT signaling pathway.

Strengths of the Study

Robust Animal Model: The use of the endovascular perforation model is a significant strength, as it closely mimics human SAH pathophysiology, including intracranial pressure dynamics and delayed cerebral ischemia.

Comprehensive Methodological Approach: The combination of in vivo and in vitro models strengthens the validity of the findings. The authors systematically explore neuronal apoptosis, brain edema, and neurological function in SAH mice, correlating these findings with cellular responses in cultured HT22 cells.

Bioinformatics and Molecular Mechanism Analysis: The study provides a mechanistic framework by identifying the miR-26a-5p/PTEN/AKT pathway as a key player in DPSC-mediated neuroprotection. The use of luciferase reporter assays to confirm miR-26a-5p’s interaction with PTEN adds rigor to the molecular analysis.

Potential Clinical Relevance: The findings provide a promising avenue for cell-based therapy in SAH, an area with limited treatment options beyond supportive care and neurosurgical intervention.

Limitations and Areas for Improvement

Lack of Long-Term Outcome Assessment: While the study effectively demonstrates short-term improvements in neurological function, brain edema, and apoptosis, long-term assessments (e.g., beyond the early post-SAH phase) are lacking. Chronic neurological outcomes, cognitive function, and potential long-term integration of DPSCs into neural circuits remain unexplored.

Limited Characterization of DPSCs: The authors do not provide sufficient details on the characterization and differentiation potential of the DPSCs used. Information on their immunophenotype, differentiation capabilities, and potential risk of ectopic differentiation would strengthen the study.

Potential Immune Response Not Addressed: Although DPSCs are considered immune-privileged, their systemic administration raises concerns about potential immunogenicity, inflammatory responses, or unwanted differentiation, which the authors do not investigate.

Reliance on a Single Cell Line for In Vitro Experiments: The study uses HT22 cells to model neuronal injury, but HT22 cells are immortalized murine hippocampal neurons, which may not fully represent primary cortical or hippocampal neurons. The use of primary neuronal cultures would enhance translational relevance.

Lack of Functional Validation of miR-26a-5p/PTEN/AKT Pathway: While the study establishes a correlation between miR-26a-5p expression and neuroprotection, direct functional validation via miR-26a-5p knockdown or overexpression in vivo would further solidify the mechanistic claims.

Absence of Dose-Response and Optimization Studies: The authors do not explore different DPSC doses, delivery routes, or timing of administration. Optimizing these parameters is crucial for translational applications.

Conclusion and Future Directions

He et al. present a well-designed study demonstrating the therapeutic potential of DPSCs in SAH-induced EBI. Their findings highlight the importance of the miR-26a-5p/PTEN/AKT pathway in mediating neuroprotection, providing a strong foundation for future research. However, several limitations, including the lack of long-term assessments, immune response considerations, and dose-optimization studies, must be addressed before DPSCs can be considered for clinical translation. Future studies should explore the safety and efficacy of DPSCs in larger animal models and examine their impact on long-term neurocognitive recovery.

1)

He P, Zhang H, Wang J, Guo Y, Tian Q, Liu C, Gong P, Ye Q, Peng Y, Li M. Dental Pulp Stem Cells Attenuate Early Brain Injury After Subarachnoid Hemorrhage via miR-26a-5p/PTEN/AKT Pathway. Neurochem Res. 2025 Jan 30;50(2):91. doi: 10.1007/s11064-025-04340-y. PMID: 39883266.

Spinal schwannoma

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Spinal schwannoma

J.Sales-Llopis

Neurosurgery Department, General University Hospital Alicante, Spain

Latest Pubmed Articles

Definition

Spinal schwannomas are well-described slow growing benign spinal tumors of the peripheral nervous system, arising from Schwann cells.

Epidemiology

see Spinal schwannoma epidemiology.

Classification

see Spinal Schwannoma Classification.

Associations

The vast majority of spinal schwannomas are solitary and sporadic (95%) 10.

However, there is an association with neurofibromatosis type 2 (NF2). In patients with NF2, almost all spinal nerve root tumors are schwannomas or mixed tumors. In a young adult without the NF2 mutation, the finding of multiple schwannomas may meet the criteria for schwannomatosis.

Pathology

Antoni A and Antoni B tissue.

Clinical features

Patients with nonsyndromic spinal schwannoma usually present to hospital with local pain and neurological deficit that exacerbate over time.

Early symptoms are often radicular.

Neurological deficits develop late.

Tumor may cause radiculopathy, myelopathy, radiculomyelopathy or cauda equina syndrome.

Diagnosis

Spinal schwannoma diagnosis

Differential diagnosis

Spinal Schwannoma differential diagnosis

Treatment

see Spinal schwannoma treatment.

Outcome

Spinal schwannoma recurrence is rare after total excision (except in neurofibromatosis).

The risk for motor deficit is higher for schwannomas than for neurofibromas, for cervical vs. lumbar tumors, and for cervical tumors wiyh extradural extension.

Systematic Review and Meta-Analysis

Alvarez-Crespo et al. conducted a systematic review and meta-analysis under the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A search of bibliographic databases from January 1, 2001, to May 31, 2021, yielded 4489 studies. Twenty-six articles were included in our final qualitative systematic review and quantitative meta-analysis.

Analysis of 2542 adult patients’ data from 26 included studies showed that 53.5% were male, and the mean age ranged from 35.8 to 57.1 years. The most common tumor location was the cervical spine (34.2%), followed by the thoracic spine (26.2%) and the lumbar spine (18.5%). Symptom severity was the most common indicator for surgical treatment, with the most common symptoms being segmental back pain, sensory/motor deficits, and urinary dysfunction. Among all patients analyzed, 93.8% were treated with gross total resection, which was associated with a better prognosis and less chance of recurrence than subtotal resection. The posterior approach was the most common (87.4% of patients). The average operative time was 4.53 hours (95% confidence interval [CI], 3.18-6.48); the average intraoperative blood loss was 451.88 mL (95% CI, 169.60-1203.95). The pooled follow-up duration was 40.6 months (95% CI, 31.04-53.07). The schwannoma recurrence rate was 5.3%. Complications were particularly low and included cerebrospinal fluid leakage, wound infection, and sensory-motor deficits. Most of the patients experienced complete recovery or significant improvement of preoperative neurological deficits and pain symptoms.

The analysis suggests that segmental back pain, sensory/motor deficits, and urinary dysfunction are the most common symptoms of spinal schwannomas. Surgical resection is the treatment of choice with overall good reported outcomes and particularly low complication rates. gross total resection offers the best prognosis with the slightest chance of tumor recurrence and minimal risk of complications 1).

Case series

see Spinal Schwannoma Case Series.

Case reports

see Spinal Schwannoma Case Reports.

1)

Alvarez-Crespo DJ, Conlon M, Kazim SF, Skandalakis GP, Bowers CA, Chhabra K, Tarawneh O, Arbuiso S, Cole KL, Dominguez J, Dicpinigaitis AJ, Vellek J, Thommen R, Bisson EF, Couldwell WT, Cole CD, Schmidt MH. Clinical Characteristics and Surgical Outcomes of 2542 Patients with Spinal Schwannomas: A Systematic Review and Meta-Analysis. World Neurosurg. 2024 Feb;182:165-183.e1. doi: 10.1016/j.wneu.2023.11.090. Epub 2023 Nov 24. PMID: 38006933.

Regorafenib for glioblastoma

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Regorafenib for glioblastoma

J.Sales-Llopis

Neurosurgery Department, General University Hospital Alicante, Spain

Regorafenib, a multi-kinase inhibitor, has emerged as a potential therapeutic option for glioblastoma, particularly in cases where standard treatments such as surgery, radiation, and temozolomide chemotherapy have failed.

Mechanism of Action

Regorafenib targets multiple receptor tyrosine kinases involved in tumor proliferation, angiogenesis, and the tumor microenvironment, including:

VEGFR (Vascular Endothelial Growth Factor Receptors)

PDGFR (Platelet-Derived Growth Factor Receptors)

FGFR (Fibroblast Growth Factor Receptors)

KIT, RET, and BRAF These pathways are often dysregulated in glioblastoma, promoting tumor growth and resistance to standard therapies.

Clinical Evidence

REGOMA Trial (2019): A phase II clinical trial evaluated regorafenib in patients with recurrent glioblastoma:

Results: The study showed an improvement in overall survival (OS) compared to lomustine, a standard second-line therapy. Median OS for regorafenib was 7.4 months versus 5.6 months for lomustine. Implications: This result demonstrated the potential of regorafenib as a viable treatment option in recurrent settings. Ongoing Studies:

Further trials (e.g., phase III) are assessing its safety, efficacy, and potential biomarkers for predicting response. Studies are exploring combination therapies, such as regorafenib with immunotherapy, to overcome resistance mechanisms.

Potential Benefits

Angiogenesis Inhibition: Glioblastoma’s hallmark feature is its high vascularity, making anti-angiogenic therapy a promising strategy. Tumor Microenvironment Modulation: Regorafenib can alter the tumor’s supportive environment, potentially enhancing the efficacy of other treatments. Side Effects Regorafenib is associated with several adverse effects that require careful management, including:

Hypertension Hand-foot skin reactions Fatigue Diarrhea Hepatotoxicity Future Directions Biomarker Development: Identifying patients who would benefit most from regorafenib based on genetic and molecular tumor profiles. Combination Therapies: Combining regorafenib with checkpoint inhibitors, radiotherapy, or other targeted agents. Optimization of Dosing: Balancing efficacy with tolerability, particularly in patients with fragile health due to glioblastoma.

Meta-analysis of randomized controlled clinical trials

A meta-analysis, based on searches in PubMed and Web Of Science, evaluated 12 randomized controlled trials (RCTs) examining PKIs in patients with newly diagnosed or recurrent GBM. Pooled analysis of shared clinical outcomes – progression-free survival (PFS) and overall survival (OS) – revealed a lack of significant improvements with the use of PKIs. In newly diagnosed GBM, no significant differences were observed in median [-1.02 months, 95% confidence interval (CI), -2.37-0.32, p=0.14] and pooled [hazard ratio (HR)=1.13, 95% CI, 0.95-1.35, p=0.17) OS, or in median (0.34 months, 95% CI, -0.9-1.58, p=0.60) and pooled (HR=0.98, 95% CI, 0.76-1.27, p=0.89) PFS, when comparing PKI addition to standard chemo-radiotherapy versus chemo-radiotherapy alone. In recurrent GBM, three different analyses were conducted: PKI versus other treatments, PKI combined with other treatments versus those treatments alone, PKI versus PKI combined with other treatments. Also, across these analyses, no significant clinical benefits were found. For instance, when comparing PKI treatment with other treatments, median OS and PFS showed no significant difference (-0.78 months, 95% CI, -2.12-0.55, p=0.25; -0.23 months, 95% CI, -0.79-0.34, p=0.43, respectively), and similar non-significant results were observed in the pooled analyses (OS: HR=0.89, 95% CI, 0.59-1.32, p=0.55; PFS: HR=0.83, 95% CI, 0.63-1.11, p=0.21). Despite these overall negative findings, some data indicate improved clinical outcomes in a subset of GBM patients treated with certain PKIs (i.e., regorafenib) and encourage further research to identify PKIs with better blood-brain barrier penetration and lower risk for resistance development 1)

This meta-analysis underscores the limited efficacy of current PKIs in GBM, despite rigorous methodological approaches. While the findings are largely negative, the identification of potential benefits in specific patient subsets offers a pathway for refining PKI therapy. Future research should prioritize biomarker-driven trials, focus on agents with enhanced BBB penetration, and explore novel combination strategies. The ultimate challenge lies in overcoming the heterogeneity and treatment resistance characteristic of GBM, which remain formidable barriers to improving patient outcomes.

Systematic Reviews

Schettini et al. conducted a systematic review and Bayesian trial-level network metaanalysis (NMA) to identify the regimens associated with the best outcomes. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS) and overall response rates (ORR). They estimated separate treatment rankings based on the surface under the cumulative ranking curve values. Only phase II/III prospective comparative trials were included.

Twenty-four studies (3733 patients and 27 different therapies) were ultimately included. Twenty-three different regimens were compared for OS, 21 for PFS, and 26 for ORR. When taking lomustine as a common comparator, only regorafenib was likely to be significantly superior in terms of OS (hazard ratio: 0.50, 95% credible interval: 0.33-0.75). Regorafenib was significantly superior to other 16 (69.6%) regimens, including NovoTTF-100A, bevacizumab monotherapy, and several bevacizumab-based combinations. Regarding PFS and ORR, no treatment was clearly superior to the others.

This NMA supports regorafenib as one of the best available options for relapsing/refractory glioblastoma. Lomustine, NovoTTF-100A, and bevacizumab emerge as other viable alternative regimens. However, evidence on regorafenib is controversial at best. Moreover, most studies were underpowered, with varying inclusion criteria and primary endpoints, and no longer adapted to the most recent glioblastoma classification. A paradigmatic change in clinical trials’ design for relapsing/refractory glioblastoma and more effective treatments are urgently required 2)

Schettini et al.’s systematic review and Bayesian NMA make an important contribution to understanding the relative efficacy of available therapies for relapsing/refractory GBM, particularly by highlighting regorafenib as a potentially effective option. However, the study is hindered by limitations inherent to the included trials and the analytical framework, including the heterogeneity of studies, underpowered designs, and outdated glioblastoma classifications.

The findings underscore the pressing need for a paradigm shift in GBM clinical trials. Future research should prioritize large, well-powered, multicenter trials incorporating molecularly stratified patient cohorts and harmonized endpoints. Additionally, the exploration of novel therapeutic strategies is critical to advancing the treatment landscape for this devastating disease. While regorafenib appears promising, its clinical utility must be validated in robust, contemporary trials to establish its place in the therapeutic arsenal for GBM.

Retrospective Studies

In a retrospective study, Kebir et al. investigated the efficacy and radiographic tumor growth patterns of regorafenib in recurrent high-grade astrocytoma.

They screened for patients with a high-grade astrocytoma in whom regorafenib was administered for at least 4 weeks. We assessed treatment efficacy in terms of progression-free survival (PFS), overall survival, and adverse events defined by Common Toxicity Criteria (CTC). In addition, radiographic tumor growth patterns were determined at baseline and recurrence.

A total of 6 patients met the eligibility criteria. The number of recurrences prior to regorafenib varied between 2 and 6. Patients were on regorafenib treatment for at least 4 weeks and maximally 14 weeks. Median PFS was 3.5 months and ranged from 2.0 to 4.0 months. Radiographic response was progressive disease in all patients with an objective response rate of 0%. CTC°3 adverse events were observed in all but one patient. The most common radiographic growth pattern was local with no change in growth pattern at recurrence. An infiltrative tumor growth was not induced in any patient.

This retrospective study indicates the very poor performance of regorafenib in recurrent high-grade astrocytoma with a fairly high number of CTC°3 adverse events. In addition, regorafenib does not seem to bear a potential for infiltrative tumor growth promotion 3).

1)

Pinto-Fraga J, García-Chico C, Lista S, Lacal PM, Carpenzano G, Salvati M, Santos-Lozano A, Graziani G, Ceci C. protein kinase inhibitors as Targeted therapy for glioblastoma: A meta-analysis of randomized controlled clinical trials. Pharmacol Res. 2024 Dec 3:107528. doi: 10.1016/j.phrs.2024.107528. Epub ahead of print. PMID: 39637954.
2)

Schettini F, Pineda E, Rocca A, Buché V, Donofrio CA, Mazariegos M, Ferrari B, Tancredi R, Panni S, Cominetti M, Di Somma A, González J, Fioravanti A, Venturini S, Generali D. Identifying the best treatment choice for relapsing/refractory glioblastoma: a systematic review with multiple Bayesian network meta-analyses. Oncologist. 2024 Dec 14:oyae338. doi: 10.1093/oncolo/oyae338. Epub ahead of print. PMID: 39674575.
3)

Kebir S, Rauschenbach L, Radbruch A, Lazaridis L, Schmidt T, Stoppek AK, Pierscianek D, Stuschke M, Forsting M, Sure U, Keyvani K, Kleinschnitz C, Scheffler B, Glas M. Regorafenib in patients with recurrent high-grade astrocytoma. J Cancer Res Clin Oncol. 2019 Apr;145(4):1037-1042. doi: 10.1007/s00432-019-02868-5. Epub 2019 Feb 28. PubMed PMID: 30820715.

Proton magnetic resonance spectroscopic imaging in glioblastoma recurrence diagnosis

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Proton magnetic resonance spectroscopic imaging in glioblastoma recurrence diagnosis

Proton magnetic resonance spectroscopic imaging (MRSI) is a non-invasive imaging technique that assesses the metabolic profile of brain tissues, offering valuable insights into the diagnosis and monitoring of glioblastoma recurrence. By measuring concentrations of metabolites such as choline (Cho), N-acetylaspartate (NAA), and creatine (Cr), MRSI aids in distinguishing between tumor recurrence and treatment-induced changes like radiation necrosis.

Key Metabolites in MRSI

– Choline (Cho): Elevated levels indicate increased cellular membrane turnover, commonly associated with tumor proliferation.

– N-acetylaspartate (NAA): Reduced levels suggest neuronal loss or dysfunction, often observed in tumor regions.

– Creatine (Cr): Serves as a reference metabolite for energy metabolism, typically stable across different tissues.

Chemical Shift Imaging: Provides information about the metabolic composition of tissues. Elevated levels of choline and decreased N-acetylaspartate (NAA) may indicate recurrent tumors.

Choline to N-Acetylaspartate Ratio in Glioblastoma Recurrence Diagnosis

Choline to N-Acetylaspartate Ratio in Glioblastoma Recurrence Diagnosis

Clinical Applications

1. Differentiating Tumor Recurrence from Radiation Injury: MRSI can help distinguish recurrent GBM from radiation-induced changes. Recurrent tumors often exhibit increased Cho/Cr and Cho/NAA ratios, whereas radiation injuries may show different metabolic patterns.

2. Guiding Radiotherapy Planning: Incorporating MRSI into radiotherapy planning allows for targeted dose escalation to metabolically active tumor regions, potentially improving local control and patient outcomes.

3. Monitoring Treatment Response: MRSI enables the assessment of metabolic changes over time, providing insights into treatment efficacy and early detection of recurrence.

Advantages of MRSI

– Non-Invasive: Offers a non-invasive method to assess tumor metabolism without the need for biopsy.

– Metabolic Insights: Provides detailed information on tumor biochemistry, complementing anatomical imaging.

– Early Detection: Facilitates the early identification of tumor recurrence before structural changes become apparent.

Limitations

– Technical Complexity: Requires specialized equipment and expertise for acquisition and interpretation.

– Spatial Resolution: May have lower spatial resolution compared to conventional MRI, potentially limiting the detection of small lesions.

In summary, proton MRSI is a valuable tool in the management of glioblastoma, enhancing the ability to differentiate between tumor recurrence and treatment effects, guiding therapy, and monitoring disease progression.

Systematic Reviews

Of 7350 records for MR spectroscopy, GBM, glioma, recurrence, diffusion, perfusion, pseudoprogression, radiomics, and advanced imaging, they screened 574 papers. A total of 228 were eligible, and analyzed 72 of them, in order to establish the role of each imaging modality and the usefulness and limitations of radiomics analysis 1).

Prospective diagnostic accuracy studies

A prospective single-institutional study aims to determine and validate thresholds for the main metabolite concentrations obtained by MR spectroscopy (MRS) and the values of the apparent diffusion coefficient (ADC) to enable distinguishing tumor recurrence from pseudoprogression. Thirty-nine patients after the standard treatment of a glioblastoma underwent advanced imaging by MRS and ADC at the time of suspected recurrence – the median time to progression was 6.7 months. The highest significant sensitivity and specificity to call the glioblastoma recurrence was observed for the total choline (tCho) to total N-acetyl aspartate (tNAA) concentration ratio with the threshold ≥ 1.3 (sensitivity 100.0% and specificity 94.7%). The ADC mean value higher than 1313 × 10(- 6) mm(2)/s was associated with pseudoprogression (sensitivity 98.3%, specificity 100.0%). The combination of MRS focused on the tCho/tNAA concentration ratio and the ADCmean value represents imaging methods applicable to early non-invasive differentiation between a glioblastoma recurrence and a pseudoprogression. However, the institutional definition and validation of thresholds for differential diagnostics are needed for the elimination of setup errors before the implementation of these multimodal imaging techniques into clinical practice, as well as into clinical trials 2).

Retrospective cohort studies

A study of Lu et al. aimed to evaluate the predictive value of metabolic parameters in preoperative non-enhancing peritumoral regions (NEPTRs) for glioblastoma recurrence, using multivoxel hydrogen proton magnetic resonance spectroscopy (1H-MRS). Clinical and imaging data from patients with recurrent glioblastoma were analyzed. Through co-registration of preoperative and post-recurrence MRI, they identified future tumor recurrence regions (FTRRs) and future non-tumor recurrence regions (FNTRRs) within the NEPTRs. Metabolic parameters were recorded separately for each region. Cox regression analysis was applied to assess the association between metabolic parameters and glioblastoma recurrence. Compared to FNTRRs, FTRRs exhibited a higher Cho/Cr ratio, higher Cho/NAA ratio, and lower NAA/Cr ratio. Both Cho/NAA and Cho/Cr ratios were recognized as risk factors in univariate and multivariate analyses (P < 0.05). The Cox regression model indicated that Cho/NAA > 1.99 and Cho/Cr > 1.73 are independent risk factors for early glioblastoma recurrence. Based on these cut-off values, patients were stratified into low-risk and high-risk groups, with a statistically significant difference in recurrence rates between the two groups (P < 0.01). The Cho/NAA and Cho/Cr ratios in NEPTRs are independent predictors of future glioblastoma recurrence. Specifically, Cho/NAA > 1.99 and/or Cho/Cr > 1.73 in NEPTRs may indicate a higher risk of early postoperative recurrence at these regions 3).

This study demonstrates that metabolic ratios (Cho/NAA and Cho/Cr) in NEPTRs are independent predictors of glioblastoma recurrence and proposes clinically relevant cut-off values for risk stratification. While the findings are promising, limitations such as small sample size, lack of external validation, and potential confounding factors highlight the need for further research. The integration of metabolic and molecular data, along with validation in larger cohorts, could significantly enhance the clinical utility of these predictors.

1)

Sidibe I, Tensaouti F, Roques M, Cohen-Jonathan-Moyal E, Laprie A. Pseudoprogression in Glioblastoma: Role of Metabolic and Functional MRI-Systematic Review. Biomedicines. 2022 Jan 26;10(2):285. doi: 10.3390/biomedicines10020285. PMID: 35203493; PMCID: PMC8869397.
2)

Kazda T, Bulik M, Pospisil P, Lakomy R, Smrcka M, Slampa P, Jancalek R. Advanced MRI increases the diagnostic accuracy of recurrent glioblastoma: Single institution thresholds and validation of MR spectroscopy and diffusion weighted MR imaging. Neuroimage Clin. 2016 Feb 26;11:316-321. doi: 10.1016/j.nicl.2016.02.016. PMID: 27298760; PMCID: PMC4893011.
3)

Lu W, Feng J, Zou Y, Liu Y, Gao P, Zhao Y, Wu X, Ma H. 1H-MRS parameters in non-enhancing peritumoral regions can predict the recurrence of glioblastoma. Sci Rep. 2024 Nov 26;14(1):29258. doi: 10.1038/s41598-024-80610-z. PMID: 39587278.

Bilingualism

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Bilingualism

Bilingualism refers to the ability to use two languages proficiently. A bilingual person can speak, understand, read, and write in two languages with varying degrees of fluency. Bilingualism is not a uniform concept; it can manifest in different ways depending on factors such as language proficiency, context, and the timing of learning.

Here are key points about bilingualism:

### Types of Bilingualism: 1. Simultaneous Bilingualism: This occurs when a person learns two languages from birth or early childhood, typically in a bilingual environment. This is common in families where parents speak different languages.

2. Sequential (or Successive) Bilingualism: This happens when a person learns a second language after already being proficient in a first language, often in childhood or adulthood. For example, a child might learn their native language at home and then acquire a second language at school.

3. Balanced Bilingualism: This refers to a situation where a person has nearly equal proficiency in both languages. While rare, this is the ideal for some bilinguals.

4. Dominant Bilingualism: In this case, one language is stronger or more frequently used than the other. For instance, someone who speaks both Spanish and English but uses English more often may be considered dominant in English.

5. Passive Bilingualism: A person understands a second language but is not able to speak or use it actively.

### Cognitive and Neurological Aspects: – Cognitive Benefits: Bilingualism has been linked to cognitive advantages, such as better executive function (e.g., problem-solving, multitasking, and memory) and delayed onset of age-related cognitive decline, including Alzheimer’s disease.

– Language Switching: Bilinguals can switch between languages depending on the context, a process known as code-switching. This flexibility relies on the brain’s ability to manage and control both languages.

– Brain Activation: Studies have shown that bilinguals often have denser gray matter in areas of the brain related to language processing. The brain of a bilingual person is particularly adept at managing the interference from competing languages, which enhances cognitive flexibility.

### Social and Cultural Aspects: – Cultural Identity: Bilingualism can be tied to cultural identity. For many bilinguals, each language may represent a different cultural aspect of their life, and they may switch languages depending on the social or cultural context.

– Communication: Bilinguals have the advantage of communicating with a wider range of people across different linguistic communities, which can be particularly useful in multilingual regions or professional settings.

### Challenges of Bilingualism: – Language Interference: Sometimes, one language can interfere with the other, causing errors such as mixing vocabulary, grammar, or pronunciation (e.g., “Spanglish” or “Franglais”). This is especially common in simultaneous bilinguals.

– Language Maintenance: Bilinguals may struggle to maintain proficiency in both languages, especially if one language is used more frequently than the other. This can lead to language attrition, where one language becomes weaker over time.

– Social Perceptions: In some regions, bilingual individuals may face social stigma or discrimination, especially if one of their languages is viewed as less prestigious or less widely spoken.

### Conclusion: Bilingualism is a dynamic and complex phenomenon that involves not just language proficiency but also cognitive, social, and cultural factors. It provides numerous benefits, both personally and professionally, but can also come with challenges, particularly in balancing both languages and navigating social perceptions.

The utility of intraoperative mapping in multilingual patients with brain tumors in speech-eloquent locations is evidenced by reports of heterogeneity of the location and number of language areas. Furthermore, preserving the ability to switch between languages is crucial for multilingual patients’ communication and quality of life. Barua et al. report the first case of intraoperative bilingual and language-switching testing in a child undergoing awake craniotomy for a tumor within the left superior temporal gyrus using a novel test paradigm. Stimulation of the posterior superior temporal gyrus resulted in anomia when switching from Polish to English, in the absence of any stimulation effect on switching from English to Polish or object naming in each language 1)

The article *“Bilingual awake craniotomy with English and Polish language mapping in a 15-year-old patient provides evidence for the role of the left superior temporal gyrus in language switching”* (Acta Neurochir, 2024 Nov 13;166(1):452) presents an intriguing study on the role of the left superior temporal gyrus (STG) in bilingual language switching. The authors—Neil U Barua, Hajira Mumtaz, Sonia Mariotti, Molly Cree, Agdaliya Mikhalkova, Greg A Fellows, and Anna E Piasecki—explore a novel approach to intraoperative language mapping in a young multilingual patient undergoing awake craniotomy for a tumor in the left superior temporal gyrus. This report highlights the utility of mapping bilingual language areas and provides significant insights into the complex brain regions involved in switching between languages.

### Strengths:

1. Novel Methodology: The use of a bilingual awake craniotomy in a 15-year-old patient is groundbreaking, as it is the first report of such an approach for mapping language switching between English and Polish. This methodology can offer a deeper understanding of the neural mechanisms underlying multilingual language processing, especially in children, who may exhibit unique brain adaptations.

2. Clinical Relevance: The study is highly relevant for clinical neuropsychology, particularly for multilingual patients with brain tumors in speech-eloquent regions. By demonstrating the distinct brain activity involved in language switching, the findings may guide surgeons in preserving both language abilities during resection of tumors in these areas, ultimately improving postoperative quality of life for patients.

3. Specific Findings: The case highlights the critical role of the posterior superior temporal gyrus (STG) in switching between languages. The stimulation-induced anomia specifically when switching from Polish to English—without affecting the ability to name objects in each language individually—emphasizes the specialized role of the STG in language switching rather than simple language production. This nuanced finding adds to the existing body of literature and suggests the need for further studies to map out language-specific regions more thoroughly.

### Weaknesses:

1. Generalizability: As a single case report, the findings should be viewed with caution. It is difficult to generalize the results to other bilingual individuals, particularly in different age groups, with different language pairs, or those with other neurological conditions. The authors themselves acknowledge that further studies with larger sample sizes are needed to confirm the results and expand the findings to a wider population.

2. Language Pair Considerations: The study examines only two languages—English and Polish. While this is an important step, the findings are limited to this particular language pair. Different language pairs may activate different regions of the brain due to variations in phonology, syntax, and other language-specific features. It would be interesting to see if similar results are observed in individuals who speak languages that are typologically distant, such as English and Mandarin, or among individuals with more complex multilingual profiles.

3. Neuroplasticity: The study does not address the potential influence of neuroplasticity on language functions in multilingual individuals. Children, in particular, may demonstrate different neural organization compared to adults, and the influence of age, experience, and neural reorganization in response to the tumor could affect the outcome. This aspect would benefit from further exploration.

### Suggestions for Future Research:

– Larger Cohort Studies: It would be valuable to conduct similar research on a larger cohort of multilingual patients to identify whether the observed effects are consistent across different language pairs and in different populations (e.g., adults vs. children).

– Long-Term Follow-Up: A longitudinal follow-up of postoperative language outcomes would offer insight into the long-term impact of preserving specific areas of the STG and other brain regions involved in language switching.

– Comparative Language Pairs: Future studies could explore different language pairs or more complex multilingual cases, which might reveal additional findings or patterns in language representation and switching.

### Conclusion:

This report provides compelling evidence for the involvement of the left superior temporal gyrus in language switching, contributing valuable knowledge to the field of multilingual neuropsychology. Although the findings are based on a single case, the study demonstrates the importance of intraoperative language mapping in bilingual patients undergoing neurosurgery. The findings hold promise for improving surgical outcomes for multilingual individuals, offering a more nuanced understanding of how the brain manages multiple languages. Nonetheless, further research is needed to validate these results and extend the implications to broader clinical practice.

Neural basis of language switching and the cognitive models of bilingualism remain controversial.

Sierpowska et al. explored the functional neuroanatomy of language switching implementing a new multimodal protocol assessing neuropsychological, functional magnetic resonance, and intraoperative Electrostimulation mapping results. A prospective series of 9 Spanish-Catalan bilingual candidates for awake brain surgery underwent a specific language-switching paradigm implemented both before and after surgery, throughout the Electrostimulation procedure, and during functional magnetic resonance both pre-and postoperatively. All patients were harboring left-hemispheric intrinsic brain lesions and were presenting functional language-related activations within the affected hemisphere. Language functional maps were reconstructed based on the intraoperative Electrostimulation results and compared to the functional magnetic resonance findings. Single language-naming sites (Spanish and Catalan), as well as language-switching naming sites were detected by Electrostimulation mapping in 8 patients (in one patient only Spanish-related sites were detected). Single naming points outnumbered the switching points and did not overlap with each other. Within the frontal lobe, the single language naming sites were found significantly more frequently within the inferior frontal gyrus as compared to the middle frontal gyrus [X2 (1) = 20.3, p < .001]. Contrarily, switching naming sites were distributed across the middle frontal gyrus significantly more often than within the inferior frontal gyrus [X2 (1) = 4.1, p = .043]. Notably, there was not always an overlap between functional magnetic resonance and Electrostimulation mapping findings. After surgery, patients did not report involuntary language switching and their neuropsychological scores did not differ significantly from the pre-surgical examinations. Our results suggest a functional division of the frontal cortex between naming and language switching functions, supporting that non-language specific cognitive control prefrontal regions (middle frontal gyrus) are essential to maintain effective communication together with the classical language-related sites (inferior frontal gyrus) 2).

1)

Barua NU, Mumtaz H, Mariotti S, Cree M, Mikhalkova A, Fellows GA, Piasecki AE. Bilingual awake craniotomy with English and Polish language mapping in a 15-year-old patient provides evidence for the role of the left superior temporal gyrus in language switching. Acta Neurochir (Wien). 2024 Nov 13;166(1):452. doi: 10.1007/s00701-024-06358-7. PMID: 39535621.
2)

Sierpowska J, Fernandez-Coello A, Gomez-Andres A, Camins À, Castañer S, Juncadella M, Gabarrós A, Rodríguez-Fornells A. Involvement of the middle frontal gyrus in language switching as revealed by Electrostimulation mapping and functional magnetic resonance imaging in bilingual brain tumor patients. Cortex. 2017 Nov 14;99:78-92. doi: 10.1016/j.cortex.2017.10.017. [Epub ahead of print] PubMed PMID: 29197227.

Vestibular Schwannoma Koos Grade 1

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Vestibular Schwannoma Koos Grade 1

Vestibular Schwannoma Koos grading scale 1 involves only the internal auditory canal without extension into the cerebellopontine angle (CPA).

– These tumors are typically less than 1 cm in diameter.

Clinical features

– They often present with early symptoms such as unilateral hearing loss, tinnitus (ringing in the ears), or a sensation of fullness in the ear.

Treatment

Treatment for a Koos Grade 1 vestibular schwannoma is typically aimed at preserving hearing and avoiding damage to surrounding structures.

Common management options include:

1. Observation with regular imaging, particularly if the tumor is asymptomatic or if the patient’s age and general health suggest that intervention is not immediately necessary.

2. Surgical resection to remove the tumor, especially if symptoms are progressive or if the tumor is growing.

3. Stereotactic radiosurgery (such as Gamma Knife), which is often used for tumors that are difficult to access surgically or when hearing preservation is a priority.

For Koos Grade I vestibular schwannomas, there is typically no compression of critical structures, and treatment options often involve active surveillance or SRS rather than surgery. These small tumors may not cause immediate symptoms and can often be monitored with regular imaging to track any growth.

Prognosis

The prognosis for Koos Grade 1 vestibular schwannomas is generally good, particularly when they are treated early. However, given the slow-growing nature of many Koos Grade I schwannomas, the necessity and timing of intervention remain topics of ongoing debate in neurosurgery, with individualized treatment being essential

Prospective observational studies

This study by Levivier et al. 1) presents an argument for early intervention with Gamma Knife Surgery (GKS) in patients with Koos grade I vestibular schwannomas (VS), suggesting it as a superior approach to the “wait and see” strategy. However, a critical examination reveals substantial limitations and questions regarding the validity of these recommendations, particularly concerning the study’s methodology and interpretation of results.

1. Short Follow-Up Period and Limited Long-Term Data: The mean follow-up in this study was a mere 1.3 years, with a range from 0.6 to 3.6 years, which is alarmingly short given the slow-growing nature of vestibular schwannomas. Tumors in this early stage often exhibit minimal or no growth over years, making this follow-up insufficient to draw conclusions about long-term outcomes, especially in terms of tumor control and cranial nerve preservation. With such limited follow-up, any claims regarding the benefits of early GKS are speculative at best.

2. Lack of Comparison with Observation Group: The study fails to include a direct comparison group of patients managed with observation, which is a common approach for small, asymptomatic, or minimally symptomatic Koos I tumors. Without this essential control, the assertion that early GKS is preferable to a “wait and see” strategy lacks robust evidence. This absence is particularly significant, as previous studies have shown that many Koos I VS can be safely observed without immediate intervention.

3. Inconsistent Hearing Preservation Results and Dose Concerns: The reported hearing preservation rate of 85% appears promising; however, the authors overlook the fact that hearing can often be maintained in Koos I tumors without intervention, as tumor growth rates are typically low. Additionally, the study does not adequately discuss the risks of radiation exposure to the cochlea and the potential for hearing deterioration over time, especially given the mean cochlear dose of 4.1 Gy, which could have cumulative adverse effects.

4. Overstatement of Preliminary Data: The authors prematurely advocate for early GKS based on “preliminary data,” which lacks the rigor and maturity required for such a definitive recommendation. Promoting early intervention based on short-term data may expose patients to unnecessary risks, especially considering that many Koos I tumors remain asymptomatic or progress very slowly. The recommendation for early GKS is therefore premature, and further research with a longer follow-up is essential before suggesting that patients with asymptomatic or minimally symptomatic tumors should undergo early intervention.

5. Methodological Concerns in Dosimetric Analysis: The study’s focus on dosimetric factors, while important, appears overly simplistic in suggesting that cochlear dose alone can predict hearing preservation. Hearing outcomes in VS are multifactorial, and the authors’ narrow focus on dose metrics overlooks other critical factors that could influence outcomes, such as baseline hearing quality, individual patient anatomy, and the biological response to radiation.

Conclusion: In summary, this study’s recommendation for early GKS in Koos I vestibular schwannomas is founded on weak preliminary data, a limited follow-up, and an absence of a control group for observation. The authors’ enthusiasm for early intervention is unwarranted without more robust, long-term evidence. Until such data is available, it would be prudent to adhere to a conservative approach of observation for Koos I tumors, reserving intervention for cases where there is documented tumor progression or symptomatic deterioration.

Retrospective cohort studies

The VISAS-K1 study is a multicenter retrospective analysis comparing stereotactic radiosurgery (SRS) with active surveillance in the management of Koos grade I vestibular schwannomas (VS). The study aimed to evaluate the safety and efficacy of SRS versus observation for these small, intracanalicular tumors.

Study Design and Methods:

Participants: The study included 142 patients with Koos grade I VS, divided into two groups: those who underwent SRS and those who were observed without immediate intervention.

Matching: Propensity score matching was utilized to balance demographics, tumor size, and audiometric data between the two groups, aiming to reduce selection bias.

Follow-up: The median follow-up period was 36 months, with some patients monitored up to 8 years.

Key Findings:

Tumor Control:

The SRS group achieved a 100% tumor control rate at both 5 and 8 years. In contrast, the observation group had control rates of 48.6% at 5 years and 29.5% at 8 years, indicating a significant advantage for SRS in preventing tumor progression. Hearing Preservation:

Preservation of serviceable hearing was comparable between the two groups. At 5 years, 70.1% of patients in the SRS group and 53.4% in the observation group maintained serviceable hearing, with no statistically significant difference (P = .33). Neurological Function:

Patients in the SRS group had a reduced likelihood of developing tinnitus (odds ratio [OR] = 0.46, P = .04), vestibular dysfunction (OR = 0.17, P = .002), and overall cranial nerve dysfunction (OR = 0.49, P = .03) at the last follow-up compared to those under observation. Conclusions:

The VISAS-K1 study suggests that SRS offers superior tumor control and a lower risk of cranial nerve dysfunction for patients with Koos grade I vestibular schwannomas, without compromising hearing preservation, compared to active surveillance. These findings support the consideration of SRS as a primary treatment option for this patient population 2).

Critical Considerations:

Study Design Limitations: As a retrospective analysis, the study may be subject to selection biases and unmeasured confounding factors, despite efforts to balance groups through propensity score matching.

Follow-up Duration: The median follow-up of 36 months may not fully capture long-term outcomes, especially given the slow-growing nature of vestibular schwannomas.

Outcome Measures: The assessment of cranial nerve function and hearing preservation relies on clinical evaluations that may vary between centers, potentially affecting the consistency of reported outcomes.

In summary, while the VISAS-K1 study provides valuable insights into the management of small vestibular schwannomas, its retrospective nature and potential biases necessitate cautious interpretation of the results. Prospective, randomized controlled trials with standardized outcome assessments are needed to confirm these findings and guide clinical decision-making.

1)

M. Levivier, C. Tuleasca, Mercy G, Schiappacasse L, M. Zeverino, Maire R. Should Koos grade I vestibular schwannomas be treated early with gamma knife surgery? A subgroup analysis in a series of 190 consecutive patients. Neurochirurgie. 2014;60(6):331-331. doi:https://doi.org/10.1016/j.neuchi.2014.10.028‌
2)

Bin-Alamer O, Abou-Al-Shaar H, Peker S, Samanci Y, Pelcher I, Begley S, Goenka A, Schulder M, Tourigny JN, Mathieu D, Hamel A, Briggs RG, Yu C, Zada G, Giannotta SL, Speckter H, Palque S, Tripathi M, Kumar S, Kaur R, Kumar N, Rogowski B, Shepard MJ, Johnson BA, Trifiletti DM, Warnick RE, Dayawansa S, Mashiach E, Vasconcellos FN, Bernstein K, Schnurman Z, Alzate J, Kondziolka D, Sheehan JP. Vestibular Schwannoma Koos Grade I International Study of Active Surveillance Versus Stereotactic Radiosurgery: The VISAS-K1 Study. Neurosurgery. 2024 Nov 6. doi: 10.1227/neu.0000000000003215. Epub ahead of print. PMID: 39503441.

The Peritumoral Brain Zone in Glioblastoma

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The article “The Peritumoral Brain Zone in Glioblastoma: A Review of the Pretreatment Approach,” published in *Pol J Radiol* (October 2024), attempts to explore the role of advanced imaging in understanding the peritumoral brain zone (PTZ) in glioblastoma, a highly aggressive and common form of brain tumor. Although the topic is undoubtedly of great importance in neurooncology, the review falls short in several critical areas that undermine its overall contribution to the field.

### Lack of Original Insight

The review essentially reiterates well-established facts about glioblastoma and its clinical challenges, particularly the difficulty in delineating tumor margins for complete resection. While it acknowledges the role of advanced imaging technologies in preoperative planning, the content feels redundant. Much of the information provided could be found in earlier foundational studies, and the article fails to introduce truly novel or groundbreaking ideas that would push the field forward. Readers hoping for fresh perspectives on how imaging can revolutionize treatment planning or innovative therapeutic strategies may be left disappointed.

### Inadequate Depth and Technical Analysis

The article briefly mentions several advanced neuroimaging techniques, such as diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), perfusion-weighted imaging (PWI), and proton magnetic resonance spectroscopy (1H MRS), yet it provides little detailed explanation on how these technologies could be practically applied to improve glioblastoma treatment. The authors reference these methods without delving into their technical intricacies or discussing how these imaging tools can overcome current clinical limitations. For instance, the article fails to adequately explore the potential of chemical exchange saturation transfer (CEST) imaging in mapping the PTZ, which has been an emerging area of interest. Without a deep dive into the challenges and breakthroughs of these technologies, the review reads more like a surface-level summary rather than a meaningful contribution to the scientific community.

### Flawed Structure and Organization

One of the most striking weaknesses of the article is its lack of cohesion and poor structure. The sections on imaging techniques and their implications for glioblastoma management feel disjointed. The transitions between topics are abrupt, and the review doesn’t offer a clear progression from one idea to the next. This lack of flow makes it difficult for the reader to follow the authors’ arguments and understand how each piece of information builds upon the previous one. Additionally, while the article mentions the critical issue of radioresistance in glioblastoma, it does not offer any substantial discussion of how imaging might inform therapeutic strategies to overcome this challenge.

### Missed Opportunity for Clinical Relevance

While the article touches on the importance of preoperative imaging for glioblastoma resection, it misses an important opportunity to translate this knowledge into actionable clinical insights. It fails to address practical challenges clinicians face when using these imaging techniques, such as cost, accessibility, and the need for multidisciplinary collaboration. Furthermore, the review does not adequately discuss how the integration of these imaging methods could change the trajectory of patient outcomes in a meaningful way. There is no discussion on how imaging could influence patient management decisions in a real-world setting, nor is there any mention of how emerging imaging technologies could be incorporated into clinical practice or trials.

### Repetitive and Lackluster Writing

Lastly, the writing style is somewhat repetitive, particularly when describing the heterogeneous nature of glioblastomas and the PTZ. These points are restated multiple times without adding substantial value to the narrative. This redundancy not only makes the article less engaging but also detracts from the potential to provide in-depth analysis or novel insights.

### Conclusion

Overall, the article fails to meet the expectations set by its title. Rather than offering a comprehensive, cutting-edge review of the peritumoral brain zone in glioblastoma, it recycles outdated information and lacks the depth needed to provide valuable insights for clinicians or researchers. While the use of advanced imaging techniques is undoubtedly an exciting area of research, this review misses the mark in providing a clear and innovative perspective on how these tools can be used to improve the treatment of glioblastoma. Researchers and clinicians looking for substantive guidance or new avenues of research will find little to take away from this article.

Mapping the global neurosurgical workforce

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Critical Review of: “Mapping the global neurosurgical workforce. 

The article “Mapping the global neurosurgery workforce. Part 1: Consultant neurosurgeon density,” published in *the Journal of Neurosurgery*, provides an ambitious attempt to quantify and map the global distribution of neurosurgeons. While the study sheds light on global disparities, it fails to deliver in multiple crucial areas, from methodological flaws to missed opportunities for impactful analysis and actionable solutions. Ultimately, the article’s findings feel shallow and underdeveloped, leaving significant gaps in understanding and addressing the real challenges in neurosurgery workforce expansion.

1. Lack of Rigorous Data Collection and Methodology

At the heart of any robust study lies the quality of the data collection process, and this is where the study falters. The authors relies heavily on “personal contacts” and “online searches” to identify survey participants. This non-rigorous, subjective approach to participant selection creates room for considerable bias. In a global study of this magnitude, using personal networks and unverified online sources compromises the reliability and representativeness of the data. For instance, countries with fewer or no strong neurosurgical networks could easily be overlooked, thus skewing the results. Moreover, the authors mention “electronic cross-sectional surveys” but do not provide a clear description of how non-respondents were handled, leading one to question whether the sample is truly reflective of the global workforce. The data gathered through such an ad hoc, unsystematic process cannot be trusted to form the foundation of a serious, scientific inquiry into global neurosurgery density.

2. Overemphasis on High-Income Countries (HICs)

While the study points out the disparities in neurosurgery workforce density between low-, middle-, and high-income countries, it spends far too much time reiterating what is already well known: that high-income countries have significantly more neurosurgeons per capita than low-income countries. At a time when the global health community is grappling with health inequalities, this basic observation does little to advance our understanding. The study highlights the numbers (e.g., 2.44 neurosurgeons per 100,000 people in HICs versus 0.12 in low-income countries) without digging deeper into the underlying causes of these disparities or offering substantial policy recommendations. The authors fail to explore how specific health system characteristics—such as political will, international aid, and government healthcare priorities—shape these disparities. Instead, they leave the reader with numbers and little context for how to address these gaps.

3. Superficial Analysis of Regional Disparities

While the paper acknowledges that the African and Southeast Asia regions have the lowest densities of neurosurgeons, it misses the opportunity to explore the social, political, and economic factors that contribute to this situation. The study simply mentions that “countries with higher income-level designations had more frequent access to resources,” without further dissection. What does “access to resources” really mean? How do governmental policies, international funding, and the prioritization of neurosurgery differ between these regions? How do factors such as local infrastructure, training capacity, and healthcare access play a role in shaping workforce densities? These are critical questions that go unanswered in the paper. The superficial analysis of these disparities gives the impression that the study is more focused on confirming preconceived notions than on uncovering the root causes of inequities in neurosurgery training and practice.

4. Lack of Actionable Recommendations

The study falls short of offering any substantial recommendations to address the glaring gaps in the global neurosurgery workforce. It mentions the correlation between the presence of a neurosurgery society and workforce growth, but this observation is left unexplored. What can be done to create or strengthen neurosurgical societies in underrepresented regions? What specific interventions could rapidly increase neurosurgeon training or resource allocation? The study does not offer concrete strategies for reducing the workforce disparities between high- and low-income countries or improving the infrastructure for neurosurgery in regions with significant gaps. This lack of actionable insights severely weakens the article’s potential impact. At best, it is a descriptive study; at worst, it is an academic exercise that fails to move the needle on the global neurosurgical crisis.

5. Inconsistent and Shallow Statistical Analysis

The study conducts a regression analysis to explore the factors associated with workforce growth, which is an admirable attempt to analyze correlations. However, the presentation of this analysis is shallow, and its implications are underexplored. For example, the authors identify that “increasing global development aid” is associated with neurosurgeon growth, yet they do not discuss how or why this aid contributes to workforce expansion. Is it due to targeted funding for education, infrastructure, or equipment? The lack of detailed interpretation of the regression results leaves the reader with a set of statistical relationships that are not fully explained or contextualized.

6. Missed Opportunity for Global Collaboration and Solutions

What is most disappointing about this study is its failure to leverage the potential for global collaboration to address the crisis. The authors briefly mentions the presence of national neurosurgery societies, but they do not explore how international partnerships, such as those between organizations like the World Federation of Neurosurgical Societies (WFNS) and local governments, could drive workforce expansion. They also miss a critical opportunity to discuss how global networks and knowledge-sharing platforms could be used to help bridge the training gaps. At a time when digital platforms, telemedicine, and international collaborations are increasingly seen as solutions to global health challenges, the study neglects to discuss these possibilities.

Conclusion

In conclusion, the study “Mapping the global neurosurgery workforce. Part 1: Consultant neurosurgeon density” provides an overview of the state of the neurosurgery workforce, but it fails to live up to its potential. The methodology is flawed, the analysis is superficial, and the lack of actionable recommendations makes the study feel like an academic exercise rather than a meaningful contribution to addressing the global neurosurgery crisis. The study’s narrow focus on high-income countries, combined with an insufficient examination of the root causes of regional disparities, leaves much to be desired. To truly make an impact, future research should go beyond the numbers, offering in-depth insights into the systemic barriers that contribute to the neurosurgery workforce gaps and proposing concrete, sustainable solutions for equitable workforce growth worldwide.

The article “Mapping the global neurosurgery workforce. Part 2: Trainee density,” published in *Journal of Neurosurgery*, offers a broad analysis of the distribution and density of neurosurgery trainees worldwide, using a dataset drawn from 187 countries and 25 additional territories, states, and disputed regions. Although the study provides a valuable overview of the global state of neurosurgical training, it suffers from significant limitations and shortcomings in its methodology, analysis, and impact.

1. Methodological Weaknesses

While the authors claim to have surveyed all 193 countries and 26 territories, the methodology for data collection raises concerns. The study’s reliance on “personal contacts” of coauthors and “bibliometric and search engine searches” to identify participants undermines its credibility. The absence of a clear, systematic, or independent verification process for participant inclusion could introduce bias, leading to the exclusion of underrepresented regions or training programs that may not have direct links to prominent neurosurgical societies. This potential sampling bias compromises the validity of the data, especially when making conclusions about global neurosurgical training.

2. Disproportionate Focus on High-Income Countries (HICs)

The study’s findings reveal a striking disparity in trainee density, with high-income countries (HICs) dominating the global landscape of neurosurgery training. While the data from these regions may seem compelling, the disproportionate focus on HICs (with a density of 0.48 trainees per 100,000 people) fails to address the systemic barriers that exist in low-income countries (LICs) and middle-income countries (MICs). The authors provide an extensive comparison of regions but fail to fully explore the reasons behind these disparities. More emphasis should have been placed on why LICs have such limited access to training resources like cadaver laboratories and subspecialty training. By glossing over these issues, the article misses an opportunity to spark deeper discussions on the global inequities in neurosurgery training.

3. Lack of Depth in Analysis of Accreditation and Training Standards

Another critical flaw in the article is its cursory treatment of accreditation processes. While the authors mention that accreditation is more common in HICs than in LICs and MICs, they do not provide enough context on how accreditation impacts training quality. For instance, how do variations in accreditation standards between countries influence the readiness and competence of neurosurgeons entering the workforce? Without a more nuanced analysis of the accreditation systems, including the role of international bodies like the WFNS and EANS, the study misses an important aspect of quality assurance in neurosurgical education.

4. Limited Discussion on Sustainable Solutions

The study rightly identifies disparities in trainee density and resource availability between regions. However, the authors fail to offer substantial recommendations or solutions to address these inequities. Given the critical importance of sustainable neurosurgical education in improving patient outcomes, the article would have benefited from a more robust exploration of global initiatives, partnerships, and funding mechanisms that could help address these gaps. Merely presenting the data without a forward-thinking approach to solving the challenges does little to drive the field of global neurosurgery forward.

5. Failure to Address the Broader Context

While the study provides a valuable snapshot of trainee density, it lacks any significant engagement with the broader socioeconomic, political, and cultural factors that influence neurosurgery training worldwide. For example, in LICs, the availability of neurosurgery training is not just a question of resources but also political will, governance, and the overall health system infrastructure. This oversight makes the conclusions feel somewhat superficial, as the authors do not sufficiently interrogate the broader structural determinants of the observed disparities.

Conclusion

In summary, while *J Neurosurg*’s study offers a broad overview of neurosurgery trainee density globally, it falls short in several critical areas. Its methodology suffers from potential biases, its analysis of global disparities lacks depth, and its conclusions do little to suggest actionable solutions to the pressing issues it highlights. As a result, while the article provides some useful information, it ultimately fails to live up to the importance of the topic it tackles. More rigorous, nuanced, and solution-oriented work is needed to effectively map and address the challenges in global neurosurgical training.

Preoperative embolization of intracranial meningioma

by

Preoperative embolization of intracranial meningioma

Preoperative embolization(POE) of intracranial meningioma is performed worldwide. Although clear evidence of the effectiveness of POE has not been reported in the literature, the technique plays an important role in open surgery, especially for large or skull base meningiomas. The purposes of embolization include: 1)induction of tumor necrosis, resulting in a safer operation, 2)reduction in intraoperative bleeding, and 3)decrease in operative time. Knowledge of the functional vascular anatomy, embolic materials, and endovascular techniques is paramount to ensure safe embolization.

Indication

Tumor vascularity can now be determined using arterial spin labeling and Dynamic Susceptibility Weighted Contrast-Enhanced Perfusion Imaging, allowing the neurosurgeon or neurointerventionalist to assess patient candidacy for Preoperative embolization of intracranial meningioma 1).

Tumor embolization may become an in-office treatment under certain conditions, such as in cases of poor general condition, multiple meningiomas, recurrent and refractory cases, difficult surgery and cases where re-irradiation is difficult after post-radiation therapy 2).

Procedure

The standard procedure is as follows: 1)embolization is performed several days before open surgery; 2)in cases with strong peritumoral edema, steroid administration or embolization may be performed immediately prior to surgery; 3)patients undergo the procedure under local anesthesia; 4)the microcatheter is inserted as close as possible to the tumor; 5)particulate emboli are the first-line material; 6)embolization is occasionally performed with N-butyl cyanoacrylate(NBCA)glue; and 7)if possible, additional proximal feeder occlusion with coils is performed. The JR-NET study previous showed the situation regarding intracranial tumor embolization in Japan. Endovascular neurosurgeons should fully discuss the indications and strategies for POE with tumor neurosurgeons to ensure safe and effective procedures 3).

The superiority and usefulness of liquid material over particles for embolization have been a topic of debate due to differences in materials and techniques. The use of particles in embolization may reduce intraoperative bleeding, but not in all cases can it be used safely. Therefore, a thorough understanding of the characteristics of both approaches and their relative advantages in clinical practice is essential to opt for the appropriate material according to the case 4)

Efficacy

There is no standardized system to assess the efficacy or extent of embolization during the embolization procedure. We sought to establish a purely angiographic grading system to facilitate consistent reporting of the outcome of meningioma embolization and to characterize the anatomic and other features of meningiomas that predict the degree of devascularization achieved through preoperative embolization.

Matsoukas et al. identified patients with meningiomas who underwent preoperative cerebral angiography and subsequent resection between 2015 and 2021. Demographic, clinical, and imaging data were collected in a research registry. We defined an angiographic devascularization grading scale as follows: grade 0 for no embolization, 1 for partial embolization, 2 for majority embolization, 3 for complete external carotid artery embolization, and 4 for complete embolization.

Eighty consecutive patients were included, 60 of whom underwent preoperative tumor embolization (20 underwent angiography with an intention to treat but ultimately not embolization). Embolized tumors were larger (59.0 vs 35.9 cc; P = .03). Gross total resection, length of stay, and complication rates did not differ among groups. The distribution of arterial feeders differed significantly across tumors in a location-specific manner. Both the tumor location and the identity of arterial feeders were predictive of the extent of embolization. Anterior midline meningiomas were associated with internal carotid (ophthalmic, ethmoidal) supply and lower devascularization grades (P = .03). Tumors fed by meningeal feeders (convexity, falcine, lateral sphenoid wing) were associated with higher devascularization grades (P < .01). The procedural complication rate for tumor embolization was 2.5%.

Angiographic outcomes can be graded to indicate the extent of tumor embolization. This system may facilitate consistency of reported angiographic results. In addition, arterial feeders vary in a manner predicted by tumor location, and these patterns correlate with typical degrees of devascularization achieved in those tumor locations 5)

Complications

Hemorrhage (intratumoral and SAH), cranial nerve deficits (usually transient), stroke from embolization through ICA or VA anastomoses, scalp necrosis, retinal embolus, and potentially dangerous tumor swelling. Some meningiomas (e.g. olfactory groove) are less amenable to embolization.

Preoperative embolization has been an option for adjunctive treatment of intracranial meningiomas, but it remains used in only a minority of cases 6).

Systematic review and meta-analysis

In 2021 a systematic review and meta-analysis aimed to evaluate the safety profile of the procedure and to compare outcomes in embolized versus non-embolized meningiomas. PubMed was queried for studies after January 1990 reporting outcomes of Preoperative embolization. Pertinent variables were extracted and synthesized from eligible articles. Heterogeneity was assessed using I2, and a random-effects model was employed to calculate pooled 95% CI effect sizes. Publication bias was assessed using funnel plots and Harbord’s and Begg’s tests. Meta-analyses were used to assess estimated blood loss and operative duration (mean difference; MD), gross-total resection (odds ratio; OR), and postsurgical complications and postsurgical mortality (risk difference; RD). Thirty-four studies encompassing 1782 preoperatively embolized meningiomas were captured. The pooled immediate complication rate following embolization was 4.3% (34 studies, n = 1782). Although heterogeneity was moderate to high (I2 = 35-86%), meta-analyses showed no statistically significant differences in estimated blood loss (8 studies, n = 1050, MD = 13.9 cc, 95% CI = -101.3 to 129.1), operative duration (11 studies, n = 1887, MD = 2.4 min, 95% CI = -35.5 to 30.8), gross-total resection (6 studies, n = 1608, OR = 1.07, 95% CI = 0.8-1.5), postsurgical complications (12 studies, n = 2060, RD = 0.01, 95% CI = -0.04 to 0.07), and post-surgical mortality (12 studies, n = 2060, RD = 0.01, 95% CI = 0-0.01). Although POE is relatively safe, no clear benefit was observed in operative and postoperative outcomes. However, results must be interpreted with caution due to heterogeneity and selection bias between studies. Well-controlled future investigations are needed to define the patient population most likely to benefit from the procedure 7).

Shah et al. analyzed new therapeutic options for the embolization of intracranial meningiomas, as well as the future of meningioma treatment through recent relevant cohorts and articles. They investigate various embolic materials, types of meningiomas amenable to embolization, imaging techniques, and potential imaging biomarkers that could aid in the delivery of embolic materials. They also analyze perfusion status, complications, and new technical aspects of endovascular preoperative embolization of meningiomas. A literature search was performed in PubMed using the terms “meningioma” and “embolization” to investigate recent therapeutic options involving embolization in the treatment of meningioma. They looked at various cohorts, complications, materials, and timings of meningioma treatment. Liquid embolic materials are preferable to particle agents because particle embolization carries a higher risk of hemorrhage. Liquid agents maximize the effect of devascularization because of deeper penetration into the trunk and distal tumor vessels. The 3 main imaging techniques, MRI, CT, and angiography, can all be used in a complementary fashion to aid in analyzing and treating meningiomas. Intraarterial perfusion MRI and a new imaging modality for identifying biomarkers, susceptibility-weighted principles of echo shifting with a train of observations (SW-PRESTO), can relay information about perfusion status and degrees of ischemia in embolized meningiomas, and they could be very useful in the realm of therapeutics with embolic material delivery. Direct puncture is yet another therapeutic technique that would allow for more accurate embolization and less blood loss during resection 8).

Preoperative embolization of skull base meningioma

Preoperative embolization of skull base meningioma

Case series

Akimoto et al. retrospectively reviewed the medical records of 186 patients with WHO grade I meningiomas who underwent surgical treatment at our hospital between January 2010 and December 2020. We used propensity score matching to generate embolization and no-embolization groups (42 patients each) to examine embolization effects.

Results: Preoperative embolization was performed in 71 patients (38.2%). In the propensity-matched analysis, the embolization group showed favorable recurrence-free survival (RFS) (mean 49.4 vs 24.1 months; Wilcoxon p=0.049). The embolization group had significantly less intraoperative blood loss (178±203 mL vs 221±165 mL; p=0.009) and shorter operation time (5.6±2.0 hours vs 6.8±2.8 hours; p=0.036). There were no significant differences in Simpson grade IV resection (33.3% vs 28.6%; p=0.637) or overall perioperative complications (21.4% vs 11.9%; p=0.241). Tumor embolization prolonged RFS in a subanalysis of cases who experienced recurrence (n=39) among the overall cases before variable control (mean RFS 33.2 vs 16.0 months; log-rank p=0.003).

Conclusions: After controlling for variables, preoperative embolization for meningioma did not improve the Simpson grade or patient outcomes. However, it might have effects outside of surgical outcomes by prolonging RFS without increasing complications 9)

Rapper et al. performed a retrospective review of patients undergoing intracranial meningioma resection between (March 2001 to December 2012). Comparisons were made between embolized and nonembolized patients, including patient and tumor characteristics, embolization method, operative blood loss, complications, and extent of resection. Logistic regression analyses were used to identify factors predictive of operative blood loss and extent of resection.

Results: Preoperatively, 224 patients were referred for embolization, of which 177 received embolization. No complications were seen in 97.1%. There were no significant differences in operative duration, extent of resection, or complications. Estimated blood loss was higher in the embolized group (410 versus 315 mL, P=.0074), but history of embolization was not a predictor of blood loss in multivariate analysis. Independent predictors of blood loss included decreasing degree of tumor embolization (P=.037), skull base location (P=.005), and male sex (P=.034). Embolization was not an independent predictor of gross total resection.

Conclusions: Preoperative embolization is a safe option for selected meningiomas. In our series, embolization did not alter the operative duration, complications, or degree of resection, but the degree of embolization was an independent predictor of decreased operative blood loss 10)

This study is based on personal experience with about 100 embolized meningiomas and on the experience of others. Embolization is performed during the same session as diagnostic angiography. The appropriate embolic materials (absorbable or nonabsorbable) are chosen according to the location of the tumor, the size of the feeding arteries, the blood flow, and the presence of any potentially dangerous vessels (dangerous anastomoses between external carotid artery and internal carotid or vertebral arteries, arteries supplying the cranial nerves). Preoperative embolization appeared to be very useful in large tumors with pure or predominant external carotid artery supply (convexity meningiomas), in skull-base meningiomas, and in middle fossa and paracavernous meningiomas. It was also useful in falx and parasagittal meningiomas receiving blood supply from the opposite side and in posterior fossa meningiomas. CT low densities demonstrated after embolization did not always correlate with necrosis on microscopic examination, and large areas of infarction could be found despite normal CT. Embolic material was found on pathologic examination in 10%-30% of cases; fresh or recent ischemic and/or hemorrhagic necrosis consistent with technically successful embolization was demonstrated in 40%-60% of cases. With careful technique complications are rare 11)

Case reports

A case of hemorrhage in a parasellar meningioma shortly after embolization of the dural cavernous carotid artery branches supplying the tumor. This represents the first report of hemorrhage within a meningioma resulting from embolization with small (50 to 150-microns) polyvinyl alcohol particles, as well as the first reported case of hemorrhage complicating meningioma embolization from internal rather than external carotid artery branch embolization. We also review previously reported cases of postembolization hemorrhage from meningiomas 12).

1)

Beutler BD, Lee J, Edminster S, Rajagopalan P, Clifford TG, Maw J, Zada G, Mathew AJ, Hurth KM, Artrip D, Miller AT, Assadsangabi R. Intracranial meningioma: A review of recent and emerging data on the utility of preoperative imaging for management. J Neuroimaging. 2024 Aug 7. doi: 10.1111/jon.13227. Epub ahead of print. PMID: 39113129.
2)

Akimoto T, Nakai Y. [Preoperative Embolization Performed Before Meningioma Resection Might Inhibit Tumor Recurrence]. No Shinkei Geka. 2024 Jul;52(4):846-850. Japanese. doi: 10.11477/mf.1436204983. PMID: 39034522.
3)

Soutome Y, Sugiu K, Hiramatsu M, Haruma J, Ebisudani Y, Kimura R, Edaki H, Kawakami M, Fujita J, Tanaka S. [Preoperative Embolization of Intracranial Meningioma]. No Shinkei Geka. 2024 Jul;52(4):794-804. Japanese. doi: 10.11477/mf.1436204978. PMID: 39034517.
4)

Iida Y, Akimoto T, Miyake S, Suzuki R, Shimohigoshi W, Hori S, Suenaga J, Nakai Y, Sakata K, Yamamoto T. Differences and Advantages of Particles versus Liquid Material for Preoperative Intracranial Tumor Embolization: A Retrospective Multicenter Study. J Neuroendovasc Ther. 2024;18(4):110-118. doi: 10.5797/jnet.oa.2023-0083. Epub 2024 Feb 20. PMID: 38721619; PMCID: PMC11076144.
5)

Matsoukas S, Feng R, Faulkner DE, Odland IC, Durbin J, Tabani H, Schlachter L, Gutzwiller E, Kellner CP, Shigematsu T, Shoirah H, Majidi S, De Leacy R, Berenstein A, Mocco J, Fifi JT, Bederson JB, Shrivastava RK, Rapoport BI. Angiographic Features of Meningiomas Predicting Extent of Preoperative Embolization. Neurosurgery. 2024 Aug 1. doi: 10.1227/neu.0000000000003054. Epub ahead of print. PMID: 39087784.
6)

Shah AH, Patel N, Raper DM, et al. The role of preoperative embolization for intracranial meningiomas. J Neurosurg 2013;119: 364 –72
7)

Jumah F, AbuRmilah A, Raju B, Jaber S, Adeeb N, Narayan V, Sun H, Cuellar H, Gupta G, Nanda A. Does preoperative embolization improve outcomes of meningioma resection? A systematic review and meta-analysis. Neurosurg Rev. 2021 Mar 16. doi: 10.1007/s10143-021-01519-z. Epub ahead of print. PMID: 33723970.
8)

Shah A, Choudhri O, Jung H, Li G. Preoperative endovascular embolization of meningiomas: update on therapeutic options. Neurosurg Focus. 2015 Mar;38(3):E7. doi: 10.3171/2014.12.FOCUS14728. PubMed PMID: 25727229.
9)

Akimoto T, Ohtake M, Miyake S, Suzuki R, Iida Y, Shimohigoshi W, Higashijima T, Nakamura T, Shimizu N, Kawasaki T, Sakata K, Yamamoto T. Preoperative tumor embolization prolongs time to recurrence of meningiomas: a retrospective propensity-matched analysis. J Neurointerv Surg. 2022 Jul 8:neurintsurg-2022-019080. doi: 10.1136/neurintsurg-2022-019080. Epub ahead of print. PMID: 35803729.
10)

Raper DM, Starke RM, Henderson F Jr, Ding D, Simon S, Evans AJ, Jane JA Sr, Liu KC. Preoperative embolization of intracranial meningiomas: efficacy, technical considerations, and complications. AJNR Am J Neuroradiol. 2014 Sep;35(9):1798-804. doi: 10.3174/ajnr.A3919. Epub 2014 Apr 10. PMID: 24722303; PMCID: PMC7966288.
11)

Manelfe C, Lasjaunias P, Ruscalleda J. Preoperative embolization of intracranial meningiomas. AJNR Am J Neuroradiol. 1986 Sep-Oct;7(5):963-72. PMID: 3096121; PMCID: PMC8331988.
12)

Kallmes DF, Evans AJ, Kaptain GJ, Mathis JM, Jensen ME, Jane JA, Dion JE. Hemorrhagic complications in embolization of a meningioma: case report and review of the literature. Neuroradiology. 1997 Dec;39(12):877-80. Review. PubMed PMID: 9457715.