Category: Oncology

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Advances of MR imaging in glioma: what the neurosurgeon needs to know

Acta Neurochirurgica (2025) 167:174

Advanced MRI techniques—including perfusion, diffusion, spectroscopy, and functional imaging—are critical in glioma diagnosis, surgical planning, and treatment monitoring. These modalities improve tumor characterization, guide safer resections, and help distinguish tumor progression from treatment effects, supporting precision neurosurgical oncology and personalized care.

• High-grade gliomas are aggressive brain tumors with poor prognosis, requiring advanced imaging for diagnosis and management.

• MRI is central throughout the patient journey, from initial detection and differential diagnosis to surgical planning, treatment response, and surveillance.

• Advanced MRI techniques—perfusion, diffusion, spectroscopy, fMRI, and DTI—improve tumor characterization, surgical planning, and assessment of infiltration and eloquent cortex involvement.

• Perfusion MRI (DSC, DCE, ASL) and DWI help distinguish high-grade gliomas from mimics and guide biopsy or surgery.

• MR spectroscopy provides metabolic information, aiding in differentiating gliomas from metastases and guiding surgical margins.

• Postoperative MRI is crucial for assessing residual tumor, complications, and radiotherapy planning.

• MRI during treatment surveillance helps differentiate true progression from pseudoprogression or radiation necrosis.

• Future advances include higher field strengths, molecular imaging, and AI integration for precision neuro-oncology.

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Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines Update for the Role of Emerging Therapies in the Management of Patients With Metastatic Brain Tumors

Neurosurgery 96:1172–1177, 2025

This 2025 CNS guideline update reviews evidence for emerging therapies in adult brain metastases, providing new recommendations on targeted therapies, immunotherapy, radiosensitizers, and laser interstitial thermal therapy, while noting insufficient evidence for some modalities. Recommendations aim to guide multidisciplinary management beyond standard surgical and radiation treatments.

• This guideline is an updated systematic review on emerging therapies for adult patients with metastatic brain tumors (MBTs), focusing on evidence-based recommendations.

• Targeted therapies and immunotherapies have the strongest new evidence, especially for NSCLC, melanoma, and breast cancer brain metastases.

• Level I recommendations include the use of specific agents such as icotinib with WBRT for EGFR-mutant NSCLC, alectinib for ALK-positive NSCLC, and dabrafenib plus trametinib for BRAFV600E-positive melanoma.

• Immune checkpoint inhibitors (e.g., ipilimumab plus nivolumab for melanoma, ICIs for NSCLC) are recommended to improve survival and intracranial control in selected patients.

• Laser interstitial thermal therapy (LITT) may be considered equivalent to craniotomy or medical management in certain cases of tumor progression or radiation necrosis after SRS.

• There is insufficient evidence to recommend interstitial modalities or high-intensity focused ultrasound (HIFU) for brain metastases.

• Future research should prioritize prospective, comparative studies for modalities like LITT and HIFU, and the guideline will be updated as new evidence emerges.

• Clinical decisions should be individualized, and participation in clinical trials is encouraged to refine treatment strategies for MBTs.

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Decoding Glioblastoma Heterogeneity: Neuroimaging Meets Machine Learning

Neurosurgery 96:1181–1192, 2025

This review highlights how advanced neuroimaging and machine learning, especially radiomics and deep learning models, are transforming the noninvasive diagnosis, molecular characterization, and prognosis prediction in IDH-wildtype glioblastoma, offering improved patient stratification and personalized treatment strategies while emphasizing the need for further clinical integration.

• Neuroimaging and machine learning have greatly improved diagnosis, classification, and prognosis of IDH-wildtype glioblastoma, a highly heterogeneous and aggressive brain tumor.

• Advanced MRI techniques, including diffusion tensor imaging (DTI) and radiomics, provide noninvasive insights into tumor infiltration, metabolic profiles, and microstructural changes.

• Machine learning algorithms, especially CNNs, enhance glioblastoma characterization, enabling accurate prediction of genetic mutations, IDH status, tumor subtypes, and survival outcomes.

• Radiomics extracts quantitative features from neuroimages, serving as potential biomarkers for tumor classification, prognosis, and guiding treatment strategies.

• Integration of radiomics and machine learning helps differentiate pseudoprogression from true tumor progression and predicts patterns of tumor invasion and recurrence.

• Imaging biomarkers and machine learning models are promising but remain complementary to molecular diagnostics and are not yet standard in clinical practice.

• Ongoing research aims to refine models, integrate emerging imaging techniques, and better link imaging features to underlying molecular processes for personalized therapy.

• The synergy of neuroimaging and AI is expected to enable noninvasive, precision management and better outcomes for glioblastoma patients.

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Prognostic value of manual versus automatic methods for assessing extents of resection and residual tumor volume in glioblastoma

J Neurosurg 142:1298–1306, 2025

This study compares manual and automatic methods for assessing tumor resection extent and residual volume in glioblastoma patients. It finds that both methods have comparable prognostic value, suggesting that automatic segmentation with Raidionics is a viable alternative for future studies.

• Objective: The study compares the prognostic value of manual versus automatic methods for assessing the extent of resection (EOR) and residual tumor (RT) volume in glioblastoma patients.

• Methods: Patients from 12 hospitals in Europe and North America underwent glioblastoma resection and were included in the study. Data were collected from local tumor registries and patient medical records.

• Results: Both manual and automatic RT volumes were negative prognostic factors for overall survival. Automatic segmentation with Raidionics showed comparable prognostic properties to manual measurements.

• Automatic Segmentation: Raidionics, an open-access software, performed automatic segmentation using pretrained deep learning models, which showed high quality and robustness.

• Survival Analysis: Cox regression models indicated that patients with gross-total resection had significantly longer overall survival compared to those with subtotal resection.

• Advantages of Automatic Methods: Automatic segmentation offers fast, quantitative image assessments and reduces interobserver variability, making it suitable for clinical trials.

• Limitations: Some cases showed a mismatch between manual and automatic segmentation, often due to poor-quality MR images or heterogeneous tumors.

• Conclusion: Automatic segmentation is a viable alternative to manual methods for evaluating tumor remnants, with similar prognostic value for survival in glioblastoma patients.

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Electrocorticography and navigated transcranial magnetic stimulation–tailored supratotal resection for epileptogenic low-grade gliomas

J Neurosurg 142:918–926, 2025

The study evaluates ECoG-nTMS–tailored supratotal resection (ETT-SpTR) for low-grade gliomas with epilepsy, demonstrating improved seizure control and preserved neurological function compared to gross-total resection. ETT-SpTR effectively identifies high-risk epilepsy areas, enhancing epileptic and functional outcomes without permanent deficits.

• Objective: Evaluate the effectiveness of ECoG-nTMS–tailored supratotal resection (ETT-SpTR) for low-grade gliomas (LGGs) in controlling seizures and preserving neurological function.

• Methods: Retrospective analysis of patients with LGG and epileptic seizures undergoing resective surgery, comparing gross-total resection (GTR) with ETT-SpTR.

• Results: ETT-SpTR significantly improved seizure control (85.7% Engel class IA) compared to GTR (25% Engel class IA) with no permanent neurological deficits.

• Conclusion: ETT-SpTR is effective in improving epileptic outcomes and preserving functions without causing permanent neurological worsening.

• Preoperative Techniques: Functional cortical areas were identified using TMS, and ECoG guided the removal of high-risk epilepsy areas (HREAs).

• Statistical Analysis: Significant differences in seizure control between groups, with ETT-SpTR showing better outcomes.

• Limitations: Small patient cohort and limited follow-up period; future studies required for confirmation.

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Mental fatigue and cognitive functioning in patients presenting with non-enhancing gliomas

Acta Neurochirurgica (2025) 167:63

The study investigates the relationship between mental fatigue and cognitive functioning in patients with lower-grade gliomas (LGG) before surgery. It found a consistent correlation between self-reported mental fatigue and cognitive functioning but no correlation between self-reports and neuropsychological test results, highlighting the complexity of evaluating these symptoms.

• Study Purpose: Investigate mental fatigue and cognitive functioning in LGG patients pre-surgery.

• Patient Cohort: 101 patients with presumed LGG; 71 with confirmed IDH-mutated LGG.

• Methods: Self-reports, neuropsychological tests, and clinical/demographic data collected.

• Key Findings: No strong correlation between self-reports and neuropsychological tests.

• Correlation: A strong link was found between self-reported mental fatigue and cognitive functioning.

• Tumor Localization: Frontal tumors had more oligodendrogliomas; non-frontal had more glioblastomas.

• Neuropsychological Impairment: Higher RAVLT, FAS, and CWT test impairment rates.

• Statistical Analysis: Spearman’s partial correlations assess variable relationships.

• Clinical Implications: Need for a multi-perspective approach in evaluating LGG patient symptoms.

• Research Recommendations: Larger cohort studies and quantitative tumor localization metrics are suggested.

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Genomic Alterations in Molecularly Defined Oligodendrogliomas

Neurosurgery 96:328–337, 2025

• Study Focus: Genomic alterations in oligodendrogliomas using standardized NGS panels.

• Key Genes: CIC, FUBP1, and TERTp are the most frequently altered genes.

• Patient Cohort: Retrospective analysis of 95 patients with NGS reports.

• Methodology: Kaplan-Meier plots and log-rank tests for survival analysis.

• Findings: CIC alterations linked to reduced PFS at earlier time points.

• Additional Genes: NOTCH1 and PIK3CA show potential prognostic value.

• Clinical Implications: Potential integration of genomic alterations into clinical practice.

• Future Research: Larger studies needed to validate findings.

• Seizures: Most common presenting symptom in patients.

• Treatment: Majority underwent surgery followed by observation.

• Tumor Grade: Predominantly WHO grade 2 at first surgery.

• Mutation Analysis: 435 cancer-related genes analyzed.

• Statistical Tools: MATLAB R2022b used for analysis.

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Clinical Predictors of Overall Survival in Very Elderly Patients With Glioblastoma: A National Cancer Database Multivariable Analysis

Neurosurgery 96:373–385, 2025

• Study Focus: The study analyzes clinical predictors of overall survival in very elderly patients (aged 80 and older) with glioblastoma, using data from the National Cancer Database.

• Patient Demographics: It includes 578 very elderly patients and 2836 elderly patients (aged 65-79), highlighting differences in insurance status and treatment patterns.

• Treatment Patterns: Very elderly patients are less likely to receive gross total resection (GTR), radiotherapy (RT), or chemotherapy (CT) compared to younger elderly counterparts, despite these treatments improving overall survival.

• Survival Outcomes: GTR, RT, and CT are associated with improved survival in very elderly patients, suggesting aggressive treatment may benefit selected patients.

• Statistical Methods: The study employs multivariable regression analysis and Cox proportional-hazards models to assess the effects of age and treatment on survival.

• Key Findings: Aggressive treatment approaches, including GTR, RT, and CT, should be considered for very elderly patients, aligning with patient and family goals.

• Limitations: The study acknowledges limitations in meeting the Cox proportional hazard assumption and suggests further research on quality of life post-treatment.

• Conclusion: The study supports offering standard multimodal treatment protocols for glioblastoma to patients aged 65 and older, enhancing external validity across the U.S.

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Presentation, surgical outcome, and supplementary motor area syndrome risk of posterior superior frontal gyrus tumors

J Neurosurg 142:162–173, 2025

Following resection of posterior superior frontal gyrus (PSFG) tumors, patients can experience supplementary motor area (SMA) syndrome consisting of contralateral hemiapraxia and/or speech apraxia. Given the heterogeneity of PSFG tumors, the authors sought to determine the risk of postoperative deficits and assess predictors of outcomes for all intraparenchymal PSFG tumors undergoing surgery (biopsy or resection), regardless of histology.

METHODS This was a retrospective single-center cohort study of adult PSFG-region tumors undergoing biopsy or resection by a single surgeon.

RESULTS A total of 106 consecutive patients undergoing 123 procedures (21 biopsies, 102 resections) fulfilled inclusion and exclusion criteria. Anaplastic astrocytomas were the most frequent among resected tumors (39% vs 29%), while glioblastomas were most common among biopsies (38% vs 27%) (p < 0.0001). The biopsy cohort was more likely to have tumor involvement outside the PSFG (90% vs 62%) (p = 0.011), most commonly in the motor cortex (67% vs 31%) (p = 0.005). Seizures were the most common presenting symptom in the resection cohort (p = 0.017), while motor deficits were more common in the biopsy cohort (58% vs 29%) (p < 0.001). Immediate postoperative neurological deficits occurred in 71 cases (58%), but only 3 of the deficits were permanent at 6 months of follow-up (2%). Postoperative SMA syndrome occurred in 48 cases (47%) and was significantly associated with involvement of the motor cortex (p = 0.018) or cingulate gyrus (p = 0.023), which were also significant in multivariate analysis as risk factors for SMA syndrome. However, postoperative SMA syndrome was not significantly associated with overall survival (p = 0.51). There were no perioperative deaths, but corpus callosum involvement (p < 0.001), contrast enhancement (p = 0.003), and glioblastoma pathology (p = 0.038) predicted worse overall survival in patients undergoing resection.

CONCLUSIONS Nearly half of all patients undergoing resection of PSFG-region tumors experience a postoperative SMA syndrome. Individuals with corpus callosum and/or motor cortex involvement may be at an increased risk of experiencing SMA syndrome. However, these deficits are usually transient, and the risk of permanent new deficits is very low (3%). Preoperative characteristics including corpus callosum involvement and tumor enhancement—in addition to pathology—might serve as predictors of overall survival within this patient population.

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Long-term survivors in 976 supratentorial glioblastoma, IDH-wildtype patients

J Neurosurg 142:174–186, 2025

Glioblastoma, isocitrate dehydrogenase (IDH)–wildtype is the most aggressive glioma with poor outcomes. The authors explored survival rates and factors associated with long-term survival in patients harboring a glioblastoma, IDH-wildtype.

METHODS In an observational, retrospective, single-center study, the authors examined the medical records of 976 adults newly diagnosed with supratentorial glioblastomas, IDH-wildtype between January 2000 and January 2021. They analyzed clinical-, imaging-, and treatment-related factors associated with 2-year and 5-year survival.

RESULTS The median overall survival was 11.2 months (12.2 months for patients included after 2005 and the introduction of standard combined chemoradiotherapy). The median progression-free survival was 9.4 months (10.0 months for patients included after 2005). Overall, 17.6% of patients reached a 2-year overall survival, while 2.2% of patients reached a 5-year overall survival. Furthermore, 6.6% of patients survived 2 years without progression, while 1.1% of patients survived 5 years without progression. Two factors that were consistently associated with 2-year and 5-year survival were first-line oncological treatment with standard combined chemoradiotherapy and methylated O 6 -methylguanineDNA methyltransferase promoter. Other factors that were significantly associated with 2-year or 5-year survival were age at diagnosis ≤ 60 years, headaches or signs of raised intracranial pressure at diagnosis, cortical contact of contrast enhancement, no contrast enhancement crossing the midline on initial imaging, total or subtotal tumor resection, and a second line of oncological treatment at recurrence. Within 21 cases of 5-year survival, 18 were confirmed to be glioblastomas, IDH-wildtype, and 7 of the 5-year survivors (38.9%) had additional genetic alterations: 3 cases had an FGFR mutation or fusion, 3 cases had a PIK3CA mutation, 1 case had a PTPN11 mutation, and 1 case had a PMS2 mutation in the context of constitutional mismatch repair deficiency syndrome.

CONCLUSIONS Five-year overall survival in patients with glioblastoma, IDH-wildtype is extremely low. Predictors of a longer survival are mostly treatment factors, emphasizing the importance of a complete oncological treatment plan, when achievable. Glioblastoma, IDH-wildtype 5-year survivors could be screened for actionable targets in case of recurrence.

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Noninvasive evaluation of the glymphatic system in diffuse gliomas using diffusion tensor image analysis along the perivascular space

J Neurosurg 142:187–196, 2025

The aim of this study was to noninvasively explore the glymphatic system (GS) in glioma and its association with glioma characteristics and prognosis by using diffusion tensor image analysis along the perivascular space (ALPS).

METHODS In the period from April 2015 to November 2021, all patients with pathologically confirmed unihemispheric glioma who had not undergone surgery, chemotherapy, radiotherapy, or stereotactic biopsy; who did not have severe brain deformation; who had undergone preoperative conventional and advanced whole-brain diffusion-weighted imaging; and whose data were available and uncompromised were included in this study. Age- and sex-matched healthy controls (HCs) who had undergone diffusion-weighted imaging were also included. The ALPS index was calculated based on diffusivity maps, allowing noninvasive analysis of the GS. The contralateral ALPS index was measured in all glioma patients, and the ipsilateral ALPS index was measured in glioma patients without severe deformation of the ipsilateral hemisphere. The ALPS index was compared between glioma patients and HCs according to tumor grade, IDH genotype, tumor and edema volume, and tumor location. The association between the bilateral ALPS index of gliomas and tumor characteristics was further analyzed. Survival analysis was conducted using Kaplan-Meier survival curves with the logrank test and univariable and multivariable Cox regressions.

RESULTS Ninety-one patients with unihemispheric glioma (33 female, mean age 46 ± 13 years) and 59 age- and sex-matched HCs were included in this study. The ipsilateral ALPS index decreased in the glioma group versus the HC group, regardless of tumor grade, IDH genotype, tumor and edema volume, or tumor location (p ≤ 0.048), whereas the contralateral ALPS index decreased in gliomas with a high grade, IDH wildtype, larger edema volume, different tumor volumes and locations (p ≤ 0.009). The ipsilateral versus contralateral ALPS index was lower regardless of tumor grade, IDH genotype, tumor and edema volume, or tumor location (p ≤ 0.044). Univariable linear regression revealed age (β = −0.004, p = 0.026), tumor grade (β = −0.114, p = 0.011), and IDH genotype (β = 0.120, p = 0.008) were associated with the ipsilateral ALPS index in glioma. Age (β = −0.005, p < 0.001), tumor grade (β = −0.144, p < 0.001), IDH genotype (β = 0.154, p < 0.001), tumor volume (β = −0.002, p = 0.001), and peritumoral edema volume (β = −0.002, p < 0.001) were correlated with the contralateral ALPS index in glioma. Multivariable linear regression revealed that tumor grade (β = −0.125, p = 0.005) was independently associated with the ipsilateral ALPS index. Age (β = −0.003, p = 0.022), IDH status (β = 0.132, p = 0.001), and tumor volume (β = −0.002, p < 0.001) were independently associated with the contralateral ALPS index. Kaplan-Meier analysis showed different survival times between low and high contralateral ALPS groups (log-rank = 10.574, p = 0.001). Univariable Cox regression analysis demonstrated that the lower contralateral ALPS index was related to a shorter survival time (HR 0.095, p = 0.005). Multivariable Cox regression analysis revealed IDH status as the only independent factor for survival (HR 0.138, p < 0.001).

CONCLUSIONS GS function was impaired in glioma and correlated with tumor characteristics, and worse contralateral GS function was associated with a shorter survival time.

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Microsurgical anatomy and approaches to thalamic gliomas. Part 2: Maximal safe resection of thalamic gliomas improves outcomes.

J Neurosurg 141:1472–1483, 2024

As presented in Part 1 of this series, thalamic gliomas (TGs) are deep-seated, difficult-to-access tumors surrounded by vital neurovascular structures. Given their high operative morbidity, TGs have historically been considered inoperable lesions. Although maximal safe resection (MSR) has become the treatment standard for lobar and even deep-seated mediobasal temporal and insular gliomas, the eloquent location of TGs has precluded this management strategy, with biopsy and adjuvant treatment being the mainstay. The authors hypothesized that MSR can be achieved with low morbidity and mortality for TGs, thus resulting in improved outcomes.

METHODS A retrospective single-center study was performed on all TG patients from 2006 to 2020. Clinical, imaging, and pathology reports were obtained. Univariate and multivariate analyses were performed to determine prognostic variables. Case examples illustrate various approaches and the rationale for staging resections of more complex TGs.

RESULTS A total of 42 patients (26 males, 16 females), among them 12 pediatric (29%) cases, were included. Their mean age was 36.0 ± 21.4 (median 30, range 3–73) years. The median maximal tumor diameter was 45 (range 19–70) mm. Eighteen patients (43%) had a prior stereotactic needle tumor biopsy, with the ultimate diagnosis changed for 7 patients (39%) following microsurgical resection. The most common surgical approaches were transtemporal (29%), anterior interhemispheric transcallosal (29%), and superior parietal lobule (25%). Overall, the combined subtotal and grosstotal resection rate was 95% (n = 40). Low-grade gliomas (LGGs; grades I and II) comprised one-third of the group, whereas half of the patients had glioblastoma multiforme. There were no operative mortalities. Although temporary postoperative motor deficits were observed in 12 patients (28.6%), all improved during the early postoperative period except 1 (2.4%), who had mild residual hemiparesis. Two patients required CSF diversion for hydrocephalus. The 2-year overall survival rate was 90% for LGG patients and 15% for high-grade glioma (HGG) patients. Multivariate analysis revealed that histological grade, age, and extent of resection were independent prognostic factors associated with survival.

CONCLUSIONS Management of TGs is challenging, with resection avoided by many, if not most, neurosurgeons, especially for HGGs. The results reported here demonstrate improved outcomes with resection, particularly in younger LGG patients. The authors therefore advocate for MSR for a select cohort of TG patients using carefully planned surgical approaches, contemporary intraoperative adjuncts, and meticulous microsurgical techniques.

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The dural attachment length predict prognosis in patients with recurrent meningiomas

Neurosurgical Review (2024) 47:843

To investigate the prognostic factors of recurrent meningioma patients who underwent reoperation, so as to make relevant recommendations for the treatment.

A retrospective analysis was performed on 73 patients with recurrent meningioma. Patients’ clinical data were obtained from their medical records. Progression-free Survival (PFS) was defined as the interval from the date of surgery to the date of tumor recurrence, or to the date of the last imaging review. Overall survival (OS) was defined as the time from the date of surgery to death from any cause, or to the date of the last follow-up.

The multivariate COX regression showed that dural attachment length (HR = 1.238, 95%CI1.011–1.516, P = 0.039) and WHO grade (HR = 2.184, 95%CI1.135–4.203, P = 0.019) were independent risk factors for tumor progression. The factors associated with survival in multivariate regression analysis were preoperative Karnofsky Performance Scale (KPS) (HR = 0.951, 95%CI0.923–0.979, P = 0.001), dural attachment length (HR = 1.520, 95%CI1.124–2.057, P = 0.007) and WHO grade (HR = 4.829, 95%CI1.89112.331, P = 0.001). The dural attachment length (OR = 1.843, 95%CI1.236–2.748, P = 0.003) was the only risk factor associated with postoperative pulmonary infection. No correlation was observed between Simpson’s grade and either PFS or OS.

The dural attachment length is closely related to the prognosis of recurrent meningioma, which should be given importance during the perioperative assessment.

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Microscope-integrated optical coherence tomography for in vivo human brain tumor detection with artificial intelligence

J Neurosurg 141:1343–1351, 2024

It has been shown that optical coherence tomography (OCT) can identify brain tumor tissue and potentially be used for intraoperative margin diagnostics. However, there is limited evidence on its use in human in vivo settings, particularly in terms of its applicability and accuracy of residual brain tumor detection (RTD). For this reason, a microscope-integrated OCT system was examined to determine in vivo feasibility of RTD after resection with automated scan analysis.

METHODS Healthy and diseased brain was 3D scanned at the resection edge in 18 brain tumor patients and investigated for its informative value in regard to intraoperative tissue classification. Biopsies were taken at these locations and labeled by a neuropathologist for further analysis as ground truth. Optical OCT properties were obtained, compared, and used for separation with machine learning. In addition, two artificial intelligence–assisted methods were utilized for scan classification, and all approaches were examined for RTD accuracy and compared to standard techniques.

RESULTS In vivo OCT tissue scanning was feasible and easily integrable into the surgical workflow. Measured backscattered light signal intensity, signal attenuation, and signal homogeneity were significantly distinctive in the comparison of scanned white matter to increasing levels of scanned tumor infiltration (p < 0.001) and achieved high values of accuracy (85%) for the detection of diseased brain in the tumor margin with support vector machine separation. A neuronal network approach achieved 82% accuracy and an autoencoder approach 85% accuracy in the detection of diseased brain in the tumor margin. Differentiating cortical gray matter from tumor tissue was not technically feasible in vivo.

CONCLUSIONS In vivo OCT scanning of the human brain has been shown to contain significant value for intraoperative RTD, supporting what has previously been discussed for ex vivo OCT brain tumor scanning, with the perspective of complementing current intraoperative methods for this purpose, especially when deciding to withdraw from further resection toward the end of the surgery.

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Use of circulating tumor cells and microemboli to predict diagnosis and prognosis in diffuse glioma

J Neurosurg 141:673–683, 2024

Circulating tumor cell (CTC) detection is a promising noninvasive technique that can be used to diagnose cancer, monitor progression, and predict prognosis. In this study, the authors aimed to investigate the clinical utility of CTCs in the management of diffuse glioma.

METHODS Sixty-three patients with newly diagnosed diffuse glioma were included in this multicenter clinical cohort. The authors used a platform based on isolation by size of epithelial tumor cells (ISET) to detect and analyze CTCs and circulating tumor microemboli (CTMs) in the peripheral blood of patients both before and after surgery. Least absolute shrinkage and selector operation (LASSO) and Cox regression analyses were used to verify whether CTCs and CTMs are independent prognostic factors for diffuse glioma.

RESULTS CTC levels were closely related to the degree of malignancy, WHO grade, and pathological subtypes. Receiver operating characteristic curve analysis revealed that a high CTC level was a predictor for glioblastoma. The results also showed that CTMs originate from the parental tumor rather than from the circulation and are an independent prognostic factor for diffuse glioma. The postoperative CTC level is related to the peripheral immune system and patient survival. Cox regression analysis showed that postoperative CTC levels and CTM status are independent prognostic factors for diffuse glioma, and CTC- and CTM-based survival models had high accuracy in internal validation.

CONCLUSIONS The authors revealed a correlation between CTCs and clinical characteristics and demonstrated that CTCs and CTMs are independent predictors for the diagnosis and prognosis of diffuse glioma. Their CTC- and CTMbased survival models can enable clinicians to evaluate patients’ response to surgery as well as their outcomes.

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Berberine as a potential enhancer for 5-ALA–mediated fluorescence in glioblastoma

J Neurosurg 141:653–663, 2024

The prognosis of glioblastoma (GBM) correlates with residual tumor volume after surgery. In fluorescenceguided surgery, 5-aminolevulinic acid (ALA) has been used to maximize resection while avoiding neurological morbidity. However, not all tumor cells, particularly glioma stem cells (GSCs), display 5-ALA–mediated protoporphyrin IX (PpIX) fluorescence (5-ALA fluorescence). The authors searched for repositioned drugs that affect mitochondrial functions and energy metabolism, identifying berberine (BBR) as a potential enhancer of 5-ALA fluorescence. In this study, they investigated whether BBR can enhance 5-ALA fluorescence in GSCs and whether BBR can be applied to clinical practice as a 5-ALA fluorescence enhancer.

METHODS The effects of BBR on 5-ALA fluorescence in glioma and GSCs were evaluated by flow cytometry (fluorescence-activated cell sorting [FACS]) analysis. As 5-ALA is metabolized for heme synthesis, the effects of BBR on mRNA expressions of 7 enzymes in the heme-synthesis pathway were analyzed. Enzymes showing significantly higher expression than control in all cells were identified and protein analysis was performed. To examine clinical availability, the detectability and cytotoxicity of BBR in tumor-transplanted mice were analyzed.

RESULTS Fluorescence microscopy revealed much more intense 5-ALA fluorescence in both GSCs and non-stem cells with 5-ALA and BBR than with 5-ALA alone. FACS showed that BBR greatly enhanced 5-ALA fluorescence compared with 5-ALA alone, and enhancement was much higher for GSCs than for glioma cells. Among the 7 enzymes examined, BBR upregulated mRNA expressions of ALA synthetase 1 (ALAS1) more highly in all cells, and activated ALAS1 through deregulating ALAS1 activity inhibited by the negative feedback of heme. An in vivo study showed that 5-ALA fluorescence with 5-ALA and BBR was significantly stronger than with 5-ALA alone, and the sensitivity and specificity of BBR-enhanced fluorescence were both 100%. In addition, BBR did not show any cytotoxicity for normal brain tissue surrounding the tumor mass.

CONCLUSIONS BBR enhanced 5-ALA–mediated PpIX fluorescence by upregulating and activating ALAS1 through deregulation of negative feedback inhibition by heme. BBR is a clinically used drug with no side effects. BBR is expected to significantly augment fluorescence-guided surgery and photodynamic therapy.

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Longitudinal brain volumetrics in glioma survivors

J Neurosurg 141:634–641, 2024

Radiation therapy (RT) is used selectively for patients with low-grade glioma (LGG) given the concerns for potential cognitive effects in survivors, but prior cognitive outcome studies among LGG survivors have had inconsistent findings. Translational studies that characterize changes in brain anatomy and physiology after treatment of LGG may help to both contextualize cognitive findings and improve the overall understanding of radiation effects in normal brain tissue. This study aimed to investigate the hypothesis that patients with LGG who are treated with RT will experience greater brain volume loss than those who do not receive RT.

METHODS This retrospective longitudinal study included all patients with WHO grade 2 glioma who received posttreatment surveillance MRI at the University of Alabama at Birmingham. Volumetric analysis of contralateral cortical white matter (WM), cortical gray matter (GM), and hippocampus was performed on all posttreatment T1-weighted MRI sequences using the SynthSeg script. The effect of clinical and treatment variables on brain volumes was assessed using two-level hierarchical linear models.

RESULTS The final study cohort consisted of 105 patients with 1974 time points analyzed. The median length of imaging follow-up was 4.6 years (range 0.36–18.9 years), and the median number of time points analyzed per patient was 12 (range 2–40). Resection was performed in 79 (75.2%) patients, RT was administered to 61 (58.1%) patients, and chemotherapy was administered to 66 (62.9%) patients. Age at diagnosis (β = −0.06, p < 0.001) and use of RT (β = −1.12, p = 0.002) were associated with the slope of the contralateral cortical GM volume model (i.e., change in GM over time). Age at diagnosis (β = −0.08, p < 0.001), midline involvement (β = 1.31, p = 0.006), and use of RT (β = −1.45, p = 0.001) were associated with slope of the contralateral cortical WM volume model. Age (β = −0.0027, p = 0.001), tumor resection (β = −0.069, p < 0.001), use of chemotherapy (β = −0.0597, p = 0.003), and use of RT (β = −0.0589, p < 0.001) were associated with the slope of the contralateral hippocampus volume model.

CONCLUSIONS This study demonstrated volume loss in contralateral brain structures among LGG survivors, and patients who received RT experienced greater volume loss than those who did not. The results of this study may help to provide context for cognitive outcome research in LGG survivors and inform the design of future strategies to preserve cognition.

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Impact of Molecular Subgroups on Prognosis and Survival Outcomes in Posterior Fossa Ependymomas: A Retrospective Study of 412 Cases

Neurosurgery 95:651–659, 2024

Posterior fossa ependymomas (PFEs) are rare brain tumors classified as PF-EPN-A (PFA) and PF-EPN-B (PFB) subgroups. The study aimed to evaluate the prognosis and survival outcomes in PFEs, with a focus on the impact of molecular subgroups.

METHODS: A retrospective study was conducted on 412 patients with PFEs. Kaplan–Meier survival analyses were conducted to evaluate the overall survival (OS) and progression-free survival. Cox regression analyses were conducted to assess the prognostic factors. A nomogram was developed to predict the OS rates of PFEs.

RESULTS: The study revealed significant differences between PFA and PFB in patient and tumor characteristics. PFAs were associated with poorer OS (hazard ratios [HR] 3.252, 95% CI 1.777-5.950, P < .001) and progression-free survival (HR 4.144, 95% CI 2.869-5.985, P < .001). World Health Organization grade 3 was associated with poorer OS (HR 2.389, 95% CI 1.236-4.617, P = .010). As for treatment patterns, gross total resection followed by radiotherapy or the combination of radiotherapy and chemotherapy yielded the most favorable OS for PFA (P = .025 for both), whereas gross total resection followed by radiotherapy rather than observation showed improved OS for PFB (P = .046). The nomogram demonstrated a high degree of accuracy and discrimination capacity for the prediction of OS rates for up to 10 years. In addition, 6 cases of PFA (3.51%) with H3K27M mutations were identified.

CONCLUSION: PFAs demonstrate worse prognosis and survival outcomes compared with PFBs. Both PFAs and PFBs necessitate maximal resection followed by intensive adjuvant therapies in long-term effects.

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Efficacy and Safety of Carmustine Wafer Implantation After Ventricular Opening in Glioblastomas, Isocitrate Dehydrogenase-Wildtype, in Adults

Neurosurgery 94:1227–1236, 2024

We assessed the impact of ventricular opening on postoperative complications and survival of carmustine wafer implantation during surgery of newly diagnosed supratentorial glioblastomas, isocitrate dehydrogenase (IDH)-wildtype in adults.

METHODS: We performed an observational, retrospective, single-center cohort study at a tertiary surgical neurooncological center between January 2006 and December 2021.

RESULTS: One hundred ninety-four patients who benefited from a first-line surgical resection with carmustine wafer implantation were included. Seventy patients (36.1%) had a ventricular opening. We showed that ventricular opening (1) did not increase overall postoperative complication rates (P = .201); (2) did not worsen the early postoperative Karnofsky Performance Status score (P = .068); (3) did not increase the time interval from surgery to adjuvant oncological treatment (P = .458); (4) did not affect the completion of the standard radiochemotherapy protocol (P = .164); (5) did not affect progression-free survival (P = .059); and (6) did not affect overall survival (P = .142).

CONCLUSION: In this study, ventricular opening during first-line surgical resection did not affect the survival and postoperative complications after use of carmustine wafer implantation in adult patients with a newly diagnosed supratentorial glioblastoma, IDH-wildtype. This warrants a prospective and multicentric study to clearly assess the impact of the ventricular opening after carmustine wafer implantation in glioblastoma, IDH-wildtype.

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A novel radiological classification of midbrain pilocytic astrocytomas and its implication for surgical management

J Neurosurg 140:1527–1539, 2024

Surgery for midbrain pilocytic astrocytoma (PA) remains a formidable challenge. To facilitate decisionmaking and achieve a better outcome in the management of patients with midbrain PA, the authors have proposed a novel radiological classification of midbrain PAs with long-term follow-up.

METHODS Fifty-seven midbrain PA patients who underwent surgery at Beijing Tiantan Hospital, Capital Medical University, from January 2008 to June 2021, were reviewed. Based on tumor location and the topological anatomical change identified on MRI, midbrain PAs were categorized into four types: crural (12/57, 21.1%), tegmental (25/57, 43.9%), aqueductal (5/57, 8.8%), and tectal (15/57, 26.3%) PAs. The relevant clinical, radiological, and pathological data; surgical procedures and results; and long-term outcomes were collected and analyzed.

RESULTS The 1-, 3-, and 5-year survival rates reached 98%, 96%, and 96%, respectively, with gross-total resection achieved in 66.7% of cases, followed by near-total resection in 17.5% cases. The clinical and radiological features, selection of surgical approaches, and long-term postoperative deficits were distinct among each type. Crural PAs were associated with younger age (median 9 years, IQR 5.0–12.8 years); the largest tumor volume (median 31.9 cm 3 , IQR 17.2–42.6 cm 3 ); the lowest preoperative Karnofsky Performance Scale (KPS) score (median 65, IQR 50–70); the most frequent preoperative motor deficit (91.7%); a mixed solid-cystic component (75%); occupation of the crural cistern; elevation and rotation of the thalamus (medial and/or lateral); displacement of the anterior third ventricle, uncus, and anterior commissure; the most diverse surgical approaches; more frequent use of multimodality image–guided surgery (58.3%); and the most remarkable improvement in KPS score at long-term follow-up. Tegmental PAs were associated with adolescents and young adults (median age 21 years, IQR 8–33 years); tumor volume (median 13.9 cm 3 , IQR 9.5–20.5 cm 3 ); a good preoperative KPS score (median 80, IQR 70–80); a mixed solid-cystic component (72%); occupation of the ambient cistern and cerebellomesencephalic fissure; a close relationship with the dorsal pons, superior cerebellar peduncle, and posterior inferior third ventricle; and a higher probability of permanent postoperative sensory deficits (40%). Aqueductal and tectal PAs were associated with small tumor volume (median 9.14 cm 3 , IQR 5.1–17.4 cm 3 and median 11.84 cm 3 , IQR 5.7–18.3 cm 3 , respectively), a higher percentage of hydrocephalus (80% and 86.7%, respectively), and a straightforward selection of limited surgical approaches.

CONCLUSIONS A novel and comprehensive radiological classification of midbrain PAs was established, which will serve as a valuable tool in patient management and promote uniform communication and comparison across different studies and publications.

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