Category: Intraoperative Imaging

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Intraoperative Evaluation of Dural Arteriovenous Fistula Obliteration Using FLOW 800 Hemodynamic Analysis

Operative Neurosurgery 30:250–259, 2026

This clinical study evaluates intraoperative indocyanine green videoangiography with FLOW 800 software to quantify hemodynamic changes during cranial and spinal dural arteriovenous fistula (dAVF) microsurgical obliteration. Using four FLOW 800 metrics across venous regions of interest, the authors compare pre- and post-obliteration measurements confirmed by intraoperative digital subtraction angiography.

Key findings identify increased Delay Time and decreased Speed as consistent, significant markers of successful dAVF obliteration, supported by nonparametric tests, logistic and Bayesian regression, and PCA visualization. The study suggests FLOW 800 as a practical adjunct to intraoperative imaging, while acknowledging limitations from small sample size and ROI selection variability.

Key Hemodynamic Parameters: Intraoperative FLOW 800 analysis of indocyanine green videoangiography quantifies four hemodynamic parameters—Delay Time, Speed, Time to Peak, and Rise Time—across venous drainage regions before and after dAVF (dural arteriovenous fistula) obliteration.

Most Sensitive Indicators: Delay Time (time for dye to reach ROI) and Speed (rate of dye flow) are the most sensitive and consistent hemodynamic indicators of successful dAVF obliteration, with Delay Time increasing and Speed decreasing significantly post-obliteration.

Statistical Significance: Delay Time increased from a median of 2.07s to 7.86s (P = .020), and Speed decreased from 13.5 s⁻¹ to 5.5 s⁻¹ (P = .029), both changes being statistically significant; Time to Peak and Rise Time showed no significant association.

Predictive Value: A 50% increase in Delay Time is associated with 2.16 times higher odds of achieving obliteration (OR = 4.59), while a 50% decrease in Speed is associated with 1.28 times higher odds; Delay Time and Speed are the strongest predictors in regression analyses.

Clinical Utility: FLOW 800 provides real-time, semiquantitative intraoperative feedback, supporting its use as a noninvasive adjunct to traditional imaging (like intraoperative DSA) for confirming dAVF obliteration, especially where DSA is unavailable.

Study Limitations: The study is limited by small sample size (8 patients, 14 ROIs), single-center design, and possible variability in ROI selection; findings require validation in larger, multicenter studies.

Practical Considerations: Complete visualization of venous outflow is necessary for FLOW 800 utility; current evidence supports its use as a complementary tool rather than a replacement for DSA.

Clinical Outcome: All patients in the study had successful dAVF obliteration confirmed by intraoperative DSA, no complications or recurrences at median 19.4 months follow-up, and FLOW 800 changes were consistent with successful surgical outcomes.

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Operative Microscope In-Field Visualization of Confocal Laser Endomicroscopy Interface (Zeiss CONVIVO )

Operative Neurosurgery 29:860–864, 2025

This study evaluates integrating the Zeiss CONVIVO confocal laser endomicroscopy interface into the operative microscope heads-up display to allow simultaneous visualization of the surgical field and real-time confocal laser endomicroscopy (CLE) images. A randomized cohort of 22 intra-axial tumor surgeries showed shorter CLE usage times, fewer total captures, and a trend toward higher usable-image proportion with heads-up integration.

The integration improved intraoperative ergonomics by reducing probe motion artifacts and image noninterpretability, streamlining workflow, and decreasing operative time while preserving diagnostic utility of CLE for margin assessment in gliomas and other brain lesions.

Confocal Laser Endomicroscopy (CLE): Provides real-time, in vivo microscopic imaging of brain tumors during neurosurgery, enabling identification of tumor margins without the need for traditional tissue extraction or frozen section analysis.

Zeiss CONVIVO® System: A CLE device recently introduced in neurosurgery, proven reliable for both ex vivo and in vivo applications, and undergoing further clinical refinement.

Technical Challenge: Standard CLE use requires the surgeon to shift attention from the operative field to a separate screen to assess image quality, potentially causing motion artifacts, prolonging surgery, and increasing the number of unusable images.

Heads-Up Display Integration: Visualization of the CONVIVO® interface was integrated as a picture-in-picture display inside the operative microscope, allowing simultaneous monitoring of the surgical field and CLE images without diverting gaze.

Study Findings: Use of the heads-up display significantly reduced CLE employment time (mean 61.1 vs. 201.6 seconds; P = .01), decreased the total number of images acquired, and increased the proportion of usable images, though the latter was not statistically significant (P = .06).

Workflow Efficiency: Direct intraoperative feedback enabled by the heads-up display led to fewer motion artifacts, more efficient image acquisition, and reduced overall operative time.

Clinical Implications: The integration supports more efficient and accurate intraoperative tumor assessment, potentially improving the extent of resection, especially in gliomas, and reducing reliance on frozen sections.

Limitations and Future Directions: Further refinement is needed for effortless image acquisition; artificial intelligence for artifact reduction and real-time interpretation by neurosurgeons are potential future improvements.

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High-grade glioma: combined use of 5-aminolevulinic acid and intraoperative ultrasound for resection and a predictor algorithm for detection

J Neurosurg 143:323–331, 2025

Combining 5-aminolevulinic acid (5-ALA) fluorescence and intraoperative ultrasound (ioUS) significantly improved the sensitivity and specificity for detecting high-grade glioma during surgery, compared to either technique alone. A machine learning algorithm (HGGPredictor) further enhanced intraoperative tumor margin prediction, suggesting a new standard for safer, more effective resections.

• Combining 5-ALA fluorescence and intraoperative ultrasound (ioUS) improves the accuracy of high-grade glioma (HGG) resection compared to using either method alone.

• 5-ALA shows higher sensitivity (84.9%), while ioUS provides higher specificity (84.5%); combined, they reach sensitivity of 91% and specificity of 86%.

• The combined approach is especially valuable for maximizing tumor removal while minimizing neurological damage, particularly near eloquent brain regions.

• A machine learning algorithm (HGGPredictor) was developed to predict tumor presence during surgery based on 5-ALA and ioUS results.

• The study included 72 patients and 301 biopsies, with histological analysis as the reference standard.

• The benefit of combination is greatest for strong fluorescence or hyperechogenicity; ioUS is particularly helpful when 5-ALA fluorescence is weak.

• The combined method is accessible and can be integrated into existing surgical protocols without major additional costs.

• Limitations include single-center design and lack of a control group, but results suggest a new standard for HGG resection.

 

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Intraoperative brain tumor classification via laser-induced fluorescence spectroscopy and machine learning

J Neurosurg 143:313–322, 2025

A laser-based device, TumorID, combined with machine learning, rapidly and nondestructively classifies brain tumor tissue intraoperatively. Tested on 46 patients, it distinguished glioma, meningioma, pituitary adenoma, and normal tissue with high accuracy, offering potential to improve neurosurgical decision-making and outcomes

• TumorID is a laser-induced endogenous fluorescence spectroscopy device paired with machine learning for rapid intraoperative brain tumor classification.

• It distinguishes glioma, meningioma, pituitary adenoma, and nonneoplastic tissue in near real time using a 405-nm laser and support vector machine (SVM) algorithm.

• The device requires only 0.5 seconds per scan and does not damage tissue.

• In a study of 46 patients and 761 scans, TumorID achieved a multiclass AUROC of 0.809, demonstrating high classification accuracy.

• Neutral porphyrin emission regions were most significant for tissue differentiation.

• TumorID offers objective, fast, and nondestructive tissue diagnostics, potentially improving surgical decision-making and resection outcomes.

• Future directions include in vivo use, prediction of tumor subtypes and genetics, and integration with other data sources for improved accuracy.

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Is FLAIRectomy Directly Correlated with Prolonged Survival in Glioblastoma? A Prospective National Multicenter Study on Correlation Between Extent of Tumor Resection and Clinical Outcome

Neurosurgery 97:489–500, 2025

This multicenter prospective study shows that the extent of FLAIRectomy (resection of FLAIR-positive areas) in glioblastoma is a stronger predictor of survival than traditional resection, with higher EOFR significantly improving progression-free and overall survival, especially in IDH-mutant tumors, without increasing neurological complications.

• FLAIRectomy, or resection of FLAIR-MRI hyperintense regions beyond the contrast-enhancing tumor, was studied in a prospective multicenter cohort of 150 glioblastoma patients.

• A higher extent of FLAIR resection (EOFR) was associated with significantly improved overall survival (OS) and progression-free survival (PFS), more so than resection of contrast-enhancing tumor alone.

• Each 1% increase in EOFR correlated with a 6.8% reduction in mortality risk for IDH-wildtype and 12.1% for IDH-mutant tumors.

• Mean OS was 28.4 months and mean PFS was 16.3 months in the study cohort.

• IDH1 mutation status was also associated with longer survival, but EOFR remained an independent predictor after adjustment.

• AI analysis confirmed that patients with higher EOFR clustered with longer survival.

• Neurological safety was addressed with intraoperative neuromonitoring and careful planning; permanent deficits occurred in 9/150 patients.

• The study concludes that FLAIR-based supramarginal resection may be a more reliable predictor of survival in glioblastoma than conventional imaging-guided resection.

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Clinical Evaluation of the NaviNetics Stereotactic System Using Intraoperative Portable Surgical Imaging System in DBS Surgery

Operative Neurosurgery 29:93–101, 2025

Intraoperative O-arm imaging with the NaviNetics stereotactic head frame enables accurate, efficient deep brain stimulation (DBS) lead placement in both awake and asleep surgeries, streamlining workflow by eliminating patient transport for imaging and achieving submillimeter accuracy comparable to traditional CT-based methods.

• The study evaluates the NaviNetics stereotactic head frame system with intraoperative O-arm imaging for deep brain stimulation (DBS) surgery.

• Intraoperative O-arm imaging was used for both stereotactic registration and lead placement confirmation in awake and asleep DBS procedures.

• A total of 17 patients were included; 1 had both CT and O-arm, while 16 had only O-arm localization.

• Accuracy of O-arm imaging was comparable to traditional CT, with less than 0.1 mm difference and a mean radial error of 0.71 ± 0.33 mm for 32 leads.

• No surgical complications, lead repositioning, or infections were reported.

• The intraoperative O-arm workflow reduces patient transport, surgical time, and allows real-time confirmation of lead placement.

• Limitations include limited hemorrhage detection by O-arm and lack of direct comparison with stereotactic CT in larger samples.

• The study concludes O-arm imaging is safe, effective, and streamlines DBS surgery without compromising accuracy.

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Navigated Transcranial Magnetic Stimulation and Diffusion Tensor Imaging Tractography in Insular Glioma Surgery

Operative Neurosurgery 29:62–70, 2025

Navigated transcranial magnetic stimulation (nTMS) and DTI tractography enable precise preoperative risk stratification in insular glioma surgery, identifying patients at higher risk for postoperative motor deficits by assessing resting motor threshold, tumor proximity to the corticospinal tract, and fiber tract integrity, thus improving surgical planning and outcomes.

• Navigated transcranial magnetic stimulation (nTMS) and nTMS-based DTI tractography were evaluated for preoperative risk stratification in insular glioma surgery.

• Thirty-two patients with insular gliomas underwent preoperative nTMS mapping and DTI tractography to assess motor cortex and corticospinal tract (CST) involvement.

• Higher resting motor threshold (RMT) ratios, CST-tumor distances <3 mm, and decreased peritumoral fractional anisotropy (pFA) ratios were significantly associated with new postoperative motor deficits.

• All patients with new postoperative motor deficits had a CST-tumor distance below 3 mm; lower pFA ratios also correlated with deficits.

• One-third of patients with intraoperative ischemic events developed permanent motor deficits, suggesting additional mediating factors such as CST integrity and cortical excitability.

• A risk model combining RMT ratio, CST distance <3 mm, and low pFA ratio predicted an 82% risk for new motor deficits.

• Preoperative nTMS-based DTI tractography may improve individual risk stratification and surgical planning for insular glioma patients.

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Efficacy and safety of intraoperative MRI in glioma surgery: a systematic review and meta-analysis of prospective randomized controlled trials

J Neurosurg 142:1319–1330, 2025

This meta-analysis of randomized controlled trials found that intraoperative MRI significantly increases gross-total resection rates and progression-free survival in glioma surgery, without increasing neurological deficits or most complications, though it prolongs surgery and may raise infection risk. iMRI is effective and generally safe for maximizing tumor removal.

• Intraoperative MRI (iMRI) significantly increases the rate of gross-total resection (GTR) in glioma surgery compared to conventional neuronavigation.

• Greater extent of resection (EOR) with iMRI leads to improved progression-free survival (PFS), especially in high-grade gliomas.

• No significant difference in overall survival (OS) was observed between iMRI and conventional surgery groups.

• Rates of postoperative neurological deterioration, motor, and language decline are similar between iMRI and control groups.

• iMRI does not increase the risk of postoperative intracranial hemorrhage, but may be associated with higher rates of wound infections in some studies.

• Use of iMRI prolongs surgery time by an average of 42 minutes.

• Only three randomized controlled trials with a total of 384 patients met inclusion criteria for this meta-analysis.

• Combined use of iMRI and 5-ALA may further enhance EOR, but more randomized studies are needed for definitive conclusions.

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Comparative analysis of intraoperative MRI and early postoperative MRI findings in glioma surgery patients

J Neurosurg 142:1289–1297, 2025

The study compares intraoperative MRI (iMRI) and early postoperative MRI (epMRI) in glioma surgery, highlighting iMRI’s accuracy in extent of resection (EOR) and reduced surgically induced contrast enhancement (SICE). iMRI better detects postoperative neurological deficits, with fewer diffusion-weighted imaging abnormalities than epMRI.

• Objective: The study compares intraoperative MRI (iMRI) and early postoperative MRI (epMRI) findings in glioma surgery to assess the extent of resection (EOR) and postoperative neurological deficits.

• Methods: A retrospective analysis of 43 glioma patients who underwent surgery with iMRI, with no additional resection after iMRI, was conducted.

• Results: Discrepancies in EOR were found in 11.1% of nonenhanced and 4.0% of enhanced lesions. iMRI showed more accurate EOR and less surgically induced contrast enhancement (SICE) compared to epMRI.

• Findings: The positive rate of SICE was higher on epMRI (67.9%) than iMRI (25.0%). The positive rate of diffusion-weighted imaging (DWI) abnormality was also higher on epMRI (89.2%) compared to iMRI (73%).

• Clinical Outcomes: Two patients developed new neurological deficits postoperatively, both showing DWI abnormality on both iMRI and epMRI. No deficits were observed in the late-developing group.

• Conclusion: iMRI is more reliable for assessing accurate EOR and detecting postoperative neurological deficits than epMRI, despite higher late-developing DWI abnormalities on epMRI.

• Significance: The study underscores the importance of iMRI in optimizing glioma surgery outcomes and minimizing misinterpretation of residual tumors.

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Brainshift correction using navigated intraoperative ultrasound informs intraoperative decision‑making during glioma surgery

Acta Neurochirurgica (2025) 167:124

This paper discusses brainshift correction in glioma surgery using navigated intraoperative ultrasound (iUS) and MRI (iUS-MR fusion). It highlights the accuracy and practical benefits of iUS in correcting brainshift, improving neuronavigation accuracy, and aiding intraoperative decisions, especially near critical brain structures.

• Brainshift (BS) can significantly impact the accuracy of neuronavigation systems during intraoperative procedures, particularly in brain tumor surgeries.

• Rigid image fusion (RIF) using intraoperative ultrasound (iUS) and MRI is a cost-effective method to correct BS and enhance surgical accuracy.

• Factors contributing to BS include physical, surgical, and biological elements, leading to both linear and complex elastic shifts.

• iUS can be repeatedly used during surgery, offering real-time updates and corrections, thus serving as an independent tool for resection control.

• Challenges with iUS include the need for careful registration and the difficulty in correcting non-linear deformations.

• Case study: A successful application of iUS-MR fusion in a glioma surgery demonstrated improved tumor margin assessment and preservation of critical structures.

• Future advancements in automation and technology are required to address the limitations of current BS correction methods.

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How Accurate Is Frameless Fiducial—Free Deep Brain Stimulation?

Operative Neurosurgery 27:431–439, 2024

Frameless deep brain stimulation (DBS) offers advantages in terms of patient comfort and reduced operative time. However, the need for bony fiducial markers for localization remains a drawback due to the time-consuming and uncomfortable procedure. An alternative localization method involves the direct tracking of an intraoperative 3-dimensional scanner. This study aims to assess the accuracy of the NexFrame frameless DBS system in conjunction with the O-Arm (Medtronic Inc.), both with and without fiducial markers.

METHODS: The locations of 100 DBS leads were determined, with 50 cases using fiducial-free localization and 50 involving fiducial markers. The coordinates were compared with the expected intraoperative targets. Absolute errors in the X, Y, and Z coordinates (ΔX, ΔY, and ΔZ) were calculated, along with the vector error (Euclidean) (vector error square root Δx 2 + Δy 2 + Δz 2 ).

RESULTS: The vector error averaged 1.61 ± 0.49 mm (right) and 1.52 ± 0.60 mm (left) for the group without fiducial bone markers and 1.66 ± 0.69 (right) and 1.44 ± 0.65 mm (left) for the other cohort (P = .76 right; P = .67 left). Absolute errors in the X, Y, and Z coordinates for the fiducial-free group were 0.88 ± 0.55, 0.79 ± 0.45, and 0.79 ± 0.57 mm (right) and 0.72 ± 0.37, 0.78 ± 0.56, and 0.77 ± 0.71 mm (left). For the group with fiducial markers, these errors were 0.87 ± 0.72, 0.92 ± 0.39, and 0.86 ± 0.50 mm (right) and 0.75 ± 0.33, 0.80 ± 0.51, and 0.73 ± 0.64 mm (left) with no statistically significant difference.

CONCLUSION: Our analysis of the accuracy of NexFrame DBS, both with and without fiducial markers, using an intraoperative navigable cone-beam computed tomography, demonstrates that both techniques provide sufficient and equivalent 3-dimensional accuracy.

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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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Intraoperative ultrasound and magnetic resonance comparative analysis in brain tumor surgery: a valuable tool to flatten ultrasound’s learning curve

Acta Neurochirurgica (2024) 166:337

Intraoperative ultrasound (IOUS) is a profitable tool for neurosurgical procedures’ assistance, especially in neuro-oncology. It is a rapid, ergonomic and reproducible technique. However, its known handicap is a steep learning curve for neurosurgeons. Here, we describe an interesting postoperative analysis that provides extra feedback after surgery, accelerating the learning process.

Method We conducted a descriptive retrospective unicenter study including patients operated from intra-axial brain tumors using neuronavigation (Curve, Brainlab) and IOUS (BK-5000, BK medical) guidance. All patients had preoperative Magnetic Resonance Imaging (MRI) prior to tumor resection. During surgery, 3D neuronavigated IOUS studies (n3DUS) were obtained through craniotomy N13C5 transducer’s integration to the neuronavigation system. At least two n3DUS studies were obtained: prior to tumor resection and at the resection conclusion. A postoperative MRI was performed within 48 h. MRI and n3DUS studies were posteriorly fused and analyzed with Elements (Brainlab) planning software, permitting two comparative analyses: preoperative MRI compared to pre-resection n3DUS and postoperative MRI to post-resection n3DUS. Cases with incomplete MRI or n3DUS studies were withdrawn from the study.

Results From April 2022 to March 2024, 73 patients were operated assisted by IOUS. From them, 39 were included in the study. Analyses comparing preoperative MRI and pre-resection n3DUS showed great concordance of tumor volume (p < 0,001) between both modalities. Analysis comparing postoperative MRI and post-resection n3DUS also showed good concordance in residual tumor volume (RTV) in cases where gross total resection (GTR) was not achieved (p < 0,001). In two cases, RTV detected on MRI that was not detected intra-operatively with IOUS could be reviewed in detail to recheck its appearance.

Conclusions Post-operative comparative analyses between IOUS and MRI is a valuable tool for novel ultrasound users, as it enhances the amount of feedback provided by cases and could accelerate the learning process, flattening this technique’s learning curve.

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Evaluation of the extent of resection of intracranial tumors with virtual intraoperative MRI

J Neurosurg 141:695–701, 2024

Intraoperative MRI (iMRI) is the gold-standard technique for intraoperative evaluation of the extent of resection in brain tumor surgery. Unfortunately, it is currently available at only a few neurosurgical centers. A commercially available software, Virtual iMRI Cranial, provides an elastic fusion between preoperative MRI and intraoperative CT (iCT). The aim of this study was to evaluate the accuracy of this software in determining the presence of residual tumor.

METHODS Virtual iMRI was performed in patients who underwent iCT after intracranial tumor resection. The results of the software in terms of presence or absence of tumor residual were then compared with postoperative MRI performed within 48 hours after surgery to evaluate the diagnostic accuracy of virtual iMRI.

RESULTS Sixty-six patients were included in the present study. The virtual iMRI findings were concordant with the postoperative MRI data in 35 cases (53%) in the detection of tumor residual (p = 0.006). No false-negative findings (i.e., presence of residual on postoperative MRI and absence of residual on virtual iMRI) were encountered. Virtual iMRI had a sensitivity of 1 (95% CI 0.86–1), specificity of 0.26 (95% CI 0.14–0.42), positive predictive value of 0.44 (95% CI 0.3–0.58), and negative predictive value of 1 (95% CI 0.72–1). Subgroup analysis revealed that the virtual iMRI findings were concordant with postoperative MRI findings in all cases (n = 9) of lower-grade glioma (LGG) with a sensitivity of 1 (95% CI 0.59–1) and a specificity of 1 (95% CI 0.16–1) (p = 0.003); a statistically significant association was also found for grade 4 gliomas with a sensitivity of 1 (95% CI 0.69–1) and a specificity of 0.33 (95% CI 0.08–0.7) (p = 0.046) (19 patients). No significant association was found when considering meningiomas or metastases.

CONCLUSIONS The commercially available virtual iMRI can predict the presence or absence of tumor residual with high sensitivity. The diagnostic accuracy of this method was higher in LGGs and much lower for meningiomas or metastases; these findings must be evaluated in prospective studies in a larger population.

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Use of 5-ALA fluorescence–guided surgery versus white-light conventional microsurgery for the resection of newly diagnosed glioblastomas (RESECT study): a French multicenter randomized phase III study

J Neurosurg 140:987–1000, 2024

Only one phase III prospective randomized study, published in 2006, has assessed the performance of 5-aminolevulinic acid (5-ALA) fluorescence–guided surgery (FGS) for glioblastoma resection. The aim of the RESECT study was to compare the onco-functional results associated with 5-ALA fluorescence and with white-light conventional microsurgery in patients with glioblastoma managed according to the current standards of care.

METHODS This was a phase III prospective randomized single-blinded study, involving 21 French neurosurgical centers, comparing 5-ALA FGS with white-light conventional microsurgery in patients with glioblastoma managed according to the current standards of care, including neuronavigation use and postoperative radiochemotherapy. Randomization was performed in a 1:1 ratio stratified by institution. 5-ALA (20 mg/kg) or placebo (ascorbic acid) was administered orally 3–5 hours before the incision. The primary endpoint was the rate of gross-total resection (GTR) blindly assessed by an independent committee. Patients without a confirmed pathological diagnosis of glioblastoma or with unavailable postoperative MRI studies were excluded from the per-protocol analysis.

RESULTS Between March 2013 and August 2016, a total of 171 patients were assigned to the 5-ALA fluorescence group (n = 88) or to the placebo group (n = 83). Twenty-four cases were excluded because the WHO histological criteria of grade 4 glioma were not met. The proportion of GTR was significantly higher in the 5-ALA fluorescence group (53/67, 79.1%) than in the placebo group (33/69, 47.8%; p = 0.0002). After adjustment for age, preoperative Karnofsky Performance Scale score, and tumor location, GTR was still associated with 5-ALA fluorescence (OR 4.13 [95% CI 1.94–8.79]). The mean 7-day postoperative Karnofsky Performance Scale score (≥ 80% in 49/71, 69.0% [5-ALA group]; 50/71, 70.4% [placebo group], p = 0.86) and the proportion of patients with a worsened neurological status 3 months postoperatively (9/68, 13.2% [5-ALA group]; 9/70, 12.9% [placebo group], p = 0.95) were similar between groups. Adverse events related to 5-ALA intake were rare and consisted of photosensitization in 4/87 (4.6%) patients and hepatic cytolysis in 1/87 (1.1%) patients. The 6-month PFS (70.2% [95% CI 57.7%–79.6%] and 68.4% [95% CI 55.7%–78.1%]; p =0.39) and 24-month OS (30.1% [95% CI 18.9%–42.0%] and 37.7% [95% CI 25.8%–49.5%]; p = 0.89) did not significantly differ. In multivariate analysis, GTR was an independent predictor of PFS (hazard ratio 0.56 [95% CI 0.36–0.86], p =0.008) and OS (hazard ratio 0.65 [95% CI 0.42–1.01], p = 0.05). The use of 5-ALA FGS generates a significant extra cost of 2732.36€ (95% CI 1658.40€–3794.11€).

CONCLUSIONS The authors found that 5-ALA FGS is an easy-to-use, cost-effective, and minimally time-consuming technique that safely optimizes the extent of resection in patients harboring glioblastoma amenable to a large resection.

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Sodium fluorescein uptake by the tumor microenvironment in human gliomas and brain metastases

J Neurosurg 140:958–967, 2024

Intravenous sodium fluorescein (SF) is increasingly used during surgery of gliomas and brain metastases to improve tumor resection. Currently, SF is believed to permeate the brain regions where the blood-brain barrier (BBB) is damaged and to accumulate in the extracellular space but not in tumor or healthy cells, making it possible to demarcate tumor margins to guide resection. By evaluating the immune contexture of a number of freshly resected gliomas and brain metastases from patients undergoing SF-guided surgery, the authors recurrently observed fluorescence-positive cells. Therefore, the aim of this study was to determine if SF accumulates inside the cells of the tumor microenvironment (TME), and if so, in which type of cells, and whether incorporation can also be observed in the leukocytes of peripheral blood.

METHODS Freshly resected tumor specimens were dissociated to single cells and analyzed by multiparametric flow cytometry. Peripheral blood leukocytes, macrophages, and a glioma cell line were treated with SF in vitro, and their cell uptake was assessed by multiparametric and imaging flow cytometry and by confocal microscopy.

RESULTS The ex vivo and in vitro analyses revealed that SF accumulates intracellularly in leukocytes as well as in tumor cells, but with a high variability of incorporation in the different cell subsets analyzed. Myeloid cells showed the highest level of fluorescence. In vitro uptake experiments showed that SF accumulation increases over time. The imaging analyses confirmed the internalization of the compound inside the cells.

CONCLUSIONS SF is not just a marker of BBB damage, but its intracellular detection suggests that it selectively accumulates intracellularly. Future efforts should target the mechanisms of its differential uptake by the different TME cell types in depth.

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Intraoperative in vivo confocal laser endomicroscopy imaging at glioma margins: can we detect tumor infiltration?

J Neurosurg 140:357–366, 2024

Confocal laser endomicroscopy (CLE) is a US Food and Drug Administration–cleared intraoperative real-time fluorescence-based cellular resolution imaging technology that has been shown to image brain tumor histoarchitecture rapidly in vivo during neuro-oncological surgical procedures. An important goal for successful intraoperative implementation is in vivo use at the margins of infiltrating gliomas. However, CLE use at glioma margins has not been well studied.

METHODS Matching in vivo CLE images and tissue biopsies acquired at glioma margin regions of interest (ROIs) were collected from 2 institutions. All images were reviewed by 4 neuropathologists experienced in CLE. A scoring system based on the pathological features was implemented to score CLE and H&E images from each ROI on a scale from 0 to 5. Based on the H&E scores, all ROIs were divided into a low tumor probability (LTP) group (scores 0–2) and a high tumor probability (HTP) group (scores 3–5). The concordance between CLE and H&E scores regarding tumor probability was determined. The intraclass correlation coefficient (ICC) and diagnostic performance were calculated.

RESULTS Fifty-six glioma margin ROIs were included for analysis. Interrater reliability of the scoring system was excellent when used for H&E images (ICC [95% CI] 0.91 [0.86–0.94]) and moderate when used for CLE images (ICC [95% CI] 0.69 [0.40–0.83]). The ICCs (95% CIs) of the LTP group (0.68 [0.40–0.83]) and HTP group (0.68 [0.39–0.83]) did not differ significantly. The concordance between CLE and H&E scores was 61.6%. The sensitivity and specificity values of the scoring system were 79% and 37%. The positive predictive value (PPV) and negative predictive value were 65% and 53%, respectively. Concordance, sensitivity, and PPV were greater in the HTP group than in the LTP group. Specificity was higher in the newly diagnosed group than in the recurrent group.

CONCLUSIONS CLE may detect tumor infiltration at glioma margins. However, it is not currently dependable, especially in scenarios where low probability of tumor infiltration is expected. The proposed scoring system has excellent intrinsic interrater reliability, but its interrater reliability is only moderate when used with CLE images. These results suggest that this technology requires further exploration as a method for consistent actionable intraoperative guidance with high dependability across the range of tumor margin scenarios. Specific-binding and/or tumor-specific fluorophores, a CLE image atlas, and a consensus guideline for image interpretation may help with the translational utility of CLE.

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Confocal laser endomicroscopy in glial tumors—a histomorphological analysis

Neurosurgical Review (2024) 47:65

The extent of resection and neurological outcome are important prognostic markers for overall survival in glioma patients. Confocal laser endomicroscopy is a tool to examine tissue without the need for fixation or staining. This study aims to analyze gliomas in confocal laser endomicroscopy and identify reliable diagnostic criteria for glial matter and glial tumors.

Material and methods One-hundred-and-five glioma specimens were analyzed using a 670-nm confocal laser endomicroscope and then processed into hematoxylin-eosin-stained frozen sections. All confocal images and frozen sections were evaluated for the following criteria: presence of tumor, cellularity, nuclear pleomorphism, changes of the extracellular glial matrix, microvascular proliferation, necrosis, and mitotic activity. Recurring characteristics were identified. Accuracy, sensitivity, specificity, and positive and negative predictive values were assessed for each feature.

Results All 125 specimens could be processed and successfully analyzed via confocal laser endomicroscopy. We found diagnostic criteria to identify white and grey matter and analyze cellularity, nuclear pleomorphism, changes in the glial matrix, vascularization, and necrosis in glial tumors. An accuracy of > 90.0 % was reached for grey matter, cellularity, and necrosis, > 80.0 % for white matter and nuclear pleomorphism, and > 70.0 % for microvascular proliferation and changes of the glial matrix. Mitotic activity could not be identified. Astroglial tumors showed significantly less nuclear pleomorphism in confocal laser endomicroscopy than oligodendroglial tumors (p < 0.001). Visualization of necrosis aids in the differentiation of low grade gliomas and high grade gliomas (p < 0.002).

Conclusion Autofluorescence-based confocal laser endomicroscopy proved not only useful in differentiation between tumor and brain tissue but also revealed useful clues to further characterize tissue without processing in a lab. Possible applications include the improvement of extent of resection and the safe harvest of representative tissue for histopathological and molecular genetic diagnostics.

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Confocal laser endomicroscopy in glial tumors—a histomorphological analysis

Neurosurgical Review (2024) 47:65

The extent of resection and neurological outcome are important prognostic markers for overall survival in glioma patients. Confocal laser endomicroscopy is a tool to examine tissue without the need for fixation or staining. This study aims to analyze gliomas in confocal laser endomicroscopy and identify reliable diagnostic criteria for glial matter and glial tumors.

Material and methods One-hundred-and-five glioma specimens were analyzed using a 670-nm confocal laser endomicroscope and then processed into hematoxylin-eosin-stained frozen sections. All confocal images and frozen sections were evaluated for the following criteria: presence of tumor, cellularity, nuclear pleomorphism, changes of the extracellular glial matrix, microvascular proliferation, necrosis, and mitotic activity. Recurring characteristics were identified. Accuracy, sensitivity, specificity, and positive and negative predictive values were assessed for each feature.

Results All 125 specimens could be processed and successfully analyzed via confocal laser endomicroscopy. We found diagnostic criteria to identify white and grey matter and analyze cellularity, nuclear pleomorphism, changes in the glial matrix, vascularization, and necrosis in glial tumors. An accuracy of > 90.0 % was reached for grey matter, cellularity, and necrosis, > 80.0 % for white matter and nuclear pleomorphism, and > 70.0 % for microvascular proliferation and changes of the glial matrix. Mitotic activity could not be identified. Astroglial tumors showed significantly less nuclear pleomorphism in confocal laser endomicroscopy than oligodendroglial tumors (p < 0.001). Visualization of necrosis aids in the differentiation of low grade gliomas and high grade gliomas (p < 0.002).

Conclusion Autofluorescence-based confocal laser endomicroscopy proved not only useful in differentiation between tumor and brain tissue but also revealed useful clues to further characterize tissue without processing in a lab. Possible applications include the improvement of extent of resection and the safe harvest of representative tissue for histopathological and molecular genetic diagnostics.

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Brain metastasis resection: the impact of fluorescence guidance (MetResect study)

Neurosurg Focus 55(2):E10, 2023

Maximal resection of brain metastases (BMs) improves both progression-free survival and overall survival (OS). Fluorescein sodium (FL) in combination with the YELLOW 560-nm filter is a safe and feasible method for visualizing residual tumor tissue during BM resection. The authors of this study aimed to show that use of FL would positively influence the volumetric extent of resection (EOR) and thus the survival outcome in patients undergoing BM resection.

METHODS Analyzing their institution’s prospective brain tumor registry, the authors identified 539 consecutive patients with BMs (247 women, mean age 62.8 years) by using preoperative high-quality MR images for volumetric analysis. BMs were resected under white light (WL) in 293 patients (54.4%; WL group) and under FL guidance in 246 patients (45.6%; FL group). Sex, age, presurgical Karnofsky Performance Status (KPS), recursive partitioning analysis class, and adjuvant treatment modalities were well balanced between the two groups. Volumetric analysis was performed in a blinded fashion by quantifying pre- and postoperative tumor volume based on gadolinium-enhanced T1-weighted sequences.

RESULTS In the FL group, the postoperative tumor volume was significantly smaller (p = 0.01), and hence the quantitative EOR was significantly larger (p = 0.024) and OS was significantly longer (p = 0.0001) (log-rank testing). Multivariate Cox regression modeling showed that age, presurgical KPS, metastasis status, and FL-guided resection are independent prognostic factors for survival.

CONCLUSIONS Compared with WL resection, FL-guided BM resection increased resection quality, significantly improved EOR, and prolonged OS.

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