Preclinical Studies with Glioblastoma Brain Organoid Co-Cultures Show Efficient 5-ALA Photodynamic Therapy.

BACKGROUND: The high recurrence of glioblastoma (GB) that occurs adjacent to the resection cavity within two years of diagnosis urges an improvement of therapies oriented to GB local control. Photodynamic therapy (PDT) has been proposed to cleanse infiltrating tumor cells from parenchyma to ameliorate short long-term progression-free survival. We examined 5-aminolevulinic acid (5-ALA)-mediated PDT effects as therapeutical treatment and determined optimal conditions for PDT efficacy without causing phototoxic injury to the normal brain tissue. METHODS: We used a platform of Glioma Initiation Cells (GICs) infiltrating cerebral organoids with two different glioblastoma cells, GIC7 and PG88. We measured GICs-5-ALA uptake and PDT/5-ALA activity in dose-response curves and the efficacy of the treatment by measuring proliferative activity and apoptosis. RESULTS: 5-ALA (50 and 100 µg/mL) was applied, and the release of protoporphyrin IX (PpIX) fluorescence measures demonstrated that the emission of PpIX increases progressively until its stabilization at 24 h. Moreover, decreased proliferation and increased apoptosis corroborated the effect of 5-ALA/PDT on cancer cells without altering normal cells. CONCLUSIONS: We provide evidence about the effectiveness of PDT to treat high proliferative GB cells in a complex in vitro system, which combines normal and cancer cells and is a useful tool to standardize new strategic therapies.

Photodynamic therapy in glioblastoma: Detection of intraoperative inadvertent 5-ALA mediated photodynamic therapeutical effect after gross total resection.

Introduction: Glioblastoma (GBM) remains the most frequent and lethal primary brain tumor in adults, despite advancements in surgical resection techniques and adjuvant chemo- and radiotherapy. The most frequent recurrence pattern (75-90%) occurs in the form of continuous growth from the border of the surgical cavity, thus emphasizing the need for locoregional tumor control. Fluorescence-guided surgical resection using 5-ALA has been widely implemented in surgical protocols for such tumors. Recent literature also highlights the applicability of 5-ALA-mediated photodynamic therapy to obtain locoregional tumor control further. This study aims to identify if 5-ALA mediated photodynamic therapeutic effect after gross total glioblastoma resection has inadvertently occurred due to the exposition of protoporphyrin IX charged peripheral tumoral cells to operative room light sources. Methods: Of 146 patients who were intervened from glioblastoma between 2015 and 2020, 33 were included in the present study. Strict gross total resection (without supralocal resection) had been accomplished, and adjuvant chemoradiotherapy protocol was administered. Two comparison groups were created regarding the location of the recurrence (group A: up to 1 centimeter from the surgical cavity, and group B: beyond 1 centimeter from the surgical cavity). The cutoff point was determined to be 1 centimeter because of the visible light penetrance to the normal brain tissue. Results: In univariate analysis, both groups only differed regarding 5-ALA administration, which was significantly related to a minor relative risk of presenting the recurrence within the first centimeter from the surgical cavity (Relative Risk = 0,655 (95% CI 0,442-0,970), p-value=0,046). Results obtained in univariate analysis were corroborated posteriorly in multivariate analysis (RR=0,730 (95% CI 0,340-0,980), p=0,017). Discussion: In the present study, a probable inadvertent 5-ALA photodynamic therapeutical effect has been detected in vivo. This finding widely opens the door for further research on this promising theragnostic tool.

Validation of Presurgical Simulation of White Matter Damage Using Diffusion Tensor Imaging.

BACKGROUND: The understanding of white matter (WM) was revolutionized by the emergence of tractography based on diffusion tensor imaging (DTI). Currently, DTI simulations are implemented in preoperative planning to optimize surgical approaches. The reliability of these simulations has been questioned and investigated seeking for correlation between neurological performance and anomalies in DTI parameters. However, the ability of preoperative WM simulations to predict a surgical injury has not been thoroughly evaluated. Our objective was to assess the reliability of preoperatively simulated WM injuries for conventional neurosurgical procedures. METHODS: WM surgical damage was preoperatively simulated by creating a 3-dimensional volume representing the endoscope or the surgical trajectory. This volume was used as an additional region of interest in the fascicle reconstruction to be subtracted from the original fascicle. Simulated, injured fascicles were compared in terms of the number of fibers and volume to those created from postoperative DTI studies. Reliability was assimilated into the correlation between the simulation and the postoperative reconstruction; evaluated using the intraclass correlation coefficient or Lin's Concordance correlation coefficient (CCC), and represented on Bland-Altman plots. RESULTS: The preoperative and postoperative DTI studies of 30 patients undergoing various neurosurgical approaches were processed. The correlation between simulated injuries and postoperative studies was high in terms of fibers (Concordance correlation coefficient = Rho.C = 0.989 [95% confidence interval = 0.979-0.995]) and volume (intraclass correlation coefficient = 0.95 [95% CI = 0.89-0.97]). Bland-Altman plots demonstrated that the great majority of cases fell within the mean ± 2 Standard deviations. CONCLUSIONS: Presurgical simulation of WM fascicles based on DTI is consistent with postoperative DTI studies. These findings require further validation by neurophysiological and clinical correlation.

Current and Future Frontiers of Molecularly Defined Oligodendrogliomas.

Oligodendrogliomas are a subtype of adult diffuse glioma characterized by their better responsiveness to systemic chemotherapy than other high-grade glial tumors. The World Health Organization (WHO) 2021 brain tumor classification highlighted defining molecular markers, including 1p19q codeletion and IDH mutations which have become key in diagnosing and treating oligodendrogliomas. The management for patients with oligodendrogliomas includes observation or surgical resection potentially followed by radiation and chemotherapy with PCV (Procarbazine, Lomustine, and Vincristine) or Temozolomide. However, most of the available research about oligodendrogliomas includes a mix of histologically and molecularly diagnosed tumors. Even data driving our current management guidelines are based on post-hoc subgroup analyses of the 1p19q codeleted population in landmark prospective trials. Therefore, the optimal treatment paradigm for molecularly defined oligodendrogliomas is incompletely understood. Many questions remain open, such as the optimal timing of radiation and chemotherapy, the response to different chemotherapeutic agents, or what genetic factors influence responsiveness to these agents. Ultimately, oligodendrogliomas are still incurable and new therapies, such as targeting IDH mutations, are necessary. In this opinion piece, we present relevant literature in the field, discuss current challenges, and propose some studies that we think are necessary to answer these critical questions.

Cost-Effectiveness of Low-Field Intraoperative Magnetic Resonance in Glioma Surgery.

OBJECT: Low-field intraoperative magnetic resonance (LF-iMR) has demonstrated a slight increase in the extent of resection of intra-axial tumors while preserving patient`s neurological outcomes. However, whether this improvement is cost-effective or not is still matter of controversy. In this clinical investigation we sought to evaluate the cost-effectiveness of the implementation of a LF-iMR in glioma surgery. METHODS: Patients undergoing LF-iMR guided glioma surgery with gross total resection (GTR) intention were prospectively collected and compared to an historical cohort operated without this technology. Socio-demographic and clinical variables (pre and postoperative KPS; histopathological classification; Extent of resection; postoperative complications; need of re-intervention within the first year and 1-year postoperative survival) were collected and analyzed. Effectiveness variables were assessed in both groups: Postoperative Karnofsky performance status scale (pKPS); overall survival (OS); Progression-free survival (PFS); and a variable accounting for the number of patients with a greater than subtotal resection and same or higher postoperative KPS (R-KPS). All preoperative, procedural and postoperative costs linked to the treatment were considered for the cost-effectiveness analysis (diagnostic procedures, prosthesis, operating time, hospitalization, consumables, LF-iMR device, etc). Deterministic and probabilistic simulations were conducted to evaluate the consistency of our analysis. RESULTS: 50 patients were operated with LF-iMR assistance, while 146 belonged to the control group. GTR rate, pKPS, R-KPS, PFS, and 1-year OS were respectively 13,8% (not significative), 7 points (p < 0.05), 17% (p < 0.05), 38 days (p < 0.05), and 3.7% (not significative) higher in the intervention group. Cost-effectiveness analysis showed a mean incremental cost per patient of 789 € in the intervention group. Incremental cost-effectiveness ratios were 111 € per additional point of pKPS, 21 € per additional day free of progression, and 46 € per additional percentage point of R-KPS. CONCLUSION: Glioma patients operated under LF-iMR guidance experience a better functional outcome, higher resection rates, less complications, better PFS rates but similar life expectancy compared to conventional techniques. In terms of efficiency, LF-iMR is very close to be a dominant technology in terms of R-KPS, PFS and pKPS.

Facial Nerve Preservation for Supraorbital Approaches: Anatomical Mapping Based on Consistent Landmarks.

BACKGROUND: The supraorbital keyhole approach (SOKA) provides a safe and advantageous access to the anterior cranial fossa. The implemented skin incision varies depending on surgeon's preferences and requirements. Facial nerve (FN) injury might appear in up to 5.6% of patients. There is a lack of validated tenets for avoiding FN injury. OBJECTIVE: To define a safety area for FN preservation during a SOKA. METHODS: Ten dried skulls and 5 injected cadaveric heads (10 sides) were used. A Cartesian frame was created with its horizontal axis at the level of the supraorbital notch and the vertical axis just lateral to the frontozygomatic junction (FZj). FNs were dissected and points along their course were registered and transferred to the Cartesian frame. RESULTS: Ten microscopic dissections of the FN were performed preserving all branches. A safety area could be defined 8 mm superior and 10 mm inferior to the FZj extending medially to the supraorbital notch and beyond. A 20 mm2 area superior and lateral to the FZj provided low probability (≤10%) of injuring the FN. Similarly, starting 4 mm inferior to the FZj, a lateral safety area was also found. A probabilistic colored heat map was built to represent the results. CONCLUSION: We provide a "safety zone" for a SOKA incision in which the probability to encounter the FN is low. Clinical studies following our method may validate our findings and add evidence to the tenets for minimizing morbidity related to the SOKA incision.

Presurgical simulation for neuroendoscopic procedures: Virtual study of the integrity of neurological pathways using diffusion tensor imaging tractography.

BACKGROUND: White matter (WM) transgression is an unexplored concept in neuroendoscopy. Diffusion tensor image (DTI) tractography could be implemented as a planning and postoperative evaluation tool in functional disconnection procedures (FDPs), which are, currently, the subject of technological innovations. We intend to prove the usefulness of this planning method focused on the assessment of WM injury that is suitable for planning FDPs. METHODS: Ten cranial magnetic resonance studies (20 sides) without pathological findings were processed. Fascicles were defined by two regions of interest (ROIs) using the fiber assignment method by the continuous tracking approach. Using three-dimensional (3D) simulation and DTI tractography, we created an 8-mm virtual endoscope and an uninjured inferior fronto-occipital fasciculus (IFOF) from two ROIs. The injured tract was generated using a third ROI built from the 3D model of the intersection of the oriented trajectory of the endoscope with the fascicle. Data and images were quantitatively and qualitatively analyzed. RESULTS: The average percentage of the injured fibers was 32.0% (range: 12.4%-70%). The average intersected volume was 1.1 cm3 (range: 0.3-2.3 cm3). Qualitative analysis showed the inferior medial quadrant of the inferior fronto-occipital fasciculus (IFOF) as the most frequently injured region. No hemispherical asymmetry was found (P > 0.5). CONCLUSION: DTI tractography is a useful surgical planning tool that could be implemented in several endoscopic procedures. Together with a functional atlas, the presented technique provides a noninvasive method to assess the potential sequelae and thus to optimize the surgical route. The suggested method could be implemented to analyze pathological WM fascicles and to assess the surgical results of FDP such as hemispherotomy or amygdalohippocampectomy. More studies are needed to overcome the limitations of the tractography based information and to develop more anatomically and functionally reliable planning systems.

Contralateral Transfalcine Versus Ipsilateral Anterior Interhemispheric Approach for Midline Arteriovenous Malformations: Surgical and Anatomical Assessment.

BACKGROUND: The contralateral anterior interhemispheric approach (CAIA) is considered to provide surgical advantages to access deep midline lesions: wider working angle, gravity enhanced dissection and retraction, more efficient lighting, and ergonomics. Our team has previously published on the merits of using a contralateral trajectory for medial frontoparietal arteriovenous malformations (AVMs) compared with the conventional anterior interhemispheric approach (IAIA). In this article, we compare the IAIA and CAIA for the resection of medial frontoparietal AVMs using quantitative surgical and anatomical analysis. METHODS: Two models were designed mimicking the most common features of midline AVMs. The CAIA and IAIA were performed bilaterally in 10 specimens. Variables to compare technical feasibility (surgical window [SW] and surgical freedom [SF], target exposure, and angle of attack) were independently assessed using stereotactic navigation. The average SW, SF, and angle of attack were compared with the Student t test. Significance threshold was set at 0.05. RESULTS: The CITA and IAIA were similar in terms of SW, target exposure, and SF in the superior aspect of the AVM. In the depth of the interhemispheric fissure, the CAIA was significantly superior to IAIA in both AVM models: 77% wider AA for the inferior aspect of the AVM (P < 0.01) and greater SF for the draining vein (54%, P = 0.01), ipsilateral (98%, P = 0.02), and contralateral ACA (117%, P < 0.01). CONCLUSIONS: This study suggests technical superiority of the CAIA for the resection of deep midline AVMs. No objective difference was noted in the superficial areas of our models, denoting that IAIA is a safer choice for superficial AVMs. Our results set the foundation for further clinical analysis comparing both approaches.

Anterior clinoidectomy using an extradural and intradural 2-step hybrid technique.

In Brief: The authors found a practical intraoperative landmark to localize the optic strut during anterior clinoidectomy and used it as the basis for performing anterior clinoidectomy in two steps: extradural phase and intradural phase. This anatomically based technique can increase the safety of anterior clinoidectomy by providing easily identifiable landmarks and reducing intradural bone drilling, which could put the adjacent neurovauscular structures at risk.

Management in chordoid glioma: Avoiding the pitfalls in this rare and challenging entity.

Chordoid glioma (CG) of the third ventricle is an unusual neoplasm of glial nature, which is almost exclusively located in the anterior wall of the third ventricle, in close relation with the hypothalamus. Magnetic resonance images show CG as a suprasellar, hypo- to isointense mass, homogeneously enhancing after the administration of gadolinium. Since its description in 1998 by Brat et al., approximately 85 cases have been reported. Some of its pathological features are under discussion and its histological origin still remains unclear. In this study, we present a patient having this rare entity. We review the management of CG reported in literature. We also studied its pathological features, the postoperative mortality and morbidity related to radical surgical resection, and the implemented adjuvant therapies. Due to its classical clinical features and its close resemblance to other lesions in the region, it is an entity unlikely to be suspected prior to its histological diagnosis. Despite the benign nature of this tumor, the clinical outcome might be poor. Its treatment may represent a real challenge because it involves critical anatomical areas, leading to high postoperative morbidity and mortality rates. An initial minimally invasive management and adjuvant therapies, such as radiosurgery, in case of symptomatic recurrences, can be effective handling strategies.

Assessment of White Matter Transgression During Neuroendoscopic Procedures Using Diffusion Tensor Image Fiber Tracking.

BACKGROUND: Presurgical planning allows anticipating intraoperative difficulties, increasing efficiency, and reducing risks. Neuroendoscopy is a minimally invasive technique whose related complications have been focused on cortical function and surface vessels injury. However, white matter disruption has been insufficiently acknowledged. OBJECTIVE: To present a new surgical planning method based on diffusion tensor image that allows quantifying subcortical transgression and optimizing neuroendoscopic trajectories. METHODS: Ten cranial magnetic resonance studies (20 sides) without pathologic findings were anonymized and processed. A standard transcortical approach to the frontal horn was used to study the transgression of the corpus callosum (CC) and cingulum (Ci) caused by a virtual endoscope (VE) oriented from the Kocher point to the foramen of Monro. An 8-mm VE model was created, oriented, and coregistered. VE-CC and VE-Ci intersections were segmented. The number and volume of injured fibers were measured, intersections were quantified, and the percentage of tract transgression was calculated. The areas damaged by the VE were also recorded. RESULTS: Among the CC fibers, 16.4% were injured (range: 3.3%-37%) and 26.7% of fibers on Ci (rank: 0%-73.4%). The average intersected volumes were 19.1% (range: 4.2%-53.2%) for CC and 33.2% for Ci (range: 0%-73.7%). Qualitative analysis showed the lateral aspect of both tracts as the most frequently injured region. No hemispherical asymmetry was found (P > 0.05). CONCLUSION: This method using tractography and oriented models of surgical instruments allows assessing white matter transgression, both qualitatively and quantitatively, for a deep brain trajectory. Thus our method permits surgeons to optimize safety and avoid transgression of eloquent tracts during surgical planning. Nevertheless, more studies are necessary.

Hearing Preservation During Anterior Petrosectomy: The "Cochlear Safety Line".

BACKGROUND: Identification and protection of the cochlea during anterior petrosectomy is key to prevent hearing loss. Currently, there is no optimal method to infer the position of the cochlea in relation to the Kawase quadrangle; therefore, damage to the cochlea during anterior petrosectomy remains a substantial risk. OBJECTIVES: To identify and define landmarks available during anterior petrosectomy to locate the cochlea and prevent its damage. METHODS: The Kawase approach was simulated in 11 cadaveric specimens. After a subtemporal craniotomy, foramen spinosum and ovale were identified. Anterior petrosectomy was performed, and the upper dural transitional fold (UDTF) was identified. Two virtual lines, from foramen spinosum (line A), and the lateral rim of the foramen ovale (line B), were projected to intersect the UDTF perpendicularly. The cochlea was exposed, and the distances between lines A and B and the closest point of the outer rim and membranous part of the cochlea were measured. RESULTS: The average distance between line A to the bony and membranous edges of the anteromedial cochlea was -0.62 ± 1.38 mm and 0.38 ± 1.63 mm, respectively. The average distance between line B to the bony and membranous edges of the cochlea was 1.82 ± 0.99 mm and 2.78 ± 1.29 mm, respectively. Line B (cochlear safety line) never intersected the cochlea. CONCLUSIONS: The cochlear safety line is a reliable landmark to avoid the cochlea during the Kawase approach. When expanding the anterior petrosectomy posteriorly, the cochlear safety line can be used as a reliable landmark to prevent exposure of the cochlea, thus preventing hearing loss.