The endoscopic treatment of fourth ventricle outlet obstruction: Report of two children and systematic review.

Fourth ventricle outlet obstruction (FVOO) is a rare cause of hydrocephalus. In the last century, the standard treatment was the suboccipital craniotomy with magendieplasty or ventriculoperitoneal shunt (VP shunt). Since the beginning of the 21st century, the endoscopic third ventriculostomy (ETV) has been considered a less invasive alternative. The medical literature lacks sufficient reports of FVOO cases and strong evidence about ETV's efficacy in treating this condition. We report two cases of FVOO treated with ETV and review published similar cases. Clinical and radiological findings of two FVOO cases with outcomes after ETV were presented. Moreover, we conducted a systematic review after protocol registration in PROSPERO (CRD42021281474). MEDLINE, Embase, Scopus, and Web of Science were searched from inception till December 31, 2022. Studies were included if they reported cases of FVOO treated initially with ETV. Cases with Chiari malformation, Dandy-Walker malformation, tuberous sclerosis, trapped fourth ventricle, or space-occupying lesions were excluded. Two reviewers independently examined title/abstract records in the first stage and full-text publications in the second for eligibility. The primary outcome was the recurrence rate, defined by the need for re-ETV or other invasive treatments (e.g., VP shunt or magendieplasty). Other outcomes included clinical state at follow-up and mortality. Two cases, a 3-year-old male and 3.5-year-old female, with FVOO, were treated with ETV in our department by the same neurosurgeon (SH) in 2013 and 2021. Both cases improved significantly after ETV, and there was no recurrence through the follow-up. Besides the present cases, we found 57 other cases of FVOO treated with ETV reported in 17 studies between 2001 and 2021. The median age was 26 years, with an IQR from 2.4 to 59 years, and 56% of cases were females. The recurrence rate was 32% in the sample (19 out of 59), with a 95% CI from 21% to 46%. The median time to recure was 2 months with IQR from 1.25 to 26. A VP shunt was the treatment for recurrence in 68% and a re-ETV in 32%. At the follow-up (41 ± 29 months), only one case died, and one deteriorated clinically. FVOO is a rare cause of hydrocephalus encountered mainly in the first or sixth decades of life. ETV provides the first reasonable treatment. Despite the moderate recurrence rate, the outcomes are favorable.

The Endoscopic-Assisted Supraorbital Approach for Resection of Anterior Skull Base Meningiomas: A Large Single-Center Retrospective Surgical Study.

Objective The endoscopic-assisted supraorbital approach (eSOA) constitutes a minimally invasive strategy for removing anterior skull base meningiomas (ASBM). We present the largest retrospective single-institution and long-term follow-up study of eSOA for ASBM resection, providing further insight regarding indication, surgical considerations, complications, and outcome. Methods We evaluated data of 176 patients operated on ASBM via the eSOA over 22 years. Results Sixty-five tuberculum sellae (TS), 36 anterior clinoid (AC), 28 olfactory groove (OG), 27 planum sphenoidale, 11 lesser sphenoid wing, seven optic sheath, and two lateral orbitary roof meningiomas were assessed. Median surgery duration was 3.35 ± 1.42 hours, being significantly longer for OG and AC meningiomas ( p <0.05). Complete resection was achieved in 91%. Complications included hyposmia (7.4%), supraorbital hypoesthesia (5.1%), cerebrospinal fluid fistula (5%), orbicularis oculi paresis (2.8%), visual disturbances (2.2%), meningitis (1.7%) and hematoma and wound infection (1.1%). One patient died due to intraoperative carotid injury, other due to pulmonary embolism. Median follow-up was 4.8 years with a tumor recurrence rate of 10.8%. Second surgery was chosen in 12 cases (10 via the previous SOA and two via pterional approach), whereas two patients received radiotherapy and in five patients a wait-and-see strategy was adopted. Conclusion The eSOA represents an effective option for ASBM resection, enabling high complete resection rates and long-term disease control. Neuroendoscopy is fundamental for improving tumor resection while reducing brain and optic nerve retraction. Potential limitations and prolonged surgical duration may arise from the small craniotomy and reduced maneuverability, especially for large or strongly adherent lesions.

Variants of the Anterior Subtemporal Approach to the Gasserian Ganglion and Related Structures: An Anatomical Study With Relevant Implications for Keyhole Surgery.

BACKGROUND: The advantages and limitations of different craniotomy positions and approach trajectories to the gasserian ganglion (GG) and related structures using an anterior subtemporal approach have not been studied systematically. Knowledge of these features is of importance when planning keyhole anterior subtemporal (kAST) approaches to the GG to optimize access and minimize risks. METHODS: Eight formalin-fixed heads were used bilaterally to assess temporal lobe retraction (TLR), trigeminal exposure, and relevant anatomical aspects of extra- and transdural classic anterior subtemporal (CLAST) approaches compared with slightly dorsally and ventrally allocated corridors. RESULTS: TLR to the GG and foramen ovale was found to be lower via the CLAST approach (P < 0.001). Using the ventral variant, TLR to access the foramen rotundum was minimized (P < 0.001). The overall TLR was maximal using the dorsal variant (P < 0.001) owing to interposition of the arcuate eminence. An extradural CLAST approach required wide exposure of the greater petrosal nerve (GPN) and middle meningeal artery (MMA) sacrifice. Both maneuvers were spared using a transdural approach. Using CLAST, medial dissection >39 mm can enter the Parkinson triangle, jeopardizing the intracavernous internal carotid artery. The ventral variant enabled access to the anterior portion of the GG and foramen ovale without the need for MMA sacrifice or GPN dissection. CONCLUSIONS: The CLAST approach provides high versatility to approach the trigeminal plexus, minimizing TLR. However, an extradural approach jeopardizes the GPN and requires MMA sacrifice. The risk of cavernous sinus violation exists when progressing medially beyond 4 cm. The ventral variant has some advantages to access the ventral structures and avoid MMA and GPN manipulation. In contrast, the usefulness of the dorsal variant is rather limited owing to the greater TLR required.

New Strategies in Diagnosis and Treatments for Brain Tumors.

In general, cancer is one of the most frequent causes of death [...].

Concurrent Activation of Both Survival-Promoting and Death-Inducing Signaling by Chloroquine in Glioblastoma Stem Cells: Implications for Potential Risks and Benefits of Using Chloroquine as Radiosensitizer.

Lysosomotropic agent chloroquine was shown to sensitize non-stem glioblastoma cells to radiation in vitro with p53-dependent apoptosis implicated as one of the underlying mechanisms. The in vivo outcomes of chloroquine or its effects on glioblastoma stem cells have not been previously addressed. This study undertakes a combinatorial approach encompassing in vitro, in vivo and in silico investigations to address the relationship between chloroquine-mediated radiosensitization and p53 status in glioblastoma stem cells. Our findings reveal that chloroquine elicits antagonistic impacts on signaling pathways involved in the regulation of cell fate via both transcription-dependent and transcription-independent mechanisms. Evidence is provided that transcriptional impacts of chloroquine are primarily determined by p53 with chloroquine-mediated activation of pro-survival mevalonate and p21-DREAM pathways being the dominant response in the background of wild type p53. Non-transcriptional effects of chloroquine are conserved and converge on key cell fate regulators ATM, HIPK2 and AKT in glioblastoma stem cells irrespective of their p53 status. Our findings indicate that pro-survival responses elicited by chloroquine predominate in the context of wild type p53 and are diminished in cells with transcriptionally impaired p53. We conclude that p53 is an important determinant of the balance between pro-survival and pro-death impacts of chloroquine and propose that p53 functional status should be taken into consideration when evaluating the efficacy of glioblastoma radiosensitization by chloroquine.

Intermodal Detection of Lumbar Instability in Degenerative Spondylolisthesis is Superior to Functional Radiographs.

Purpose: In this study, we compare different imaging modalities to find the most sensitive and efficient way of detecting instability in lumbar spondylolisthesis. Methods: Patients presenting with spondylolisthesis from June 01, 2018 to May 31, 2020 with functional radiographs and either CT scans or MRI images were included in our single-center retrospective cohort study. The amount of translation, in millimeters, was measured on supine MRI images, CT scans, and radiographs of inclination while sitting, standing, or prone and reclination while standing using the Meyerding technique. The amount of translation was compared among the different modalities. Results: A total of 113 patients with spondylolisthesis on 125 vertebral levels were included in this study. The mean patient age was 73.52 ± 12.59 years; 69 (60.5%) patients were females. The most affected level was L4/5 (62.4%), followed by L3/4 (16%) and L5/S1 (13.6%). The average translations measured on supine CT were 4.13 ± 5.93 mm and 4.42 ± 3.49 mm on MRI (p = 0.3 for the difference between MRI and CT). The difference of inclination while sitting radiograph to slice imaging was 3.37 ± 3.64 mm (p < 0.0001), inclination while standing to slice imaging was 2.67 ± 3.03 mm (p < 0.0001), reclination while standing to slice imaging was 1.6 ± 3.15 mm (p = 0.03), and prone to slice imaging was 2.19 ± 3.02 mm (p = 0.03). Conclusion: We found that a single radiograph in either inclination, reclination, or prone position compared to a CT scan or an MRI image in supine position can detect instability in spondylolisthesis more efficiently than comparison of functional radiographs in any position.

Endoscopic-assisted paramedian supracerebellar infratentorial approach to the posterior portion of the third ventricle. Anatomical study and surgical cases.

BACKGROUND: To date, morphometrical data providing a systematic quantification of accessibility and operability parameters to the boundaries of the posterior portion of the third ventricle (PTV) when applying an endoscopic-assisted paramedian supracerebellar infratentorial approach (EPSIA) are lacking. We performed an anatomical study and complemented our findings with surgical cases. METHODS: Eight EPSIAs towards the PTV were performed in cadaveric specimens. Optimal approach angles (OA), surgical freedom (SF) and operability indexes (Oi) to the PTV boundaries were assessed. Additionally, a 54-year-old man and 33-year-old woman were operated on PTV tumors applying the EPSIA. RESULTS: Sagittal OA to ventricle's roof and floor was 36±1.4° and 25.5±3.5° respectively, axial OA to the ipsilateral and contralateral ventricle's wall were 9.5±1.3° and 28.5±1.6°. SF was maximal on the contralateral wall (121.2±19.3mm2), followed by the roof (112.7±18.8mm2), floor (106.6±19.2mm2) and ipsilateral wall (94.1±15.7mm2). SF was significantly lower along the ipsilateral compared the contralateral wall (p<0.01) and roof (p<0.05). Facilitated surgical maneuvers with multiangled exposure were possible up to 8.5±1.07mm anterior to ventricle's entrance, whereas surgical maneuvers were possible but difficult up to 15.25±3.7mm. Visualization of more anterior was possible up to a distance of 27±2.9mm, but surgical maneuvers were barely feasible. EPSIA enabled successful resection of both PTV tumors and postoperative course was uneventful. CONCLUSIONS: EPSIA can be effective for approaching the PTV, enabling surgery along all boundaries, but especially on its roof and contralateral wall. In the not-enlarged ventricle, surgical maneuvers are feasible up to the level of the Monro foramen, becoming more limited anteriorly.

Two-stage endoscopic assisted approach for large pineal region and falcotentorial meningioma: first stage paramedian supracerebellar infratentorial approach, second stage interhemispheric occipital transtentorial approach: surgical cases and anatomical study.

Resection of complex falcotentorial meningiomas, growing along the pineal region (PR), and posterior incisural space (PIS) represents a neurosurgical challenge. Here, we present our strategy for effective resection of large falcotentorial meningiomas applying a paramedian supracerebellar infratentorial and interhemispheric occipital transtentorial approach in staged surgeries. We further systematically compared the effectiveness of midline (MSIA) and paramedian (PSIA) supracerebellar infratentorial, as well as interhemispheric occipital transtentorial approaches (IOTA) to operate along the PR and PIS in 8 cadaveric specimens. The staged PSIA and IOTA enabled successful resection of both falcotentorial meningiomas with an uneventful postoperative course. In our anatomo-morphometrical study, superficial vermian veins at an average depth of 11.38 ± 1.5 mm and the superior vermian vein (SVV) at 54.13 ± 4.12 mm limited the access to the PIS during MSIA. MSIA required sacrifice of these veins and retraction of the vermian culmen of 20.88 ± 2.03 mm to obtain comparable operability indexes to PSIA and IOTA. Cerebellar and occipital lobe retraction averaged 14.31 ± 1.014 mm and 14.81 ± 1.17 mm during PSIA and IOTA respectively, which was significantly lower than during MSIA (p < 0.001). Only few minuscule veins were encountered along the access through PSIA and IOTA. The application of PSIA provided high operability scores around the pineal gland, ipsilateral colliculus and splenium, and acceptable scores on contralateral structures. The main advantage of IOTA was improving surgical maneuvers along the ipsilateral splenium. In summary, IOTA and PSIA may be advantageous in terms of brain retraction, vein sacrifice, and operability along the PR and PIS and can be effective for resection of complex falcotentorial meningiomas.

Algorithmically Deduced FREM2 Molecular Pathway Is a Potent Grade and Survival Biomarker of Human Gliomas.

Gliomas are the most common malignant brain tumors with high mortality rates. Recently we showed that the FREM2 gene has a role in glioblastoma progression. Here we reconstructed the FREM2 molecular pathway using the human interactome model. We assessed the biomarker capacity of FREM2 expression and its pathway as the overall survival (OS) and progression-free survival (PFS) biomarkers. To this end, we used three literature and one experimental RNA sequencing datasets collectively covering 566 glioblastomas (GBM) and 1097 low-grade gliomas (LGG). The activation level of deduced FREM2 pathway showed strong biomarker characteristics and significantly outperformed the FREM2 expression level itself. For all relevant datasets, it could robustly discriminate GBM and LGG (p < 1.63 × 10-13, AUC > 0.74). High FREM2 pathway activation level was associated with poor OS in LGG (p < 0.001), and low PFS in LGG (p < 0.001) and GBM (p < 0.05). FREM2 pathway activation level was poor prognosis biomarker for OS (p < 0.05) and PFS (p < 0.05) in LGG with IDH mutation, for PFS in LGG with wild type IDH (p < 0.001) and mutant IDH with 1p/19q codeletion(p < 0.05), in GBM with unmethylated MGMT (p < 0.05), and in GBM with wild type IDH (p < 0.05). Thus, we conclude that the activation level of the FREM2 pathway is a potent new-generation diagnostic and prognostic biomarker for multiple molecular subtypes of GBM and LGG.

Load Distribution in the Lumbar Spine During Modeled Compression Depends on Lordosis.

Excessive or incorrect loading of lumbar spinal structures is commonly assumed as one of the factors to accelerate degenerative processes, which may lead to lower back pain. Accordingly, the mechanics of the spine under medical conditions, such as scoliosis or spondylolisthesis, is well-investigated. Treatments via both conventional therapy and surgical methods alike aim at restoring a "healthy" (or at least pain-free) load distribution. Yet, surprisingly little is known about the inter-subject variability of load bearings within a "healthy" lumbar spine. Hence, we utilized computer tomography data from 28 trauma-room patients, whose lumbar spines showed no visible sign of degeneration, to construct simplified multi-body simulation models. The subject-specific geometries, measured by the corresponding lumbar lordosis (LL) between the endplates of vertebra L1 and the sacrum, served as ceteris paribus condition in a standardized forward dynamic compression procedure. Further, the influence of stimulating muscles from the M. multifidus group was assessed. For the range of available LL from 28 to 66°, changes in compressive and shear forces, bending moments, as well as facet joint forces between adjacent vertebrae were calculated. While compressive forces tended to decrease with increasing LL, facet forces were tendentiously increasing. Shear forces decreased between more cranial vertebrae and increased between more caudal ones, while bending moments remained constant. Our results suggest that there exist significant, LL-dependent variations in the loading of "healthy" spinal structures, which should be considered when striving for individually appropriate therapeutic measures.

Comparison of Unruptured Intracranial Aneurysm Treatment Score and PHASES Score in Subarachnoid Hemorrhage Patients With Multiple Intracranial Aneurysms.

Objective: Unruptured Intracranial Aneurysm (UIA) Treatment Score (UIATS) and PHASES score are used to inform treatment decision making for UIAs (treatment or observation). We assessed the ability of the scoring systems to discriminate between ruptured aneurysms and UIAs in a subarachnoid hemorrhage (SAH) cohort with multiple aneurysms. Methods: We retrospectively applied PHASES and UIATS scoring to the aneurysms of 40 consecutive patients with SAH and multiple intracranial aneurysms. Results: PHASES score discriminated better between ruptured aneurysms and UIAs than UIATS. PHASES scores and the difference between the UIATS subscores were higher for ruptured aneurysms compared with UIAs, which reached significance for the PHASES score. PHASES score estimated a low 5-year rupture risk in a larger proportion of the UIAs (≤0.7% in 62.3%, ≤1.7% in 98.4%) than of the ruptured aneurysms (≤0.7% in 22.5%, ≤1.7% in 82.5%). In the 40 ruptured aneurysms, UIATS provided recommendation for treatment in 11 (27.5%), conservative management in 14 (35.0%), and was inconclusive in 15 cases (37.5%). In the 61 UIAs, UIATS recommended treatment in 16 (26.2%), conservative management in 29 (47.5%), and was inconclusive in 16 (26.2%) cases. Conclusion: Similar to previous SAH cohorts, a significant proportion of the ruptured aneurysms exhibited a low-rupture risk. Nevertheless, PHASES score discriminated between ruptured aneurysms and UIAs in our cohort; the lower discriminatory power of UIATS was due to high weights of aneurysm-independent factors. We recommend careful integration of the scores for individual decision making. Large-scale prospective trials are required to establish score-based treatment strategies for UIAs.

An age-dependent outcome analysis of microvascular decompression and percutaneous thermocoagulation in trigeminal neuralgia.

BACKGROUND: Trigeminal neuralgia (TN) is a severe pain condition and the most common facial neuralgia. While microvascular decompression (MVD) presents an excellent treatment in neurovascular compression cases, percutaneous thermocoagulation (PT) of the ganglion Gasseri is an alternative option. This study aimed to evaluate post-operative complication rate and outcome of both treatment strategies related to the patient's age. METHODS: The medical records of all patients with the diagnosis of trigeminal neuralgia undergoing an MVD or PT of the ganglion Gasseri (between January 2007 and September 2017) were reviewed to determine the efficacy and the complication rate of both methods in regard to the patient's age. RESULTS: Seventy-nine patients underwent MVD surgery and 39 a PT. The mean age of patients in the MVD group was 61 years and 73 years in the PT group. There were 59 (50%) female patients. Nerve-vessel conflict could be identified in 78 (98.7%) MVD and 17 (43.6%) PT patients on preoperative MRI. Charlson comorbidity index was significantly higher in PT group (2.4 (1.8) versus 3.8 (1.8) p < 0.001). The Barrow pain score (BPS) at the last follow-up demonstrated higher scores after PT (p = 0.007). The complication rate was markedly higher in PT group, mostly due to the facial hypesthesia (84.6% versus 27.8%; p < 0.001). Mean symptom-free survival was significantly shorter in the PT group (9 vs. 26 months, p < 0.001). It remained statistically significant when stratified into age groups: (65 years and older: 9 vs. 18 months, p = 0.001). Duration of symptoms (OR 1.005, 95% CI 1.000-1.010), primary procedure (OR 6.198, 95% CI 2.650-14.496), patient age (OR 1.033, 95% CI 1.002-1.066), and postoperative complication rate (OR 2.777, 95% CI 1.309-5.890) were associated with treatment failure. CONCLUSION: In this patient series, the MVD is confirmed to be an excellent treatment option independent of patient's age. However, while PT is an effective procedure, time to pain recurrence is shorter, and the favorable outcome (BPS 1 and 2) rate is lower compared to MVD. Hence MVD should be the preferred treatment and PT should remain an alternative in very selected cases when latter is not possible but not in the elderly patient per se.

Muscle-driven and torque-driven centrodes during modeled flexion of individual lumbar spines are disparate.

Lumbar spine biomechanics during the forward-bending of the upper body (flexion) are well investigated by both in vivo and in vitro experiments. In both cases, the experimentally observed relative motion of vertebral bodies can be used to calculate the instantaneous center of rotation (ICR). The timely evolution of the ICR, the centrode, is widely utilized for validating computer models and is thought to serve as a criterion for distinguishing healthy and degenerative motion patterns. While in vivo motion can be induced by physiological active structures (muscles), in vitro spinal segments have to be driven by external torque-applying equipment such as spine testers. It is implicitly assumed that muscle-driven and torque-driven centrodes are similar. Here, however, we show that centrodes qualitatively depend on the impetus. Distinction is achieved by introducing confidence regions (ellipses) that comprise centrodes of seven individual multi-body simulation models, performing flexion with and without preload. Muscle-driven centrodes were generally directed superior-anterior and tail-shaped, while torque-driven centrodes were located in a comparably narrow region close to the center of mass of the caudal vertebrae. We thus argue that centrodes resulting from different experimental conditions ought to be compared with caution. Finally, the applicability of our method regarding the analysis of clinical syndromes and the assessment of surgical methods is discussed.

Diversity of Clinically Relevant Outcomes Resulting from Hypofractionated Radiation in Human Glioma Stem Cells Mirrors Distinct Patterns of Transcriptomic Changes.

Hypofractionated radiotherapy is the mainstay of the current treatment for glioblastoma. However, the efficacy of radiotherapy is hindered by the high degree of radioresistance associated with glioma stem cells comprising a heterogeneous compartment of cell lineages differing in their phenotypic characteristics, molecular signatures, and biological responses to external signals. Reconstruction of radiation responses in glioma stem cells is necessary for understanding the biological and molecular determinants of glioblastoma radioresistance. To date, there is a paucity of information on the longitudinal outcomes of hypofractionated radiation in glioma stem cells. This study addresses long-term outcomes of hypofractionated radiation in human glioma stem cells by using a combinatorial approach integrating parallel assessments of the tumor-propagating capacity, stemness-associated properties, and array-based profiling of gene expression. The study reveals a broad spectrum of changes in the tumor-propagating capacity of glioma stem cells after radiation and finds association with proliferative changes at the onset of differentiation. Evidence is provided that parallel transcriptomic patterns and a cumulative impact of pathways involved in the regulation of apoptosis, neural differentiation, and cell proliferation underly similarities in tumorigenicity changes after radiation.

Automated Grading of Cerebral Vasospasm to Standardize Computed Tomography Angiography Examinations After Subarachnoid Hemorrhage.

Background: Computed tomography angiography (CTA) is frequently used with computed tomography perfusion imaging (CTP) to evaluate whether endovascular vasospasm treatment is indicated for subarachnoid hemorrhage patients with delayed cerebral ischemia. However, objective parameters for CTA evaluation are lacking. In this study, we used an automated, investigator-independent, digital method to detect vasospasm, and we evaluated whether the method could predict the need for subsequent endovascular vasospasm treatment. Methods: We retrospectively reviewed the charts and analyzed imaging data for 40 consecutive patients with subarachnoid hemorrhages. The cerebrovascular trees were digitally reconstructed from CTA data, and vessel volume and the length of the arteries of the circle of Willis and their peripheral branches were determined. Receiver operating characteristic curve analysis based on a comparison with digital subtraction angiographies was used to determine volumetric thresholds that indicated severe vasospasm for each vessel segment. Results: The automated threshold-based volumetric evaluation of CTA data was able to detect severe vasospasm with high sensitivity and negative predictive value for predicting cerebral hypoperfusion on CTP, although the specificity and positive predictive value were low. Combining the automated detection of vasospasm on CTA and cerebral hypoperfusion on CTP was superior to CTP or CTA alone in predicting endovascular vasospasm treatment within 24 h after the examination. Conclusions: This digital volumetric analysis of the cerebrovascular tree allowed the objective, investigator-independent detection and quantification of vasospasms. This method could be used to standardize diagnostics and the selection of subarachnoid hemorrhage patients with delayed cerebral ischemia for endovascular diagnostics and possible interventions.

Intratumoral Heterogeneity and Longitudinal Changes in Gene Expression Predict Differential Drug Sensitivity in Newly Diagnosed and Recurrent Glioblastoma.

Background: Inevitable recurrence after radiochemotherapy is the major problem in the treatment of glioblastoma, the most prevalent type of adult brain malignancy. Glioblastomas are notorious for a high degree of intratumor heterogeneity manifest through a diversity of cell types and molecular patterns. The current paradigm of understanding glioblastoma recurrence is that cytotoxic therapy fails to target effectively glioma stem cells. Recent advances indicate that therapy-driven molecular evolution is a fundamental trait associated with glioblastoma recurrence. There is a growing body of evidence indicating that intratumor heterogeneity, longitudinal changes in molecular biomarkers and specific impacts of glioma stem cells need to be taken into consideration in order to increase the accuracy of molecular diagnostics still relying on readouts obtained from a single tumor specimen. Methods: This study integrates a multisampling strategy, longitudinal approach and complementary transcriptomic investigations in order to identify transcriptomic traits of recurrent glioblastoma in whole-tissue specimens of glioblastoma or glioblastoma stem cells. In this study, 128 tissue samples of 44 tumors including 23 first diagnosed, 19 recurrent and 2 secondary recurrent glioblastomas were analyzed along with 27 primary cultures of glioblastoma stem cells by RNA sequencing. A novel algorithm was used to quantify longitudinal changes in pathway activities and model efficacy of anti-cancer drugs based on gene expression data. Results: Our study reveals that intratumor heterogeneity of gene expression patterns is a fundamental characteristic of not only newly diagnosed but also recurrent glioblastomas. Evidence is provided that glioblastoma stem cells recapitulate intratumor heterogeneity, longitudinal transcriptomic changes and drug sensitivity patterns associated with the state of recurrence. Conclusions: Our results provide a transcriptional rationale for the lack of significant therapeutic benefit from temozolomide in patients with recurrent glioblastoma. Our findings imply that the spectrum of potentially effective drugs is likely to differ between newly diagnosed and recurrent glioblastomas and underscore the merits of glioblastoma stem cells as prognostic models for identifying alternative drugs and predicting drug response in recurrent glioblastoma. With the majority of recurrent glioblastomas being inoperable, glioblastoma stem cell models provide the means of compensating for the limited availability of recurrent glioblastoma specimens.

Multicolor 3D Printing of Complex Intracranial Tumors in Neurosurgery.

Three-dimensional (3D) printing technologies offer the possibility of visualizing patient-specific pathologies in a physical model of correct dimensions. The model can be used for planning and simulating critical steps of a surgical approach. Therefore, it is important that anatomical structures such as blood vessels inside a tumor can be printed to be colored not only on their surface, but throughout their whole volume. During simulation this allows for the removal of certain parts (e.g., with a high-speed drill) and revealing internally located structures of a different color. Thus, diagnostic information from various imaging modalities (e.g., CT, MRI) can be combined in a single compact and tangible object. However, preparation and printing of such a fully colored anatomical model remains a difficult task. Therefore, a step-by-step guide is provided, demonstrating the fusion of different cross-sectional imaging data sets, segmentation of anatomical structures, and creation of a virtual model. In a second step the virtual model is printed with volumetrically colored anatomical structures using a plaster-based color 3D binder jetting technique. This method allows highly accurate reproduction of patient-specific anatomy as shown in a series of 3D-printed petrous apex chondrosarcomas. Furthermore, the models created can be cut and drilled, revealing internal structures that allow for simulation of surgical procedures.

Image-Guided Transcranial Doppler Ultrasound for Monitoring Posthemorrhagic Vasospasms of Infratentorial Arteries: A Feasibility Study.

BACKGROUND: A considerable number of patients with subarachnoid hemorrhage (SAH) develop vasospasms of the infratentorial arteries. Transcranial Doppler sonography (TCD) is used to screen for vasospasm. In this study, we used a technical modification that combines TCD with an image guidance device that the operator can use to navigate to the ultrasonic window and to predefined intracranial vascular targets. Our aim was to analyze the feasibility, spatial precision, and spatial reproducibility of serial image-guided TCD of infratentorial and-for comparison-supratentorial arteries in the clinical setting of monitoring for vasospasm after SAH. METHODS: The study included 10 SAH patients, who each received 5 serial image-guided TCD examinations. Using computed tomography angiography data, trajectories to the infratentorial and supratentorial cerebral arteries were planned and loaded into an image guidance device tracking the Doppler probe. As a measure of spatial precision and spatial reproducibility, we analyzed the distances between the positions of preplanned vascular targets and optimal Doppler signals. RESULTS: The mean distance between preplanned and optimal target points was 4.8 ± 2.1 mm (first exam), indicating high spatial precision. The spatial precision decreased with increasing depth of the vascular target. In all patients, image-guided TCD detected all predefined supratentorial and infratentorial vascular segments. There were no significant changes in spatial precision in serial exams, indicating high reproducibility. CONCLUSIONS: Image-guided TCD is feasible for supratentorial and infratentorial arteries. It shows high spatial precision and reproducibility. This study provides a basis for future clinical studies on image-guided TCD for post-SAH vasospasm screening.

Neutrophils mediate early cerebral cortical hypoperfusion in a murine model of subarachnoid haemorrhage.

Cerebral hypoperfusion in the first hours after subarachnoid haemorrhage (SAH) is a major determinant of poor neurological outcome. However, the underlying pathophysiology is only partly understood. Here we induced neutropenia in C57BL/6N mice by anti-Ly6G antibody injection, induced SAH by endovascular filament perforation, and analysed cerebral cortical perfusion with laser SPECKLE contrast imaging to investigate the role of neutrophils in mediating cerebral hypoperfusion during the first 24 h post-SAH. SAH induction significantly increased the intracranial pressure (ICP), and significantly reduced the cerebral perfusion pressure (CPP). At 3 h after SAH, ICP had returned to baseline and CPP was similar between SAH and sham mice. However, in SAH mice with normal neutrophil counts cortical hypoperfusion persisted. Conversely, despite similar CPP, cortical perfusion was significantly higher at 3 h after SAH in mice with neutropenia. The levels of 8-iso-prostaglandin-F2α in the subarachnoid haematoma increased significantly at 3 h after SAH in animals with normal neutrophil counts indicating oxidative stress, which was not the case in neutropenic SAH animals. These results suggest that neutrophils are important mediators of cortical hypoperfusion and oxidative stress early after SAH. Targeting neutrophil function and neutrophil-induced oxidative stress could be a promising new approach to mitigate cerebral hypoperfusion early after SAH.

The approach angle to the interoptic triangle limits surgical workspace when targeting the contralateral internal carotid artery.

BACKGROUND: The interoptic triangle (IOT) offers a key access to the contralateral carotid artery's ophthalmic segment (oICA) and its perforating branches (PB), the ophthalmic artery (OA), and the superior hypophyseal artery (SHA). It has been previously reported that the assessment of IOT's size is relevant when attempting approaches to the contralateral oICA. However, previous studies have overseen that, since the oICA is a paramedian structure and a lateralized contralateral approach trajectory is then required, the real access to the oICA is further limited by the approach angle adopted by the surgeon with respect to the IOT's plane. For this reason, we determined the surgical accessibility to the contralateral oICA and its branches though the IOT by characterizing the morphometry of this triangle relative to the optimal contralateral approach angle. METHODS: We defined the "relative interoptic triangle" (rIOT) as the two-dimensional projection of the IOT to the surgeon's view, when the microscope has been positioned with a certain angle with respect to the midline to allow the maximal contralateral oICA visualization. We correlated the surface of the rIOT to the visualization of oICA, OA, SHA, and PBs on 8 cadavers and 10 clinical datasets, using for the last a 3D-virtual reality system. RESULTS: A larger rIOT correlated positively with the exposure of the contralateral oICA (R = 0.967, p < 0.001), OA (R = 0.92, p < 0.001), SHA (R = 0.917, p < 0.001), and the number of perforant vessels of the oICA visible (R = 0.862, p < 0.001). The exposed length of oICA, OA, SHA, and number PB observed increased as rIOT's surface enlarged. The correlation patterns observed by virtual 3D-planning matched the anatomical findings closely. CONCLUSIONS: The exposure of contralateral oICA, OA, SHA, and PB directly correlates to rIOT's surface. Therefore, preoperative assessment of rIOT's surface is helpful when considering contralateral approaches to the oICA. A virtual 3D planning tool greatly facilitates this assessment.