From molecular signatures to radiomics: tailoring neurooncological strategies through forecasting of glioma growth.

OBJECTIVE: Contemporary oncological paradigms for adjuvant treatment of low- and intermediate-grade gliomas are often guided by a limited array of parameters, overlooking the dynamic nature of the disease. The authors' aim was to develop a comprehensive multivariate glioma growth model based on multicentric data, to facilitate more individualized therapeutic strategies. METHODS: Random slope models with subject-specific random intercepts were fitted to a retrospective cohort of grade II and III gliomas from the database at Kepler University Hospital (n = 191) to predict future mean tumor diameters. Deep learning-based radiomics was used together with a comprehensive clinical dataset and evaluated on an external prospectively collected validation cohort from University Hospital Zurich (n = 9). Prediction quality was assessed via mean squared prediction error. RESULTS: A mean squared prediction error of 0.58 cm for the external validation cohort was achieved, indicating very good prognostic value. The mean ± SD time to adjuvant therapy was 28.7 ± 43.3 months and 16.1 ± 14.6 months for the training and validation cohort, respectively, with a mean of 6.2 ± 5 and 3.6 ± 0.7, respectively, for number of observations. The observed mean tumor diameter per year was 0.38 cm (95% CI 0.25-0.51) for the training cohort, and 1.02 cm (95% CI 0.78-2.82) for the validation cohort. Glioma of the superior frontal gyrus showed a higher rate of tumor growth than insular glioma. Oligodendroglioma showed less pronounced growth, anaplastic astrocytoma-unlike anaplastic oligodendroglioma-was associated with faster tumor growth. Unlike the impact of extent of resection, isocitrate dehydrogenase (IDH) had negligible influence on tumor growth. Inclusion of radiomics variables significantly enhanced the prediction performance of the random slope model used. CONCLUSIONS: The authors developed an advanced statistical model to predict tumor volumes both pre- and postoperatively, using comprehensive data prior to the initiation of adjuvant therapy. Using radiomics enhanced the precision of the prediction models. Whereas tumor extent of resection and topology emerged as influential factors in tumor growth, the IDH status did not. This study emphasizes the imperative of advanced computational methods in refining personalized low-grade glioma treatment, advocating a move beyond traditional paradigms.

Surgeon experience in glioblastoma surgery of the elderly-a multicenter, retrospective cohort study.

PURPOSE: To assess the impact of individual surgeon experience on overall survival (OS), extent of resection (EOR) and surgery-related morbidity in elderly patients with glioblastoma (GBM), we performed a retrospective case-by-case analysis. METHODS: GBM patients aged ≥ 65 years who underwent tumor resection at two academic centers were analyzed. The experience of each neurosurgeon was quantified in three ways: (1) total number of previously performed glioma surgeries (lifetime experience); (2) number of surgeries performed in the previous five years (medium-term experience) and (3) in the last two years (short-term experience). Surgeon experience data was correlated with survival (OS) and surrogate parameters for surgical quality (EOR, morbidity). RESULTS: 198 GBM patients (median age 73.0 years, median preoperative KPS 80, IDH-wildtype status 96.5%) were included. Median OS was 10.0 months (95% CI 8.0-12.0); median EOR was 89.4%. Surgery-related morbidity affected 19.7% patients. No correlations of lifetime surgeon experience with OS (P = .693), EOR (P = .693), and surgery-related morbidity (P = .435) were identified. Adjuvant therapy was associated with improved OS (P < .001); patients with surgery-related morbidity were less likely to receive adjuvant treatment (P = .002). In multivariable testing, adjuvant therapy (P < .001; HR = 0.064, 95%CI 0.028-0.144) remained the only significant predictor for improved OS. CONCLUSION: Less experienced neurosurgeons achieve similar surgical results and outcome in elderly GBM patients within the setting of academic teaching hospitals. Adjuvant treatment and avoidance of surgery-related morbidity are crucial for generating a treatment benefit for this cohort.

Reduction of spondylolisthesis and restoration of lumbar lordosis after anterior lumbar interbody fusion (ALIF).

BACKGROUND: Anterior lumbar interbody fusion (ALIF) is a well-established surgical treatment option for various diseases of the lumbar spine, including spondylolisthesis. This study aimed to evaluate the postoperative correction of spondylolisthesis and restoration of lumbar and segmental lordosis after ALIF. METHODS: Patients with spondylolisthesis who underwent ALIF between 2013 and 2019 were retrospectively assessed. We assessed the following parameters pre-and postoperatively (6-months follow-up): Visual Analogue Scale (VAS) for pain, Oswestry Disability Index (ODI), lumbar lordosis (LL), segmental lordosis (SL), L4/S1 lordosis, and degree of spondylolisthesis. RESULTS: 96 patients were included. In 84 cases (87.50%), additional dorsal instrumentation was performed. The most frequent diagnosis was isthmic spondylolisthesis (73.96%). VAS was reduced postoperatively, from 70 to 40, as was ODI (50% to 32%). LL increased from 59.15° to 64.45°, as did SL (18.95° to 28.55°) and L4/S1 lordosis (37.90° to 44.00°). Preoperative spondylolisthesis was 8.90 mm and was reduced to 6.05 mm postoperatively. Relative spondylolisthesis was 21.63% preoperatively and 13.71% postoperatively. All clinical and radiological improvements were significant (all p < 0.001). No significant difference considering the lordosis values nor spondylolisthesis was found between patients who underwent ALIF surgery without dorsal instrumentation and patients who received additional dorsal instrumentation. Venous laceration was the most frequent complication (10.42%). CONCLUSIONS: With ALIF, good clinical results and safe and effective reduction of spondylolisthesis and restoration of lordosis can be achieved. Additional dorsal instrumentation does not significantly affect postoperative lordosis or spondylolisthesis. Individual vascular anatomy must be reviewed preoperatively before considering ALIF.

Reconstruction of the cranial vault, surgical drainage of brain abscesses, and the treatment of rhinoliquorrhea: the "Luftwaffen Lazarett 6/XVII Bad Ischl," the first neurosurgical department in Austria.

The main purpose of neurosurgery during World War II was the treatment of traumatic brain injury, injuries to the spine, and injuries to peripheral nerves-mostly penetrating injuries caused by bullets or shrapnel. After heavy bombings of Berlin, in 1943 the main neurosurgical hospital was moved to Bad Ischl, a small town in the Austrian countryside. There, Wilhelm Toennis and his successor Dietrich W. Krueger made important observations treating soldiers suffering from traumatic brain injuries. During the war and also in the postwar period, they focused on techniques for the reconstruction of the cranial vault, the treatment of brain abscesses by drainage instead of extirpation, and also the treatment of rhinoliquorrhea due to frontobasal trauma. Their approaches were sometimes contradictory to the standard of care of the times. Nevertheless, many of the principles of the techniques described are still practiced by today's neurosurgeons.

KINFix--A formalin-free non-commercial fixative optimized for histological, immunohistochemical and molecular analyses of neurosurgical tissue specimens.

An optimal fixative should ideally combine the advantages of formalin fixation and freezing, allowing for good preservation of histology and molecular components, easy handling and storage, lack of toxicity, and low costs. Most of these criteria are fulfilled by ethanol-based solutions, and due to our good experience with the commercial RCL2 fixative, reflected by our published single-center trial, we initiated a multicenter ring trial. However, during its course, RCL2 was discontinued on the market. Therefore, we created our own agent, KINFix, composed of the same main constituents as RCL2, and employed it in our laboratory with similar results. Here we present our evaluation of the three fixatives formalin, RCL2, and KINFix from the perspective of histopathology as well as nucleic acid and protein analyses in comparison to fresh frozen tissues together with the multicenter ring trial data for RCL2. We observe that RCL2 and KINFix offer comparable histomorphology and superior template for molecular analyses than formalin. Moreover, KINFix as freely available fixative might overcome some of the difficulties related to the commercial agents. Therefore, we conclude that KINFix might be an attractive complement to formalin in tissue processing and advocate its use in neuropathological practice.

Drug priming enhances radiosensitivity of adamantinomatous craniopharyngioma via downregulation of survivin.

OBJECTIVE In this study, the authors investigated the underlying mechanisms responsible for high tumor recurrence rates of adamantinomatous craniopharyngioma (ACP) after radiotherapy and developed new targeted treatment protocols to minimize recurrence. ACPs are characterized by the activation of the receptor tyrosine kinase epidermal growth factor receptor (EGFR), known to mediate radioresistance in various tumor entities. The impact of tyrosine kinase inhibitors (TKIs) gefitinib or CUDC-101 on radiation-induced cell death and associated regulation of survivin gene expression was evaluated. METHODS The hypothesis that activated EGFR promotes radioresistance in ACP was investigated in vitro using human primary cell cultures of ACP (n = 10). The effects of radiation (12 Gy) and combined radiochemotherapy on radiosensitivity were assessed via cell death analysis using flow cytometry. Changes in target gene expression were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Survivin, identified in qRT-PCR to be involved in radioresistance of ACP, was manipulated by small interfering RNA (siRNA), followed by proliferation and vitality assays to further clarify its role in ACP biology. Immunohistochemically, survivin expression was assessed in patient tumors used for primary cell cultures. RESULTS In primary human ACP cultures, activation of EGFR resulted in significantly reduced cell death levels after radiotherapy. Treatment with TKIs alone and in combination with radiotherapy increased cell death response remarkably, assessed by flow cytometry. CUDC-101 was significantly more effective than gefitinib. The authors identified regulation of survivin expression after therapeutic intervention as the underlying molecular mechanism of radioresistance in ACP. EGFR activation promoting ACP cell survival and proliferation in vitro is consistent with enhanced survivin gene expression shown by qRT-PCR. TKI treatment, as well as the combination with radiotherapy, reduced survivin levels in vitro. Accordingly, ACP showed reduced cell viability and proliferation after survivin downregulation by siRNA. CONCLUSIONS These results indicate an impact of EGFR signaling on radioresistance in ACP. Inhibition of EGFR activity by means of TKI treatment acts as a radiosensitizer on ACP tumor cells, leading to increased cell death. Additionally, the results emphasize the antiapoptotic and pro-proliferative role of survivin in ACP biology and its regulation by EGFR signaling. The suppression of survivin by treatment with TKI and combined radiotherapy represents a new promising treatment strategy that will be further assessed in in vivo models of ACP.

Molecular stratification of medulloblastoma: comparison of histological and genetic methods to detect Wnt activated tumours.

AIMS: Wnt activation in medulloblastomas is associated with good outcome. Upfront testing and risk-adapted stratification of patients will be done in future clinical studies. In a cohort of 186 paediatric medulloblastomas our aim was to identify the optimal methods in standard clinical practice to detect this subgroup. METHODS: Nuclear accumulation of ß-catenin was analysed by immunohistochemistry (IHC). DNA of FFPE tissue was amplified by PCR for single-strand conformation polymorphism analysis and direct sequencing of CTNNB1 exon 3. Copy number of chromosome 6 was analysed by multiplex ligation-dependent probe amplification and molecular inversion profiling. RESULTS: Different automated immunostaining systems showed similar results. Twenty-one of 186 samples had nuclear accumulation in ≥5% of cells, 17 samples showed <5% ß-catenin positive nuclei. None of these 17 cases had CTNNB1 mutations, but 18 of 21 cases with ≥5% accumulation did, identifying these 18 cases as Wnt-subgroup medulloblastomas. Fifteen of 18 mutated cases showed monosomy 6, 3 had balanced chromosome 6. On the contrary, none of the CTNNB1 wild-type tumours had monosomy 6. CONCLUSIONS: Standard neuropathological evaluation of medulloblastoma samples should include IHC of ß-catenin because tumours with high nuclear accumulation of ß-catenin most probably belong to the Wnt subgroup of medulloblastomas. Still, IHC alone may be insufficient to detect all Wnt cases. Similarly, chromosome 6 aberrations were not present in all CTNNB1-mutated cases. Therefore, we conclude that sequencing analysis of CTNNB1 exon 3 in combination with ß-catenin IHC (possibly as pre-screening method) is a feasible and cost-efficient way for the determination of Wnt medulloblastomas.

Medulloblastoma with multi-lineage differentiation including myogenic and melanotic elements: a case report with molecular data.

We present an unusual medulloblastoma in a 3.9-year-old boy who had a 2-week history of nausea and vertigo. MRI revealed a 5×5.5×5 cm sized tumor located in the fourth ventricle and spinal leptomeningeal dissemination. The patient was treated according to the MET-HIT 2000-BIS4 protocol but showed tumor progression after 6 months and died 9 months postoperatively. Histopathologically and immunohistochemically, the tumor showed PNET-like areas with focal anaplasia, admixed rhabdomyoblastic and pigmented elements, cartilage and bone formation, as well as areas with neurocytic and glial differentiation. Neither CTNNB1 mutation nor MYCC/MYCN amplification was detected. The combination of rhabdomyoblastic and melanotic elements in medulloblastoma is exceptionally rare. Although the histopathological features suggested a teratoid tumor, the endodermal cell lineage required for this diagnosis was not present. An atypical teratoid-rhabdoid tumor was ruled out due to the presence of the INI1-protein. Regarding the molecular profile with 1q and 17q chromosomal gains and loss of chromosome 8, this tumor could be compatible with a molecular medulloblastoma Group 3 or 4. Yet, it cannot be definitively ruled out that medulloblastomas with multi-lineage differentiation represent a distinct subgroup of medulloblastoma, and it remains to be clarified whether these tumors are associated with a distinct clinical behavior.

Feasibility, Clinical Potential, and Limitations of Trans-Burr Hole Ultrasound for Postoperative Evaluation of Chronic Subdural Hematoma: A Prospective Pilot Study.

BACKGROUND AND OBJECTIVES: Chronic subdural hematoma (CSDH) is commonly managed through burr hole surgery. Routine follow-up using computed tomography (CT) imaging is frequently used at many institutions, contributing to significant radiation exposure. This study evaluates the feasibility, safety, and reliability of trans-burr hole sonography as an alternative postoperative imaging modality, aiming to reduce radiation exposure by decreasing the frequency of CT scans. METHODS: We conducted a prospective pilot study on 20 patients who underwent burr hole surgery for CSDH. Postoperative imaging included both CT and sonographic examinations through the burr hole. We assessed the ability to measure residual subdural fluid thickness under the burr hole sonographically compared with CT, the occurrence of complications, and the potential factors affecting sonographic image quality. The Pearson correlation coefficient was used to demonstrate relationships between CT and ultrasound and axial and coronal ultrasound. RESULTS: Sonography through the burr hole was feasible in 73.5% of cases, providing measurements of residual fluid that closely paralleled CT findings, with an average discrepancy of 1.2 mm for axial and 1.4 mm for coronal sonographic views. A strong positive correlation was found between axial and coronal ultrasound (r = 0.955), CT and axial ultrasound (r = 0.936), and CT and coronal ultrasound (r = 0.920). The primary obstacle for sonographic imaging was the presence of air within the burr hole or the subdural space, which typically resolved over time after surgery. CONCLUSION: Trans-burr hole sonography emerges as a promising technique for postoperative monitoring of CSDH, with the potential to safely reduce reliance on CT scans and associated radiation exposure in selected patients. Our results support further investigation into the extended use of sonography during the follow-up phase. Prospective multicenter studies are recommended to establish the method's efficacy and to explore strategies for minimizing air presence postsurgery.

Turning the operating room into a mixed-reality environment: a prospective clinical investigation for cerebral aneurysm clipping.

OBJECTIVE: The overall aim of this study was to demonstrate the potential benefit of a novel mixed-reality-head-mounted display (MR-HMD) on the spatial orientation of surgeons. METHODS: In a prospective clinical investigation, the authors applied for the first time a new multicamera navigation technology in an operating room setting that allowed them to directly compare MR-HMD navigation to standard monitor navigation. In the study, which included 14 patients with nonruptured middle cerebral artery aneurysms, the authors investigated how intuitively and effectively surgical instruments could be guided in 5 different visual navigation conditions. RESULTS: The authors demonstrate that multicamera tracking can be reliably integrated in a clinical setting (usability score 1.12 ± 0.31). Moreover, the technology captures large volumes of the operating room, allowing the team to track and integrate different devices and instruments, including MR-HMDs. Directly comparing mixed-reality navigation to standard monitor navigation revealed a significantly improved intuition in mixed reality, leading to navigation times that were twice as fast (2.1×, p ≤ 0.01). Despite the enhanced speed, the same targeting accuracy (approximately 2.5 mm, freehand tool use) in comparison to monitor navigation could be observed. Intraoperative planning strategies with mixed reality clearly outperformed classic preoperative planning: surgeons scored the mixed-reality plan as the best trajectory in 63% of the cases (chance level 33%). CONCLUSIONS: The incorporation of mixed reality in neurosurgical operations marks a significant advancement in the field. The use of mixed reality in brain surgery enhances the spatial awareness of surgeons, enabling more instinctive and precise surgical interventions. This technological integration promises to refine the execution of complex procedures without compromising accuracy.

Which parameters influence cognitive, psychiatric and long-term seizure outcome in mesial temporal lobe epilepsy after selective amygdalohippocampectomy?

BACKGROUND: We aimed to analyze potentially prognostic factors which could have influence on postoperative seizure, neuropsychological and psychiatric outcome in a cohort of patients with mesial temporal lobe epilepsy (MTLE) due to hippocampal sclerosis (HS) after selective amygdalohippocampectomy (SAHE) via transsylvian approach. METHODS: Clinical variables of 171 patients with drug-resistant MTLE with HS (88 females) who underwent SAHE between 1994 and 2019 were evaluated using univariable and multivariable logistic regression models, to investigate which of the explanatory parameters can best predict the outcome. RESULTS: At the last available follow-up visit 12.3 ± 6.3 years after surgery 114 patients (67.9%) were seizure-free. Left hemispheric MTLE was associated with worse postoperative seizure outcome at first year after surgery (OR = 0.54, p = 0.01), female sex-with seizure recurrence at years 2 (OR = 0.52, p = 0.01) and 5 (OR = 0.53, p = 0.025) and higher number of preoperative antiseizure medication trials-with seizure recurrence at year 2 (OR = 0.77, p = 0.0064), whereas patients without history of traumatic brain injury had better postoperative seizure outcome at first year (OR = 2.08, p = 0.0091). All predictors lost their predictive value in long-term course. HS types had no prognostic influence on outcome. Patients operated on right side performed better in verbal memory compared to left (VLMT 1-5 p < 0.001, VLMT 7 p = 0.001). Depression occurred less frequently in seizure-free patients compared to non-seizure-free patients (BDI-II Z = - 2.341, p = 0.019). CONCLUSIONS: SAHE gives an improved chance of achieving good postoperative seizure, psychiatric and neuropsychological outcome in patients with in MTLE due to HS. Predictors of short-term outcome don't predict long-term outcome.

Innervated ectopic salivary gland associated with Rathke's cleft cyst clinically mimicking pituitary adenoma.

Herein, we report an exceptional case of a young female patient with progressive enlargement of a sellar mass, clinically suggestive of pituitary adenoma. Histopathology, however, demonstrated Rathke's cleft cyst associated with salivary gland remnants. In contrast to the majority of prior reports, the ectopic salivary glands were found in close proximity to the anterior pituitary lobe and showed active production of mucous secret, which caused progressive growth and symptoms in this patient. We further demonstrate nerve fibers surrounding the ectopic salivary glands, thereby suggesting parasympathetic innervation as a plausible mechanism triggering seromucous secretion. Neurosurgeons and neuropathologists need to be aware of this rare clinical condition expanding the spectrum of differential diagnoses of sellar masses.

Clinical neuropathology practice guide 3-2013: levels of evidence and clinical utility of prognostic and predictive candidate brain tumor biomarkers.

A large number of potential tissue biomarkers has been proposed for brain tumors. However, hardly any have been adopted for routine clinical use, so far. For most candidate biomarkers substantial controversy exists with regard to their usefulness in clinical practice. The multidisciplinary neurooncology taskforce of the Vienna Comprehensive Cancer Center Central Nervous System Unit (CCC-CNS) addressed this issue and elaborated a four-tiered levels-of-evidence system for assessing analytical performance (reliability of test result) and clinical performance (prognostic or predictive) based on consensually defined criteria. The taskforce also consensually agreed that only biomarker candidates should be considered as ready for clinical use, which meet defined quality standards for both, analytical and clinical performance. Applying this levels-of-evidence system to MGMT, IDH1, 1p19q, Ki67, MYCC, MYCN and ß-catenin, only immunohistochemical IDH1 mutation testing in patients with diffuse gliomas is supported by sufficient evidence in order to be unequivocally qualified for clinical use. For the other candidate biomarkers lack of published evidence of sufficiently high analytical test performance and, in some cases, also of clinical performance limits evidence-based confirmation of their clinical utility. For most of the markers, no common standard of laboratory testing exists. We conclude that, at present, there is a strong need for studies that specifically address the analytical performance of candidate brain tumor biomarkers. In addition, standardization of laboratory testing is needed. We aim to regularly challenge and update the present classification in order to systematically clarify the current translational status of candidate brain tumor biomarkers and to identify specific research needs for accelerating the translational pace.

Tailored Intraoperative MRI Strategies in High-Grade Glioma Surgery: A Machine Learning-Based Radiomics Model Highlights Selective Benefits.

BACKGROUND AND OBJECTIVES: In high-grade glioma (HGG) surgery, intraoperative MRI (iMRI) has traditionally been the gold standard for maximizing tumor resection and improving patient outcomes. However, recent Level 1 evidence juxtaposes the efficacy of iMRI and 5-aminolevulinic acid (5-ALA), questioning the continued justification of iMRI because of its associated costs and extended surgical duration. Nonetheless, drawing from our clinical observations, we postulated that a subset of intricate HGGs may continue to benefit from the adjunctive application of iMRI. METHODS: In a prospective study of 73 patients with HGG, 5-ALA was the primary technique for tumor delineation, complemented by iMRI to detect residual contrast-enhanced regions. Suboptimal 5-ALA efficacy was defined when (1) iMRI detected contrast-enhanced remnants despite 5-ALA's indication of a gross total resection or (2) surgeons observed residual fluorescence, contrary to iMRI findings. Radiomic features from preoperative MRIs were extracted using a U2-Net deep learning algorithm. Binary logistic regression was then used to predict compromised 5-ALA performance. RESULTS: Resections guided solely by 5-ALA achieved an average removal of 93.14% of contrast-enhancing tumors. This efficacy increased to 97% with iMRI integration, albeit not statistically significant. Notably, for tumors with suboptimal 5-ALA performance, iMRI's inclusion significantly improved resection outcomes (P-value: .00013). The developed deep learning-based model accurately pinpointed these scenarios, and when enriched with radiomic parameters, showcased high predictive accuracy, as indicated by a Nagelkerke R2 of 0.565 and a receiver operating characteristic of 0.901. CONCLUSION: Our machine learning-driven radiomics approach predicts scenarios where 5-ALA alone may be suboptimal in HGG surgery compared with its combined use with iMRI. Although 5-ALA typically yields favorable results, our analyses reveal that HGGs characterized by significant volume, complex morphology, and left-sided location compromise the effectiveness of resections relying exclusively on 5-ALA. For these intricate cases, we advocate for the continued relevance of iMRI.

Machine learning based outcome prediction of microsurgically treated unruptured intracranial aneurysms.

Machine learning (ML) has revolutionized data processing in recent years. This study presents the results of the first prediction models based on a long-term monocentric data registry of patients with microsurgically treated unruptured intracranial aneurysms (UIAs) using a temporal train-test split. Temporal train-test splits allow to simulate prospective validation, and therefore provide more accurate estimations of a model's predictive quality when applied to future patients. ML models for the prediction of the Glasgow outcome scale, modified Rankin Scale (mRS), and new transient or permanent neurological deficits (output variables) were created from all UIA patients that underwent microsurgery at the Kepler University Hospital Linz (Austria) between 2002 and 2020 (n = 466), based on 18 patient- and 10 aneurysm-specific preoperative parameters (input variables). Train-test splitting was performed with a temporal split for outcome prediction in microsurgical therapy of UIA. Moreover, an external validation was conducted on an independent external data set (n = 256) of the Department of Neurosurgery, University Medical Centre Hamburg-Eppendorf. In total, 722 aneurysms were included in this study. A postoperative mRS > 2 was best predicted by a quadratic discriminant analysis (QDA) estimator in the internal test set, with an area under the receiver operating characteristic curve (ROC-AUC) of 0.87 ± 0.03 and a sensitivity and specificity of 0.83 ± 0.08 and 0.71 ± 0.07, respectively. A Multilayer Perceptron predicted the post- to preoperative mRS difference > 1 with a ROC-AUC of 0.70 ± 0.02 and a sensitivity and specificity of 0.74 ± 0.07 and 0.50 ± 0.04, respectively. The QDA was the best model for predicting a permanent new neurological deficit with a ROC-AUC of 0.71 ± 0.04 and a sensitivity and specificity of 0.65 ± 0.24 and 0.60 ± 0.12, respectively. Furthermore, these models performed significantly better than the classic logistic regression models (p < 0.0001). The present results showed good performance in predicting functional and clinical outcomes after microsurgical therapy of UIAs in the internal data set, especially for the main outcome parameters, mRS and permanent neurological deficit. The external validation showed poor discrimination with ROC-AUC values of 0.61, 0.53 and 0.58 respectively for predicting a postoperative mRS > 2, a pre- and postoperative difference in mRS > 1 point and a GOS < 5. Therefore, generalizability of the models could not be demonstrated in the external validation. A SHapley Additive exPlanations (SHAP) analysis revealed that this is due to the most important features being distributed quite differently in the internal and external data sets. The implementation of newly available data and the merging of larger databases to form more broad-based predictive models is imperative in the future.

A randomized, single ascending dose safety, tolerability and pharmacokinetics study of NicaPlant® in aneurysmal subarachnoid hemorrhage patients undergoing clipping.

Introduction: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. Post-hemorrhagic vasospasm with neurological deterioration is a major concern in this context. NicaPlant®, a modified release formulation of the calcium channel blocker nicardipine, has shown vasodilator efficacy preclinically and a similar formulation known as NPRI has shown anti-vasospasm activity in aSAH patients under compassionate use. Research question: The study aimed to assess pharmacokinetics and pharmacodynamics of NicaPlant® pellets to prevent vasospasm after clip ligation in aSAH. Material and methods: In this multicenter, controlled, randomized, dose escalation trial we assessed the safety and tolerability of NicaPlant®. aSAH patients treated by clipping were randomized to receive up to 13 NicaPlant® implants, similarly to the dose of NPRIs previous used, or standard of care treatment. Results: Ten patients across four dose groups were treated with NicaPlant® (3-13 implants) while four patients received standard of care. 45 non-serious and 13 serious adverse events were reported, 4 non-serious adverse events and 5 serious adverse events assessed a probable or possible causal relationship to the investigational medical product. Across the NicaPlant® groups there was 1 case of moderate vasospasm, while in the standard of care group there were 2 cases of severe vasospasm. Discussion and conclusion: The placement of NicaPlant® during clip ligation of a ruptured cerebral aneurysm raised no safety concern. The dose of 10 NicaPlant® implants was selected for further clinical studies.

Clinical Neuropathology Practice News 4-2012: levels of evidence for brain tumor biomarkers.

The National Comprehensive Cancer Network (NCCN) recently published a task force report on the evaluation of the clinical utility of tumor biomarkers in oncology. In this report, common terminology and the use of levels of evidence scores to aid the evaluation of biomarker tests in oncology were proposed. Furthermore, the task force applied a level of evidence system to selected biomarkers of several cancer types. According to this system, the highest level of evidence, IA, is granted to a biomarker only if it has been evaluated in at least one adequately powered and specifically designed prospective controlled trial. For gliomas, only 1p/19q testing in oligodendroglial tumors was classified as IA by the NCCN task force. For all of the following biomarkers the present evidence level for clinical utility was regarded as lower than that of 1p/19q status: MGMT gene promoter methylation testing (glioblastoma), IDH mutation testing (diffusely growing gliomas), BRAF fusion testing (pilocytic astrocytoma) and CIMP testing (diffusely growing gliomas). The task force acknowledged that the exact application of levels of evidence needs further refinement. To our mind, the implementation of a brain tumor expert panel seems vital to evaluate the evidence levels of neurooncological biomarkers according to generally accepted criteria on a regular basis. Systematic identification of current research needs and widely accepted up-to-date recommendations for efficient biomarker application in everyday practice could be gained.

Prominent oligodendroglial response in surgical specimens of patients with temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is characterized by distinct neuropathological findings, such as hippocampal sclerosis and reactive astrogliosis. Recently, MRI studies have revealed the presence of white matter pathology in brains of epilepsy patients. The purpose of this study is to evaluate the involvement of oligodendroglia in the epileptogenic process. Using TPPP/p25 as a marker for mature oligodendroglia, we evaluated the hippocampus in 26 surgical specimens from patients with TLE and 9 autopsy controls without neuropathological alterations for changes in oligodendroglial cell densities (mm2) in hippocampal, entorhinal, and temporal white matter, and the amount of perineuronal oligodendrocytes in CA1 subregion. Oligodendrocyte cell densities were significantly elevated in epilepsy patients compared to controls in all four examined white matter subregions. In addition, in the CA1 sector, the percentage of neurons showing more than one perineuronal oligodendrocyte was significantly higher in epilepsy patients. In conclusion, our study expands the glial reactions beyond astrogliosis and shows that prominent oligodendroglial response is a consistent pathological feature characteristic for TLE.

Nonsteroidal anti-inflammatory drugs (NSAID) do not increase blood loss or the incidence of postoperative epidural hematomas when using minimally invasive fusion techniques in the degenerative lumbar spine.

Objective: Nonsteroidal anti-inflammatory drugs (NSAID) are essential in surgeons' armamentarium for pain relief and antiphlogistic effects. However, spine surgeons are concerned about the drugs' impact on coagulation, fearing hemodynamic instability due to blood loss and neurological complications due to postoperative hematoma. Furthermore, there are no clear guidelines for the use of these drugs. Materials and methods: In this retrospective subgroup analysis of a prospective observational study, we investigated 181 patients who underwent minimally invasive spinal fusions in degenerative lumbar spine pathologies. 83 patients were given NSAID perioperatively, 54 of which were female and 29 male. Of these patients who took NSAID, 39 were on NSAID until at least one day before surgery or perioperatively, whilst the others discontinued their NSAID medication at least three days before surgery. Differences in perioperative blood loss, as well as complication rates between patients with and without NSAID treatment, were investigated. Results: A significantly higher amount of blood loss during surgery and the monitoring period was encountered in patients whose spine was fused in more than one level, regardless of whether NSAID medication was taken or not and up until what point. Furthermore, it was found that taking NSAID medication had no effect on the incidence of postoperative epidural hematomas. Conclusion: Perioperatively taking NSAID medication does not increase blood loss or the incidence of postoperative hematoma in patients undergoing minimally invasive lumbar spinal fusion surgery.

Current trends and outcomes of non-elective neurosurgical care in Central Europe during the second year of the COVID-19 pandemic.

Reflecting the first wave COVID-19 pandemic in Central Europe (i.e. March 16th-April 15th, 2020) the neurosurgical community witnessed a general diminution in the incidence of emergency neurosurgical cases, which was impelled by a reduced number of traumatic brain injuries (TBI), spine conditions, and chronic subdural hematomas (CSDH). This appeared to be associated with restrictions imposed on mobility within countries but also to possible delayed patient introduction and interdisciplinary medical counseling. In response to one year of COVID-19 experience, also mapping the third wave of COVID-19 in 2021 (i.e. March 16 to April 15, 2021), we aimed to reevaluate the current prevalence and outcomes for emergency non-elective neurosurgical cases in COVID-19-negative patients across Austria and the Czech Republic. The primary analysis was focused on incidence and 30-day mortality in emergency neurosurgical cases compared to four preceding years (2017-2020). A total of 5077 neurosurgical emergency cases were reviewed. The year 2021 compared to the years 2017-2019 was not significantly related to any increased odds of 30 day mortality in Austria or in the Czech Republic. Recently, there was a significant propensity toward increased incidence rates of emergency non-elective neurosurgical cases during the third COVID-19 pandemic wave in Austria, driven by their lower incidence during the first COVID-19 wave in 2020. Selected neurosurgical conditions commonly associated with traumatic etiologies including TBI, and CSDH roughly reverted to similar incidence rates from the previous non-COVID-19 years. Further resisting the major deleterious effects of the continuing COVID-19 pandemic, it is edifying to notice that the neurosurgical community´s demeanor to the recent third pandemic culmination keeps the very high standards of non-elective neurosurgical care alongside with low periprocedural morbidity. This also reflects the current state of health care quality in the Czech Republic and Austria.