Surgical Treatment of Calcified Thoracic Herniated Disc Disease via the Transthoracic Approach with the Use of Intraoperative Computed Tomography (iCT) and Microscope-Based Augmented Reality (AR).

Background and Objectives: The aim of this study is to present our experience in the surgical treatment of calcified thoracic herniated disc disease via a transthoracic approach in the lateral position with the use of intraoperative computed tomography (iCT) and augmented reality (AR). Materials and Methods: All patients who underwent surgery for calcified thoracic herniated disc via a transthoracic transpleural approach at our Department using iCT and microscope-based AR were included in the study. Results: Six consecutive patients (five female, median age 53.2 ± 6.4 years) with calcified herniated thoracic discs (two patients Th 10-11 level, two patients Th 7-8, one patient Th 9-10, one patient Th 11-12) were included in this case series. Indication for surgery included evidence of a calcified thoracic disc on magnet resonance imaging (MRI) and CT with spinal canal stenosis of >50% of diameter, intractable pain, and neurological deficits, as well as MRI-signs of myelopathy. Five patients had paraparesis and ataxia, and one patient had no deficit. All surgeries were performed in the lateral position via a transthoracic transpleural approach (Five from left side). CT for automatic registration was performed following the placement of the reference array, with a high registration accuracy. Microscope-based AR was used, with segmented structures of interest such as vertebral bodies, disc space, herniated disc, and dural sac. Mean operative time was 277.5 ± 156 min. The use of AR improved orientation in the operative field for identification, and tailored the resection of the herniated disc and the identification of the course of dural sac. A control-iCT scan confirmed the complete resection in five patients and incomplete resection of the herniated disc in one patient. In one patient, complications occurred, such as postoperative hematoma, and wound healing deficit occurred. Mean follow-up was 22.9 ± 16.5 months. Five patients improved following surgery, and one patient who had no deficits remained unchanged. Conclusions: Optimal surgical therapy in patients with calcified thoracic disc disease with compression of dural sac and myelopathy was resectioned via a transthoracic transpleural approach. The use of iCT-based registration and microscope-based AR significantly improved orientation in the operative field and facilitated safe resection of these lesions.

Enabling Navigation and Augmented Reality in the Sitting Position in Posterior Fossa Surgery Using Intraoperative Ultrasound.

Despite its broad use in cranial and spinal surgery, navigation support and microscope-based augmented reality (AR) have not yet found their way into posterior fossa surgery in the sitting position. While this position offers surgical benefits, navigation accuracy and thereof the use of navigation itself seems limited. Intraoperative ultrasound (iUS) can be applied at any time during surgery, delivering real-time images that can be used for accuracy verification and navigation updates. Within this study, its applicability in the sitting position was assessed. Data from 15 patients with lesions within the posterior fossa who underwent magnetic resonance imaging (MRI)-based navigation-supported surgery in the sitting position were retrospectively analyzed using the standard reference array and new rigid image-based MRI-iUS co-registration. The navigation accuracy was evaluated based on the spatial overlap of the outlined lesions and the distance between the corresponding landmarks in both data sets, respectively. Image-based co-registration significantly improved (p < 0.001) the spatial overlap of the outlined lesion (0.42 ± 0.30 vs. 0.65 ± 0.23) and significantly reduced (p < 0.001) the distance between the corresponding landmarks (8.69 ± 6.23 mm vs. 3.19 ± 2.73 mm), allowing for the sufficient use of navigation and AR support. Navigated iUS can therefore serve as an easy-to-use tool to enable navigation support for posterior fossa surgery in the sitting position.

Single-Center Experience in Microsurgical Resection of Acoustic Neurinomas and the Benefit of Microscope-Based Augmented Reality.

Background and Objectives: Microsurgical resection with intraoperative neuromonitoring is the gold standard for acoustic neurinomas (ANs) which are classified as T3 or T4 tumors according to the Hannover Classification. Microscope-based augmented reality (AR) can be beneficial in cerebellopontine angle and lateral skull base surgery, since these are small areas packed with anatomical structures and the use of this technology enables automatic 3D building of a model without the need for a surgeon to mentally perform this task of transferring 2D images seen on the microscope into imaginary 3D images, which then reduces the possibility of error and provides better orientation in the operative field. Materials and Methods: All patients who underwent surgery for resection of ANs in our department were included in this study. Clinical outcomes in terms of postoperative neurological deficits and complications were evaluated, as well as neuroradiological outcomes for tumor remnants and recurrence. Results: A total of 43 consecutive patients (25 female, median age 60.5 ± 16 years) who underwent resection of ANs via retrosigmoid osteoclastic craniotomy with the use of intraoperative neuromonitoring (22 right-sided, 14 giant tumors, 10 cystic, 7 with hydrocephalus) by a single surgeon were included in this study, with a median follow up of 41.2 ± 32.2 months. A total of 18 patients underwent subtotal resection, 1 patient partial resection and 24 patients gross total resection. A total of 27 patients underwent resection in sitting position and the rest in semi-sitting position. Out of 37 patients who had no facial nerve deficit prior to surgery, 19 patients were intact following surgery, 7 patients had House Brackmann (HB) Grade II paresis, 3 patients HB III, 7 patients HB IV and 1 patient HB V. Wound healing deficit with cerebrospinal fluid (CSF) leak occurred in 8 patients (18.6%). Operative time was 317.3 ± 99 min. One patient which had recurrence and one further patient with partial resection underwent radiotherapy following surgery. A total of 16 patients (37.2%) underwent resection using fiducial-based navigation and microscope-based AR, all in sitting position. Segmented objects of interest in AR were the sigmoid and transverse sinus, tumor outline, cranial nerves (CN) VII, VIII and V, petrous vein, cochlea and semicircular canals and brain stem. Operative time and clinical outcome did not differ between the AR and the non-AR group. However, use of AR improved orientation in the operative field for craniotomy planning and microsurgical resection by identification of important neurovascular structures. Conclusions: The single-center experience of resection of ANs showed a high rate of gross total (GTR) and subtotal resection (STR) with low recurrence. Use of AR improves intraoperative orientation and facilitates craniotomy planning and AN resection through early improved identification of important anatomical relations to structures of the inner auditory canal, venous sinuses, petrous vein, brain stem and the course of cranial nerves.

Predictors of short-term anxiety outcome in subthalamic stimulation for Parkinson's disease.

The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on anxiety in Parkinson's disease (PD) are understudied. We identified clinical predictors of STN-DBS effects on anxiety in this study. In this prospective, open-label, multicentre study, we assessed patients with anxiety undergoing STN-DBS for PD preoperatively and at 6-month follow-up postoperatively. We assessed the Hospital Anxiety and Depression Scale (HADS-anxiety and depression subscales), Unified PD Rating Scale-motor examination, Scales for Outcomes in PD-motor (SCOPA-M)-activities of daily living (ADL) and -motor complications, Non-Motor Symptom Scale (NMSS), PDQuestionnaire-8 (PDQ-8), and levodopa-equivalent daily dose. We tested changes at follow-up with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We identified patients with a clinically relevant anxiety improvement of anxiety based on a designated threshold of ½ standard deviation of baseline HADS-anxiety. Moreover, we investigated predictors of HADS-anxiety changes with correlations and linear regressions. We included 50 patients with clinically relevant baseline anxiety (i.e., HADS-anxiety ≥ 8) aged 63.1 years ± 8.3 with 10.4 years ± 4.5 PD duration. HADS-anxiety improved significantly at 6-month follow-up as 80% of our cohort experienced clinically relevant anxiety improvement. In predictor analyses, worse baseline SCOPA-ADL and NMSS-urinary domain were associated with greater HADS-anxiety improvements. HADS-anxiety and PDQ-8 changes correlated moderately. Worse preoperative ADL and urinary symptoms predicted favourable postoperative anxiety outcome, which in turn was directly proportionate to greater QoL improvement. This study highlights the importance of detailed anxiety assessments alongside other non-motor and motor symptoms when advising and monitoring patients undergoing STN-DBS for PD.

Microstructure predicts non-motor outcomes following deep brain stimulation in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) effectively treats motor and non-motor symptoms in advanced Parkinson's disease (PD). As considerable interindividual variability of outcomes exists, neuroimaging-based biomarkers, including microstructural metrics, have been proposed to anticipate treatment response. In this prospective open-label study, we sought to detect microstructural properties of brain areas associated with short-term non-motor outcomes following STN-DBS. Thirty-seven PD patients underwent diffusion MRI and clinical assessments at preoperative baseline and 6-month follow-up. Whole brain voxel-wise analysis assessed associations between microstructural metrics and non-motor outcomes. Intact microstructure within specific areas, including the right insular cortex, right putamen, right cingulum, and bilateral corticospinal tract were associated with greater postoperative improvement of non-motor symptom burden. Furthermore, microstructural properties of distinct brain regions were associated with postoperative changes in sleep, attention/memory, urinary symptoms, and apathy. In conclusion, diffusion MRI could support preoperative patient counselling by identifying patients with above- or below-average non-motor responses.

Head model dataset for mixed reality navigation in neurosurgical interventions for intracranial lesions.

Mixed reality navigation (MRN) technology is emerging as an increasingly significant and interesting topic in neurosurgery. MRN enables neurosurgeons to "see through" the head with an interactive, hybrid visualization environment that merges virtual- and physical-world elements. Offering immersive, intuitive, and reliable guidance for preoperative and intraoperative intervention of intracranial lesions, MRN showcases its potential as an economically efficient and user-friendly alternative to standard neuronavigation systems. However, the clinical research and development of MRN systems present challenges: recruiting a sufficient number of patients within a limited timeframe is difficult, and acquiring low-cost, commercially available, medically significant head phantoms is equally challenging. To accelerate the development of novel MRN systems and surmount these obstacles, the study presents a dataset designed for MRN system development and testing in neurosurgery. It includes CT and MRI data from 19 patients with intracranial lesions and derived 3D models of anatomical structures and validation references. The models are available in Wavefront object (OBJ) and Stereolithography (STL) formats, supporting the creation and assessment of neurosurgical MRN applications.

A Novel Approach for Glioblastoma Treatment by Combining Apoptosis Inducers (TMZ, MTX, and Cytarabine) with E.V.A. (Eltanexor, Venetoclax, and A1210477) Inhibiting XPO1, Bcl-2, and Mcl-1.

Adjuvant treatment for Glioblastoma Grade 4 with Temozolomide (TMZ) inevitably fails due to therapeutic resistance, necessitating new approaches. Apoptosis induction in GB cells is inefficient, due to an excess of anti-apoptotic XPO1/Bcl-2-family proteins. We assessed TMZ, Methotrexate (MTX), and Cytarabine (Ara-C) (apoptosis inducers) combined with XPO1/Bcl-2/Mcl-1-inhibitors (apoptosis rescue) in GB cell lines and primary GB stem-like cells (GSCs). Using CellTiter-Glo® and Caspase-3 activity assays, we generated dose-response curves and analyzed the gene and protein regulation of anti-apoptotic proteins via PCR and Western blots. Optimal drug combinations were examined for their impact on the cell cycle and apoptosis induction via FACS analysis, paralleled by the assessment of potential toxicity in healthy mouse brain slices. Ara-C and MTX proved to be 150- to 10,000-fold more potent in inducing apoptosis than TMZ. In response to inhibitors Eltanexor (XPO1; E), Venetoclax (Bcl-2; V), and A1210477 (Mcl-1; A), genes encoding for the corresponding proteins were upregulated in a compensatory manner. TMZ, MTX, and Ara-C combined with E, V, and A evidenced highly lethal effects when combined. As no significant cell death induction in mouse brain slices was observed, we conclude that this drug combination is effective in vitro and expected to have low side effects in vivo.

Single-Center Experience of Resection of 120 Cases of Intradural Spinal Tumors.

BACKGROUND: Our study presents a single-center experience of resection of intradural spinal tumors either with or without using intraoperative computed tomography-based registration and microscope-based augmented reality (AR). Microscope-based AR was recently described for improved orientation in the operative field in spine surgery, using superimposed images of segmented structures of interest in a two-dimensional or three-dimensional mode. METHODS: All patients who underwent surgery for resection of intradural spinal tumors at our department were retrospectively included in the study. Clinical outcomes in terms of postoperative neurologic deficits and complications were evaluated, as well as neuroradiologic outcomes for tumor remnants and recurrence. RESULTS: 112 patients (57 female, 55 male; median age 55.8 ± 17.8 years) who underwent 120 surgeries for resection of intradural spinal tumors with the use of intraoperative neuromonitoring were included in the study, with a median follow-up of 39 ± 34.4 months. Nine patients died during the follow-up for reasons unrelated to surgery. The most common tumors were meningioma (n = 41), schwannoma (n = 37), myopapillary ependymomas (n = 12), ependymomas (n = 10), and others (20). Tumors were in the thoracic spine (n = 46), lumbar spine (n = 39), cervical spine (n = 32), lumbosacral spine (n = 1), thoracic and lumbar spine (n = 1), and 1 tumor in the cervical, thoracic, and lumbar spine. Four biopsies were performed, 10 partial resections, 13 subtotal resections, and 93 gross total resections. Laminectomy was the common approach. In 79 cases, patients experienced neurologic deficits before surgery, with ataxia and paraparesis as the most common ones. After surgery, 67 patients were unchanged, 49 improved and 4 worsened. Operative time, extent of resection, clinical outcome, and complication rate did not differ between the AR and non-AR groups. However, the use of AR improved orientation in the operative field by identification of important neurovascular structures. CONCLUSIONS: High rates of gross total resection with favorable neurologic outcomes in most patients as well as low recurrence rates with comparable complication rates were noted in our single-center experience. AR improved intraoperative orientation and increased surgeons' comfort by enabling early identification of important anatomic structures; however, clinical and radiologic outcomes did not differ, when AR was not used.

Status epilepticus in patients with brain tumors and metastases: A multicenter cohort study of 208 patients and literature review.

OBJECTIVE: Brain tumors and metastases account for approximately 10% of all status epilepticus (SE) cases. This study described the clinical characteristics, treatment, and short- and long-term outcomes of this population. METHODS: This retrospective, multi-center cohort study analyzed all brain tumor patients treated for SE at the university hospitals of Frankfurt and Marburg between 2011 and 2017. RESULTS: The 208 patients (mean 61.5 ± 14.7 years of age; 51% male) presented with adult-type diffuse gliomas (55.8%), metastatic entities (25.5%), intracranial extradural tumors (14.4%), or other tumors (4.3%). The radiological criteria for tumor progression were evidenced in 128 (61.5%) patients, while 57 (27.4%) were newly diagnosed with tumor at admission and 113 (54.3%) had refractory SE. The mean hospital length of stay (LOS) was 14.8 days (median 12.0, range 1-57), 171 (82.2%) patients required intensive care (mean LOS 8.9 days, median 5, range 1-46), and 44 (21.2%) were administered mechanical ventilation. All patients exhibited significant functional status decline (modified Rankin Scale) post-SE at discharge (p < 0.001). Mortality at discharge was 17.3% (n = 36), with the greatest occurring in patients with metastatic disease (26.4%, p = 0.031) and those that met the radiological criteria for tumor progression (25%, p < 0.001). Long-term mortality at one year (65.9%) was highest in those diagnosed with adult-type diffuse gliomas (68.1%) and metastatic disease (79.2%). Refractory status epilepticus cases showed lower survival rates than non-refractory SE patients (log-rank p = 0.02) and those with signs of tumor progression (log-rank p = 0.001). CONCLUSIONS: SE occurrence contributed to a decline in functional status in all cases, regardless of tumor type, tumor progression status, and SE refractoriness, while long-term mortality was increased in those with malignant tumor entities, tumor progressions, and refractory SE. SE prevention may preserve functional status and improve survival in individuals with brain tumors.

Structural connectivity of low-frequency subthalamic stimulation for improving stride length in Parkinson's disease.

BACKGROUND: A reduction in stride length is considered a key characteristic of gait kinematics in Parkinson's disease (PD) and has been identified as a predictor of falls. Although low-frequency stimulation (LFS) has been suggested as a method to improve gait characteristics, the underlying structural network is not well understood. OBJECTIVE: This study aims to investigate the structural correlates of changes in stride length during LFS (85 Hz). METHODS: Objective gait performance was retrospectively evaluated in 19 PD patients who underwent deep brain stimulation (DBS) at 85 Hz and 130 Hz. Individual DBS contacts and volumes of activated tissue (VAT) were computed using preoperative magnetic resonance imaging (MRI) and postoperative computed tomography (CT) scans. Structural connectivity profiles to predetermined cortical and mesencephalic areas were estimated using a normative connectome. RESULTS: LFS led to a significant improvement in stride length compared to 130 Hz stimulation. The intersection between VAT and the associative subregion of the subthalamic nucleus (STN) was associated with an improvement in stride length and had structural connections to the supplementary motor area, prefrontal cortex, and pedunculopontine nucleus. Conversely, we found that a lack of improvement was linked to stimulation volumes connected to cortico-diencephalic fibers bypassing the STN dorsolaterally. The robustness of the connectivity model was verified through leave-one-patient-out, 5-, and 10-fold cross cross-validation paradigms. CONCLUSION: These findings offer new insights into the structural connectivity that underlies gait changes following LFS. Targeting the non-motor subregion of the STN with LFS on an individual level may present a potential therapeutic approach for PD patients with gait disorders.

The Feasibility and Accuracy of Holographic Navigation with Laser Crosshair Simulator Registration on a Mixed-Reality Display.

Addressing conventional neurosurgical navigation systems' high costs and complexity, this study explores the feasibility and accuracy of a simplified, cost-effective mixed reality navigation (MRN) system based on a laser crosshair simulator (LCS). A new automatic registration method was developed, featuring coplanar laser emitters and a recognizable target pattern. The workflow was integrated into Microsoft's HoloLens-2 for practical application. The study assessed the system's precision by utilizing life-sized 3D-printed head phantoms based on computed tomography (CT) or magnetic resonance imaging (MRI) data from 19 patients (female/male: 7/12, average age: 54.4 ± 18.5 years) with intracranial lesions. Six to seven CT/MRI-visible scalp markers were used as reference points per case. The LCS-MRN's accuracy was evaluated through landmark-based and lesion-based analyses, using metrics such as target registration error (TRE) and Dice similarity coefficient (DSC). The system demonstrated immersive capabilities for observing intracranial structures across all cases. Analysis of 124 landmarks showed a TRE of 3.0 ± 0.5 mm, consistent across various surgical positions. The DSC of 0.83 ± 0.12 correlated significantly with lesion volume (Spearman rho = 0.813, p < 0.001). Therefore, the LCS-MRN system is a viable tool for neurosurgical planning, highlighting its low user dependency, cost-efficiency, and accuracy, with prospects for future clinical application enhancements.

A disintegrin and metalloproteinase 22 activates integrin ß1 through its disintegrin domain to promote the progression of pituitary adenoma.

BACKGROUND: Approximately 35% of pituitary adenoma (PA) display an aggressive profile, resulting in low surgical total resection rates, high recurrence rates, and worse prognosis. However, the molecular mechanism of PA invasion remains poorly understood. Although "a disintegrin and metalloproteinases" (ADAMs) are associated with the progression of many tumors, there are no reports on ADAM22 in PA. METHODS: PA transcriptomics databases and clinical specimens were used to analyze the expression of ADAM22. PA cell lines overexpressing wild-type ADAM22, the point mutation ADAM22, the mutated ADAM22 without disintegrin domain, and knocking down ADAM22 were generated. Cell proliferation/invasion assays, flow cytometry, immunohistochemistry, immunofluorescence, co-immunoprecipitation, mass spectrometry, Reverse transcription-quantitative real-time PCR, phos-tag SDS-PAGE, and Western blot were performed for function and mechanism research. Nude mice xenograft models and rat prolactinoma orthotopic models were used to validate in vitro findings. RESULTS: ADAM22 was significantly overexpressed in PA and could promote the proliferation, migration, and invasion of PA cells. ADAM22 interacted with integrin ß1 (ITGB1) and activated FAK/PI3K and FAK/ERK signaling pathways through its disintegrin domain to promote PA progression. ADAM22 was phosphorylated by PKA and recruited 14-3-3, thereby delaying its degradation. ITGB1-targeted inhibitor (anti-itgb1) exerted antitumor effects and synergistic effects in combination with somatostatin analogs or dopamine agonists in treating PA. CONCLUSIONS: ADAM22 was upregulated in PA and was able to promote PA proliferation, migration, and invasion by activating ITGB1 signaling. PKA may regulate the degradation of ADAM22 through post-transcriptional modification levels. ITGB1 may be a potential therapeutic target for PA.

Proteometabolomics of initial and recurrent glioblastoma highlights an increased immune cell signature with altered lipid metabolism.

BACKGROUND: There is an urgent need to better understand the mechanisms associated with the development, progression, and onset of recurrence after initial surgery in glioblastoma (GBM). The use of integrative phenotype-focused -omics technologies such as proteomics and lipidomics provides an unbiased approach to explore the molecular evolution of the tumor and its associated environment. METHODS: We assembled a cohort of patient-matched initial (iGBM) and recurrent (rGBM) specimens of resected GBM. Proteome and metabolome composition were determined by mass spectrometry-based techniques. We performed neutrophil-GBM cell coculture experiments to evaluate the behavior of rGBM-enriched proteins in the tumor microenvironment. ELISA-based quantitation of candidate proteins was performed to test the association of their plasma concentrations in iGBM with the onset of recurrence. RESULTS: Proteomic profiles reflect increased immune cell infiltration and extracellular matrix reorganization in rGBM. ASAH1, SYMN, and GPNMB were highly enriched proteins in rGBM. Lipidomics indicates the downregulation of ceramides in rGBM. Cell analyses suggest a role for ASAH1 in neutrophils and its localization in extracellular traps. Plasma concentrations of ASAH1 and SYNM show an association with time to recurrence. CONCLUSIONS: We describe the potential importance of ASAH1 in tumor progression and development of rGBM via metabolic rearrangement and showcase the feedback from the tumor microenvironment to plasma proteome profiles. We report the potential of ASAH1 and SYNM as plasma markers of rGBM progression. The published datasets can be considered as a resource for further functional and biomarker studies involving additional -omics technologies.

Stratifying quality of life outcome in subthalamic stimulation for Parkinson's disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) for Parkinson's disease (PD) improves quality of life (QoL), motor and non-motor symptoms (NMS). However, in previous studies, 43%-49% of patients did not experience clinically relevant postoperative QoL improvement. To inform individualised prediction of postoperative QoL improvement, we developed a stratification analysis of QoL outcomes based on preoperative non-motor total burden, severity of motor progression and motor response in levodopa challenge tests. METHODS: This was a prospective, open-label, multicentre, international study with a 6-month follow-up. A distribution-based threshold identified 'QoL responders' in the PDQuestionnaire-8 Summary Index (PDQ-8 SI). After baseline stratification based on the NMS Scale, Hoehn and Yahr Scale and levodopa response assessed with the Unified PD Rating Scale-III, we compared postoperative QoL response between these strata. To assess the clinical usefulness and statistical feasibility of stratifications, we compared cumulative distribution function curves, respectively PDQ-8 within-stratum variation. RESULTS: All main outcomes improved postoperatively. Based on the 8.1 points threshold for clinically meaningful PDQ-8 SI improvement, only 80/161 patients were classified as 'QoL responders'. The absolute risk reductions for QoL non-response among respective non-motor, motor progression and levodopa response strata were 23%, 8% and 3%, respectively. Only non-motor stratification reduced PDQ-8 within-stratum variation compared with the overall cohort. CONCLUSIONS: Non-motor stratification, but not motor progression or levodopa response stratification, is clinically useful and statistically feasible for personalised preoperative prediction of postoperative QoL outcome of STN-DBS for PD. Our findings highlight that non-motor assessments are necessary components of a case-based, holistic approach of DBS indication evaluations geared towards optimising postoperative QoL outcomes. TRIAL REGISTRATION NUMBER: GermanClinicalTrialsRegister: #6735.

Correlation of MR-Based Metabolomics and Molecular Profiling in the Tumor Microenvironment of Temozolomide-Treated Orthotopic GL261 Glioblastoma in Mice.

The tumor microenvironment in glioblastoma (GB) is considered to be "cold", i.e., the fraction of cytotoxic T cells, for instance, is low. Instead, macrophages are the major immune cell population in GB, which stem either from tissue response (resident microglia) or recruitment of macrophages from the periphery, thereby undergoing tumor-dependent "imprinting" mechanisms by which macrophages can adapt a tumor-supportive phenotype. In this regard, it is important to describe the nature of macrophages associated with GB, in particular under therapy conditions using the gold standard chemotherapy drug temozolomide (TMZ). Here, we explored the suitability of combining information from in vivo magnetic resonance spectroscopic (MRS) approaches (metabolomics) with in vitro molecular analyses to assess therapy response and characterize macrophage populations in mouse GB using an isogenic GL261 model. For macrophage profiling, expression levels of matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs) were determined, since their gene products affect macrophage-tumor cell communication by extensive cleavage of immunomodulatory membrane proteins, such as PD-L1. In tumor mice with an overall therapy response, expression of genes encoding the proteases ADAM8, ADAM10, and ADAM17 was increased and might contribute to the immunosuppressive phenotype of GB and immune cells. In tumors responding to therapy, expression levels of ADAM8 were upregulated by TMZ, and higher levels of PD-L1 were correlated significantly. Using a CRISPR/Cas9 knockout of ADAM8 in GL261 cells, we demonstrated that soluble PD-L1 (sPD-L1) is only generated in the presence of ADAM8. Moreover, primary macrophages from WT and ADAM8-deficient mice showed ADAM8-dependent release of sPD-L1, independent of the macrophage polarization state. Since ADAM8 expression is induced in responding tumors and PD-L1 shedding is likely to decrease the anti-tumor activities of T-cells, we conclude that immunotherapy resistance is caused, at least in part, by the increased presence of proteases, such as ADAM8.

A Novel Registration Method for a Mixed Reality Navigation System Based on a Laser Crosshair Simulator: A Technical Note.

Mixed Reality Navigation (MRN) is pivotal in augmented reality-assisted intelligent neurosurgical interventions. However, existing MRN registration methods face challenges in concurrently achieving low user dependency, high accuracy, and clinical applicability. This study proposes and evaluates a novel registration method based on a laser crosshair simulator, evaluating its feasibility and accuracy. A novel registration method employing a laser crosshair simulator was introduced, designed to replicate the scanner frame's position on the patient. The system autonomously calculates the transformation, mapping coordinates from the tracking space to the reference image space. A mathematical model and workflow for registration were designed, and a Universal Windows Platform (UWP) application was developed on HoloLens-2. Finally, a head phantom was used to measure the system's target registration error (TRE). The proposed method was successfully implemented, obviating the need for user interactions with virtual objects during the registration process. Regarding accuracy, the average deviation was 3.7 ± 1.7 mm. This method shows encouraging results in efficiency and intuitiveness and marks a valuable advancement in low-cost, easy-to-use MRN systems. The potential for enhancing accuracy and adaptability in intervention procedures positions this approach as promising for improving surgical outcomes.

Case report: Unilateral GPi DBS in secondary myoclonus-dystonia syndrome after acute disseminated encephalomyelitis.

Introduction: Deep brain stimulation (DBS) is an established and effective therapy for movement disorders. Here, we present a case of secondary myoclonus-dystonia syndrome following acute disseminated encephalomyelitis (ADEM) in childhood, which was alleviated by DBS. Using a patient-specific connectome analysis, we sought to characterise the fibres and circuits affected by stimulation. Case report: We report a case of a 20-year-old man with progressive dystonia, myoclonic jerks, and impaired concentration following childhood ADEM. Motor assessments utilising the Unified Myoclonus Rating Scale (UMRS) and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) revealed a greater improvement in dystonia compared to myoclonus following adjustments of DBS parameters. These adjustments were based on visualisation of electrode position and volume of tissue activated (VTA) 3 years after surgery. A patient-specific connectome analysis using the VTA as a region of interest revealed fibre tracts connecting to the cerebello-thalamo-cortical network and the superior frontal gyrus in addition to basal ganglia circuits as particularly effective. Conclusion: Globus pallidus internus (GPi) DBS shows promise as a treatment for secondary myoclonus-dystonia syndromes. Personalised structural considerations, tailored to individual symptoms and clinical characteristics, can provide significant benefits. Patient-specific connectome analysis, specifically, offers insights into the structures involved and may enable a favourable treatment response.

Implementation and Assessment of a Laparotomy-Assisted Three-Port Fetoscopic Spina Bifida Repair Program.

Open spina bifida (OSB) is a congenital, non-lethal malformation with multifactorial etiology. Fetal therapy can be offered under certain conditions to parents after accurate prenatal diagnostic and interdisciplinary counseling. Since the advent of prenatal OSB surgery, various modifications of the original surgical techniques have evolved, including laparotomy-assisted fetoscopic repair. After a two-year preparation time, the team at the University of Giessen and Marburg (UKGM) became the first center to provide a three-port, three-layer fetoscopic repair of OSB via a laparotomy-assisted approach in the German-speaking area. We point out that under the guidance of experienced centers and by intensive multidisciplinary preparation and training, a previously described and applied technique could be transferred to a different setting.

Changes in calpain-2 expression during glioblastoma progression predisposes tumor cells to temozolomide resistance by minimizing DNA damage and p53-dependent apoptosis.

BACKGROUND: Glioblastoma multiforme (GBM) is characterized by an unfavorable prognosis for patients affected. During standard-of-care chemotherapy using temozolomide (TMZ), tumors acquire resistance thereby causing tumor recurrence. Thus, deciphering essential molecular pathways causing TMZ resistance are of high therapeutic relevance. METHODS: Mass spectrometry based proteomics were used to study the GBM proteome. Immunohistochemistry staining of human GBM tissue for either calpain-1 or -2 was performed to locate expression of proteases. In vitro cell based assays were used to measure cell viability and survival of primary patient-derived GBM cells and established GBM cell lines after TMZ ± calpain inhibitor administration. shRNA expression knockdowns of either calpain-1 or calpain-2 were generated to study TMZ sensitivity of the specific subunits. The Comet assay and É£H2AX signal measurements were performed in order to assess the DNA damage amount and recognition. Finally, quantitative real-time PCR of target proteins was applied to differentiate between transcriptional and post-translational regulation. RESULTS: Calcium-dependent calpain proteases, in particular calpain-2, are more abundant in glioblastoma compared to normal brain and increased in patient-matched initial and recurrent glioblastomas. On the cellular level, pharmacological calpain inhibition increased the sensitivities of primary glioblastoma cells towards TMZ. A genetic knockdown of calpain-2 in U251 cells led to increased caspase-3 cleavage and sensitivity to neocarzinostatin, which rapidly induces DNA strand breakage. We hypothesize that calpain-2 causes desensitization of tumor cells against TMZ by preventing strong DNA damage and subsequent apoptosis via post-translational TP53 inhibition. Indeed, proteomic comparison of U251 control vs. U251 calpain-2 knockdown cells highlights perturbed levels of numerous proteins involved in DNA damage response and downstream pathways affecting TP53 and NF-κB signaling. TP53 showed increased protein abundance, but no transcriptional regulation. CONCLUSION: TMZ-induced cell death in the presence of calpain-2 expression appears to favor DNA repair and promote cell survival. We conclude from our experiments that calpain-2 expression represents a proteomic mode that is associated with higher resistance via "priming" GBM cells to TMZ chemotherapy. Thus, calpain-2 could serve as a prognostic factor for GBM outcome.

Identification of Dysregulated microRNAs in Glioblastoma Stem-like Cells.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Despite multimodal therapy, median survival is poor at 12-15 months. At the molecular level, radio-/chemoresistance and resulting tumor progression are attributed to a small fraction of tumor cells, termed glioblastoma stem-like cells (GSCs). These CD133-expressing, self-renewing cells display the properties of multi-lineage differentiation, resulting in the heterogenous composition of GBM. MicroRNAs (miRNAs) as regulators of gene expression at the post-transcriptional level can alter many pathways pivotal to cancer stem cell fate. This study explored changes in the miRNA expression profiles in patient-derived GSCs altered on differentiation into glial fiber acid protein (GFAP)-expressing, astrocytic tumor cells using a polymerase chain reaction (PCR) array. Initially, 22 miRNAs showed higher expression in GSCs and 9 miRNAs in differentiated cells. The two most downregulated miRNAs in differentiated GSCs were miR-17-5p and miR-425-5p, whilst the most upregulated miRNAs were miR-223-3p and let-7-5p. Among those, miR-425-5p showed the highest consistency in an upregulation in all three GSCs. By transfection of a 425-5p miRNA mimic, we demonstrated downregulation of the GFAP protein in differentiated patient-derived GBM cells, providing potential evidence for direct regulation of miRNAs in the GSC/GBM cell transition.