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BackgroundGlioblastoma (GBM) evades the immune system by creating an immune-suppressive tumor microenvironment (TME), where GBM-associated myeloid cells are geared towards tumor-supportive roles. However, it is unclear whether recruited myeloid cells are phenotypically and functionally identical. Here, we aim to understand the TME heterogeneity in GBM patients recapitulated in patient-derived orthotopic xenografts (PDOXs) and systematically characterize myeloid cell type identities at the molecular and functional level.MethodsWe applied single-cell RNA-sequencing and spatial transcriptomics, multicolor flow cytometry, immunohistochemistry and functional assays to examine the heterogeneity of the TME in GBM. Various GBM PDOXs representing different tumor phenotypes were analyzed and compared to the patient tumors, normal brain and mouse GL261 glioma model.ResultsPDOX models recapitulate the major components of the TME detected in human GBM, where tumor cells reciprocally interact with host cells to create a GBM-specific TME. We detect the most prominent transcriptomic adaptations in myeloid cells, which are largely of microglial origin. We reveal intra-tumoral heterogeneity of microglia and identify diverse phenotypic states across distinct GBM landscapes and tumor niches. GBM-educated microglia acquire dendritic cell-like features, displaying increased migration and phagocytosis. We further find novel microglial states expressing astrocytic and endothelial markers. Lastly, we show that temozolomide (TMZ) treatment leads to transcriptomic plasticity of both GBM tumor cells and adjacent TME components.ConclusionsOur data provide insight into the phenotypic adaptation of the heterogeneous TME instructed by GBM. We uncover that GBM-educated microglia are represented by various concomitant states, both in patients and recapitulated in PDOXs, displaying different pro- or anti-tumoral properties that are modulated by anti-neoplastic treatments, such as TMZ.KEY POINTSGBM-educated tumor microenvironment is faithfully recapitulated and modulated in PDOX modelsMicroglia represent an essential myeloid cell population in the GBM microenvironmentGBM-educated microglia acquire heterogeneous transcriptomic states across distinct tumor nichesGBM-educated microglia subsets display phagocytic and dendritic cell-like gene expression programs, which are modulated upon TMZ treatmentIMPORTANCE OF THE STUDYThis manuscript addresses tumor-immune interactions in GBM, focusing on the molecular changes of the myeloid compartment. We find that myeloid cells, the most abundant immune cell population in brain tumors, undergo the most prominent transcriptional adaptation in the TME. Resident microglia represent the main myeloid cell population in the cellular tumor, while peripheral-derived myeloid cells appear to infiltrate the brain at sites of blood-brain barrier disruption. We identify reactive dendritic cell-like gene expression programs associated with enhanced phagocytic and antigen-presentation features in GBM-educated microglia subsets that might be harnessed for novel immunotherapeutic approaches. Overall, PDOX models faithfully recapitulate the major components of the GBM-educated TME and allow assessment of phenotypic changes in the GBM ecosystem upon treatment.

Programming in deep brain stimulation (DBS) is a labour-intensive process for treating advanced motor symptoms. Specifically for patients with medication-refractory tremor in multiple sclerosis (MS). Wearable sensors are able to detect some manifestations of pathological signs, such as intention tremor in MS. However, methods are needed to visualise the response of tremor to DBS parameter changes in a clinical setting while patients perform the motor task finger-to-nose. To this end, we attended DBS programming sessions of a MS patient and intention tremor was effectively quantified by acceleration amplitude and frequency. A new method is introduced which results in the generation of therapeutic maps for a systematic review of the programming procedure in DBS. The maps visualise the combination of tremor acceleration power, clinical rating scores, total electrical energy delivered to the brain and possible side effects. Therapeutic maps have not yet been employed and could lead to a certain degree of standardisation for more objective decisions about DBS settings. The maps provide a base for future research on visualisation tools to assist physicians who frequently encounter patients for DBS therapy.

ZusammenfassungIn diesem Artikel werden die Besonderheiten der konservativen und operativen Therapie bei der kindlichen Spondylodiszitis und der spezifischen, tuberkulösen Spondylitis besprochen. Beides sind seltene Erkrankungen, bei beiden gibt es sinnvolle konservative Therapieansätze und bei beiden stellen Deformitäten im weiteren Verlauf häufige und ernsthafte Komplikationen dar.

Within this chapter, we describe the main deformities within the cervical spine, pathologies resulting in this, diagnostic tools, indications for surgery, techniques used for closed initial reduction including some helpful tools, surgical approaches, techniques for osteotomies, open and closed reduction, surgical stabilization, and postoperative care.

OBJECT Although cervical total disc replacement (TDR) has shown equivalence or superiority to anterior cervical discectomy and fusion (ACDF), potential problems include nonphysiological motion (hypermobility), accelerated degeneration of the facet joints, particulate wear, and compromise of the mechanical integrity of the endplate during device fixation. Dynamic cervical stabilization is a novel motion-preserving concept that facilitates controlled, limited flexion and extension, but prevents axial rotation and lateral bending, thereby reducing motion across the facet joints. Shock absorption of the Dynamic Cervical Implant (DCI) device is intended to protect adjacent levels from accelerated degeneration. METHODS The authors conducted a prospective evaluation of 53 consecutive patients who underwent DCI stabilization for the treatment of 1-level (n = 42), 2-level (n = 9), and 3-level (n = 2) cervical disc disease with radiculopathy or myelopathy. Forty-seven patients (89%) completed all clinical and radiographic outcomes at a minimum of 24 months. Clinical outcomes consisted of Neck Disability Index (NDI) and visual analog scale (VAS) scores, neurological function at baseline and at latest follow-up, as well as patient satisfaction. Flexion-extension radiography was evaluated for device motion, implant migration, subsidence, and heterotopic ossification. Cervical sagittal alignment (Cobb angle), functional spinal unit (FSU) angle, and range of motion (ROM) at index and adjacent levels were evaluated with WEB 1000 software. RESULTS The NDI score, VAS neck and arm pain scores, and neurological deficits were significantly reduced at each postoperative time point compared with baseline (p < 0.0001). At 24 months postoperatively, 91% of patients were very satisfied and 9% somewhat satisfied, while 89% would definitely and 11% would probably elect to have the same surgery again. In 47 patients with 58 operated levels, the radiographic assessment showed good motion (5°–12°) of the device in 57%, reduced motion (2°–5°) in 34.5%, and little motion (0–2°) in 8.5%. The Cobb and FSU angles improved, showing a clear tendency for lordosis with the DCI. Motion greater than 2° of the treated segment could be preserved in 91.5%, while 8.5% had a near segmental fusion. Mean ROM at index levels demonstrated satisfying motion preservation with DCI. Mean ROM at upper and lower adjacent levels showed maintenance of adjacent-level kinematics. Heterotopic ossification, including 20% minor and 15% major, had no direct impact on clinical results. There were 2 endplate subsidences detected with an increased segmental lordosis. One asymptomatic anterior device migration required reoperation. Three patients underwent a secondary surgery in another segment during follow-up, twice for a new disc herniation and once for an adjacent degeneration. There was no posterior migration and no device breakage. CONCLUSIONS Preliminary results indicate that the DCI implanted using a proper surgical technique is safe and facilitates excellent clinical outcomes, maintains index-and adjacent-level ROM in the majority of cases, improves sagittal alignment, and may be suitable for patients with facet arthrosis who would otherwise not be candidates for cervical TDR. Shock absorption together with maintained motion in the DCI may protect adjacent levels from early degeneration in longer follow-up.

In deep brain stimulation (DBS), post-operative imaging has been used on the one hand to assess complications, such as haemorrhage; and on the other hand, to detect misplaced contacts. The post-operative determination of the accurate location of the final electrode plays a critical role in evaluating the precise area of effective stimulation and for predicting the potential clinical outcome; however, safety remains a priority in postoperative DBS imaging. A plethora of diverse post-operative imaging methods have been applied at different centres. There is neither a consensus on the most efficient post-operative imaging methodology, nor is there any standardisation for the automatic or manual analysis of the images within the different imaging modalities. In this article, we give an overview of currently applied post-operative imaging modalities and discuss the current challenges in post-operative imaging in DBS.

DTI is a technique that identifies white matter tracts (WMT) non-invasively in healthy and non-healthy patients using diffusion measurements. Similar to visual pathways (VP), WMT are not visible with classical MRI or intra-operatively with microscope. DIT will help neurosurgeons to prevent destruction of the VP while removing lesions adjacent to this WMT. We have performed DTI on fifty patients before and after surgery between March 2012 to January 2014. To navigate we used a 3DT1-weighted sequence. Additionally, we performed a T2-weighted and DTI-sequences. The parameters used were, FOV: 200 x 200 mm, slice thickness: 2 mm, and acquisition matrix: 96 x 96 yielding nearly isotropic voxels of 2 x 2 x 2 mm. Axial MRI was carried out using a 32 gradient direction and one b0-image. We used Echo-Planar-Imaging (EPI) and ASSET parallel imaging with an acceleration factor of 2 and b-value of 800 s/mm². The scanning time was less than 9 min. The DTI-data obtained were processed using a FDA approved surgical navigation system program which uses a straightforward fiber-tracking approach known as fiber assignment by continuous tracking (FACT). This is based on the propagation of lines between regions of interest (ROI) which is defined by a physician. A maximum angle of 50, FA start value of 0.10 and ADC stop value of 0.20 mm²/s were the parameters used for tractography. There are some limitations to this technique. The limited acquisition time frame enforces trade-offs in the image quality. Another important point not to be neglected is the brain shift during surgery. As for the latter intra-operative MRI might be helpful. Furthermore the risk of false positive or false negative tracts needs to be taken into account which might compromise the final results.