Discoveries leading to an improved understanding of immune surveillance of the central nervous system (CNS) have repeatedly provoked dismissal of the existence of immune privilege of the CNS. Recent ...rediscoveries of lymphatic vessels within the dura mater surrounding the brain, made possible by modern live-cell imaging technologies, have revived this discussion. This review emphasizes the fact that understanding immune privilege of the CNS requires intimate knowledge of its unique anatomy. Endothelial, epithelial and glial brain barriers establish compartments in the CNS that differ strikingly with regard to their accessibility to immune-cell subsets. There is a unique system of lymphatic drainage from the CNS to the peripheral lymph nodes. We summarize current knowledge on the cellular and molecular mechanisms involved in immune-cell trafficking and lymphatic drainage from the CNS, and we take into account differences in rodent and human CNS anatomy.
The spine is one of the organs that is most affected by metastasis in cancer patients. Since the control of primary tumor is continuously improving, treatment of metastases is becoming one of the ...major challenges to prevent cancer-related death. Due to the anatomical proximity to the spinal cord, local spread of metastasis can directly cause neurological deficits, severely limiting the patient’s quality of life. To investigate the underlying mechanisms and to develop new therapies, preclinical models are required which represent the complexity of the multistep cascade of metastasis. Current research of metastasis focuses on the formation of the premetastatic niche, tumor cell dormancy and the influence and regulating function of the immune system. To unveil whether these influence the organotropism to the spine, spinal models are irreplaceable. Mouse models are one of the most suitable models in oncologic research. Therefore, this review provides an overview of currently used mouse models of spinal metastasis. Furthermore, it discusses technical aspects clarifying to what extend these models can picture key steps of the metastatic process. Finally, it addresses proposals to develop better mouse models in the future and could serve as both basis and stimulus for researchers and clinicians working in this field.
Microglia-driven cerebral spreading inflammation is a key contributor to secondary brain injury after SAH. Genetic depletion or deactivation of microglia has been shown to ameliorate neuronal cell ...death. Therefore, clinically feasible anti-inflammatory approaches counteracting microglia accumulation or activation are interesting targets for SAH treatment. Here, we tested two different methods of interference with microglia-driven cerebral inflammation in a murine SAH model: (i) inflammatory preconditioning and (ii) pharmacological deactivation.
7T-MRI-controlled SAH was induced by endovascular perforation in four groups of C57Bl/6 mice: (i) Sham-operation, (ii) SAH naïve, (iii) SAH followed by inflammatory preconditioning (LPS intraperitoneally), and (iv) SAH followed by pharmacological microglia deactivation (colony-stimulating factor-1 receptor-antagonist PLX3397 intraperitoneally). Microglia accumulation and neuronal cell death (immuno-fluorescence), as well as activation status (RT-PCR for inflammation-associated molecules from isolated microglia) were recorded at day 4 and 14. Toll-like receptor4 (TLR4) status was analyzed using FACS.
Following SAH, significant cerebral spreading inflammation occurred. Microglia accumulation and pro-inflammatory gene expression were accompanied by neuronal cell death with a maximum on day 14 after SAH. Inflammatory preconditioning as well as PLX3397-treatment resulted in significantly reduced microglia accumulation and activation as well as neuronal cell death. TLR4 surface expression in preconditioned animals was diminished as a sign for receptor activation and internalization.
Microglia-driven cerebral spreading inflammation following SAH contributes to secondary brain injury. Two microglia-focused treatment strategies, (i) inflammatory preconditioning with LPS and (ii) pharmacological deactivation with PLX3397, led to significant reduction of neuronal cell death. Increased internalization of inflammation-driving TLR4 after preconditioning leaves less receptor molecules on the cell surface, providing a probable explanation for significantly reduced microglia activation. Our findings support microglia-focused treatment strategies to overcome secondary brain injury after SAH. Delayed inflammation onset provides a valuable clinical window of opportunity.
For decades, it has been known that the tumor microenvironment is significant for glioma progression, namely the infiltration of myeloid cells like microglia and macrophages. Hence, these cell types ...and their specific tasks in tumor progression are subject to ongoing research. However, the distribution of the brain resident microglia and the peripheral macrophages within the tumor tissue and their functional activity are highly debated. Results depend on the method used to discriminate between microglia and macrophages, whereby this specification is already difficult due to limited options to distinguish between these both cell populations that show mostly the same surface markers and morphology. Moreover, there are indications about various functions of microglia and macrophages but again varying on the method of discrimination. In our review, we summarize the current literature to determine which methods have been applied to differentiate the brain resident microglia from tumor-infiltrated macrophages. Furthermore, we compiled data about the proportion of microglia and macrophages in glioma tissues and ascertained if pro- or anti-tumoral effects could be allocated to one or the other myeloid cell population. Recent research made tremendous efforts to distinguish microglia from recruited macrophages. For future studies, it could be essential to verify which role these cells play in brain tumor pathology to proceed with novel immunotherapeutic strategies.
The authors report on an observational study designed to isolate the impact of navigated transcranial magnetic stimulation (nTMS) on surgical outcome in glioblastoma treatment. We undertook a ...controlled observational study to identify the additive impact of presurgical nTMS in patients scheduled for surgical treatment of glioblastoma in or near motor eloquent locations. The trial data is derived from a large university hospital with a differential availability of its nTMS mapping service at its two campuses, both equally served by a single neurosurgical department. When available, the nTMS cortical mapping data and nTMS-based fiber tractography are used for surgical planning and patient counseling as well as intraoperative identification of the primary motor cortex and guidance in subcortical motor mapping. The addition of preoperative nTMS mapping data to a clinical routine already incorporating preoperative fiber tractography and intraoperative neuronavigation and electrophysiology was shown to improve surgical outcomes by increasing the extent of resection, without compromising patient safety or long-term functional outcomes in comparison to the concurrent non-TMS control group. This study is the first to prove that the improved surgical outcomes observed in previous studies after the implementation of nTMS to presurgical work-up are not caused by any overall improvement in patient care or a paradigm shift toward more aggressive resection but by the additional functional data provided by nTMS.
OBJECT Visual field defects (VFDs) due to optic radiation (OR) injury are a common complication of temporal lobe surgery. The authors analyzed whether preoperative visualization of the optic tract ...would reduce this complication by influencing the surgeon's decisions about surgical approaches. The authors also determined whether white matter shifts caused by temporal lobe tumors would follow predetermined patterns based on the tumor's topography. METHODS One hundred thirteen patients with intraaxial tumors of the temporal lobe underwent preoperative diffusion tensor imaging (DTI) fiber tracking. In 54 of those patients, both pre- and postoperative VFDs were documented using computerized perimetry. Brainlab's iPlan 2.5 navigation software was used for tumor reconstruction and fiber visualization after the fusion of DTI studies with their respective magnetization-prepared rapid gradient-echo (MP-RAGE) images. The tracking algorithm was as follows: minimum fiber length 100 mm, fractional anisotropy threshold 0.1. The lateral geniculate body and the calcarine cortex were employed as tract seeding points. Shifts of the OR caused by tumor were visualized in comparison with the fiber tracking of the patient's healthy hemisphere. RESULTS Temporal tumors produced a dislocation of the OR but no apparent fiber destruction. The shift of white matter tracts followed fixed patterns dependent on tumor location: Temporolateral tumors resulted in a medial fiber shift, and thus a lateral transcortical approach is recommended. Temporopolar tumors led to a posterior shift, always including Meyer's loop; therefore, a pterional transcortical approach is recommended. Temporomesial tumors produced a lateral and superior shift; thus, a transsylvian-transcisternal approach will result in maximum sparing of the fibers. Temporocentric tumors also induced a lateral fiber shift. For those tumors, a transsylvian-transopercular approach is recommended. Tumors of the fusiform gyrus generated a superior (and lateral) shift; consequently, a subtemporal approach is recommended to avoid white matter injury. In applying the approaches recommended above, new or worsened VFDs occurred in 4% of the patient cohort. Total neurological and surgical morbidity were less than 10%. In 90% of patients, gross-total resection was accomplished. CONCLUSIONS Preoperative visualization of the OR may help in avoiding postoperative VFDs.
Background
Moyamoya disease (MMD) is a cerebrovascular disorder characterized by fragile vascular system. Previous studies suggested that the blood-brain barrier (BBB) destabilizing cytokine ...angiopoietin-2 plays a critical role in increasing vascular plasticity and endothelial disintegration in MMD. The aim of this study was to assess cerebrovascular integrity in vivo in patients affected by MMD.
Methods
We retrospectively analyzed 11 patients that underwent bypass for MMD (MMD group), 11 patients that underwent bypass for atherosclerotic cerebrovascular disease (ACVD—control group I), and 5 patients that underwent clipping for unruptured aneurysms (non-ischemic—control group II). Sodium fluorescein (NaFL) extravasation was evaluated during videoangiography when checking for bypass patency. A grading system (0, +, ++, +++) was used to define the extent of extravasation. Frequency and intensity of leakage was compared among different groups.
Results
NaFL extravasation appeared in 10/11 (91%) patients with MMD and in 8/11 (73%) patients with ACVD during bypass procedures. Extravasation was observed in none of the patients undergoing clipping for unruptured aneurysms. Although both chronic ischemic patient groups showed a comparably high incidence of NaFL extravasation, the MMD group was characterized by a much greater intensity of NaFL extravasation (grade +++ in 82%) than the ACVD group (grade +++ in 27%,
p
< 0.05).
Conclusions
We demonstrate blood-brain barrier impairment in MMD patients for the first time in vivo. This may be due to mechanisms intrinsic to the unique pathology of MMD, probably explaining the higher association with hemorrhage and post-operative hyperperfusion.
STUDY DESIGN:A prospective case-series study plus a retrospective analysis of historical patients for comparison of data.
OBJECTIVE:To compare accuracy and limitations of intraoperative computed ...tomography (iCT)- versus 3D C-arm-based spinal navigation for posterior pedicle screw implantation.
SUMMARY OF BACKGROUND DATA:Despite the higher accuracy of navigated compared to non-navigated pedicle screw implantation, it remains a matter of debate whether the use of iCT imaging may further benefit navigated spinal instrumentation compared to more commonly used isocentric 3D C-arm imaging.
METHODS:Between 2013 and 2016, 1527 pedicle screws were implanted in 260 patients with iCT (1219 screws) or 3D C-arm (308 screws) based spinal navigation. Screw positioning was intraoperatively assessed by a second iCT or 3D C-arm (intraoperative accuracy). If necessary, immediate intraoperative screw revision was performed. Thereafter, a third iCT or 3D C-arm scan was performed to confirm repositioning (final accuracy). Clinical and patient data, intraoperative screw assessability and accuracy rates were retrospectively reviewed and analyzed by an independent observer.
RESULTS:Intraoperative CT permitted immediate intraoperative assessment of each implanted screw. In contrast, 39 of the screws visualized with 3D C-arm imaging were intraoperatively not clearly assessable. Regarding the overall precision, iCT and 3D-C-arm navigation yielded a comparable intraoperative accuracy (iCT 94.7% vs. 3D C-arm 89.4%) and immediate correction of misplaced screws was feasible with both modalities (final accuracyiCT 95.4% vs. 3D C-arm 91.6%). Regarding the region specific performance, however, iCT-based navigation yielded significantly higher final accuracy rates in the cervical (iCT 99.5% vs. 3D C-arm 88.9%, *p<0.01) and thoracic (iCT 97.7% vs. 3D C-arm 88.8%, *p<0.001) regions.
CONCLUSIONS:Both iCT and 3D C-arm-based spinal navigation provides high pedicle screw accuracy rates. However, immediate screw assessability and placement accuracy in the cervical-thoracic spine appear to be limited with intraoperative 3D C-arm imaging alone.Level of Evidence3
With a median patient survival of 15 months, glioblastoma (GBM) is still one of the deadliest malign tumors. Despite immense efforts, therapeutic regimens fail to prolong GBM patient overall survival ...due to various resistance mechanisms. Chemokine signaling as part of the tumor microenvironment plays a key role in gliomagenesis, proliferation, neovascularization, metastasis and tumor progression. In this review, we aimed to investigate novel therapeutic approaches targeting various chemokine axes, including CXCR2/CXCL2/IL-8, CXCR3/CXCL4/CXCL9/CXCL10, CXCR4/CXCR7/CXCL12, CXCR6/CXCL16, CCR2/CCL2, CCR5/CCL5 and CX3CR1/CX3CL1 in preclinical and clinical studies of GBM. We reviewed targeted therapies as single therapies, in combination with the standard of care, with antiangiogenic treatment as well as immunotherapy. We found that there are many antagonist-, antibody-, cell- and vaccine-based therapeutic approaches in preclinical and clinical studies. Furthermore, targeted therapies exerted their highest efficacy in combination with other established therapeutic applications. The novel chemokine-targeting therapies have mainly been examined in preclinical models. However, clinical applications are auspicious. Thus, it is crucial to broadly investigate the recently developed preclinical approaches. Promising preclinical applications should then be investigated in clinical studies to create new therapeutic regimens and to overcome therapy resistance to GBM treatment.
Rechallenge with temozolomide (TMZ) at first progression of glioblastoma after temozolomide chemoradiotherapy (TMZ/RT→TMZ) has been studied in retrospective and single-arm prospective studies, ...applying temozolomide continuously or using 7/14 or 21/28 days schedules. The DIRECTOR trial sought to show superiority of the 7/14 regimen.
Patients with glioblastoma at first progression after TMZ/RT→TMZ and at least two maintenance temozolomide cycles were randomized to Arm A one week on (120 mg/m(2) per day)/one week off or Arm B 3 weeks on (80 mg/m(2) per day)/one week off. The primary endpoint was median time-to-treatment failure (TTF) defined as progression, premature temozolomide discontinuation for toxicity, or death from any cause. O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation was prospectively assessed by methylation-specific PCR.
Because of withdrawal of support, the trial was prematurely closed to accrual after 105 patients. There was a similar outcome in both arms for median TTF A: 1.8 months; 95% confidence intervals (CI), 1.8-3.2 vs. B: 2.0 months; 95% CI, 1.8-3.5 and overall survival A: 9.8 months (95% CI, 6.7-13.0) vs. B: 10.6 months (95% CI, 8.1-11.6). Median TTF in patients with MGMT-methylated tumors was 3.2 months (95% CI, 1.8-7.4) versus 1.8 months (95% CI, 1.8-2) in MGMT-unmethylated glioblastoma. Progression-free survival rates at 6 months (PFS-6) were 39.7% with versus 6.9% without MGMT promoter methylation.
Temozolomide rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation.
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