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Study Design: A prospective randomized controlled clinical study. Objective: To investigate the feasibility of a calcium phosphate cement (CaP) in balloon kyphoplasty if compared to polymethylmethacrylate (PMMA). Summary Of Background Data: In kyphoplasty and vertebroplasty, PMMA currently represents the standard in augmentation materials. It is characterized, however, by a lack of osseointegration and limited biocompatibility. Consequently, CaP is currently being investigated as an alternative material for vertebral augmentation. Methods: Inclusion criteria were 1 or 2 adjacent osteoporotic fractures of vertebral bodies in the thoracolumbar spine, patient age > or =65 years, and fracture age < or =4 months. Exclusion criteria were tumor lesions and additional posterior instrumentation. Results: A total of 60 osteoporotic vertebral body fractures in 56 patients were included. CaP and PMMA were randomly applied in 30 vertebrae each with 2-fracture-patients receiving only 1 type of cement for both vertebrae. All 60 fractures were classified compression fractures (type A). Of these, 27 were classified burst fractures (type A3). 52/56 patients experienced statistically significant pain relief (7.9 +/- 1.9 to 1.8 +/- 2.1 on a Visual Analog Scale from 0 "best" to 10 "worst"). Bisegmental endplate angles were restored by 6.2 degrees +/- 5.9 degrees on average. Complications that turned out to be cement-specific were: vascular embolism (n = 2) for PMMA; subtotal cement washout (n = 1); and radiographic loss of correction (n = 9) due to cement failure in burst fractures for CaP. There was no case of cement failure, when PMMA had been used. Conclusion: The routine use of the CaP tested is not currently recommended for kyphoplasty. Because of its low resistance against flexural, tractive, and shear forces compared to PMMA, in certain constellations (burst fractures), there is a higher risk of cement failure and subsequent loss of correction. [ABSTRACT FROM AUTHOR]

TUBA1A tubulinopathy is a rare neurodevelopmental disorder associated with brain malformations as well as early-onset and intractable epilepsy. As pathomechanisms and genotype-phenotype correlations are not completely understood, we aimed to provide further insights into the phenotypic and genetic spectrum. We here present a multicenter case series of ten unrelated individuals from four European countries using systematic MRI re-evaluation, protein structure analysis, and prediction score modeling. In two cases, pregnancy was terminated due to brain malformations. Amongst the eight living individuals, the phenotypic range showed various severity. Global developmental delay and severe motor impairment with tetraparesis was present in 63% and 50% of the subjects, respectively. Epilepsy was observed in 75% of the cases, which showed infantile onset in 83% and a refractory course in 50%. One individual presented a novel TUBA1A-associated electroclinical phenotype with evolvement from early myoclonic encephalopathy to continuous spike-and-wave during sleep. Neuroradiological features comprised a heterogeneous spectrum of cortical and extracortical malformations including rare findings such as cobblestone lissencephaly and subcortical band heterotopia. Two individuals developed hydrocephalus with subsequent posterior infarction. We report four novel and five previously published TUBA1A missense variants whose resulting amino acid substitutions likely affect longitudinal, lateral, and motor protein interactions as well as GTP binding. Assessment of pathogenic and benign variant distributions in synopsis with prediction scores revealed sections of variant enrichment and intolerance to missense variation. We here extend the clinical, neuroradiological, and genetic spectrum of TUBA1A tubulinopathy and provide insights into residue-specific pathomechanisms and genotype-phenotype correlations., (© 2022. The Author(s).)

Loss of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a prerequisite for tumor cell-specific expression of vascular endothelial growth factor receptor (VEGFR)-2 in glioblastoma defining a subgroup prone to develop evasive resistance towards antiangiogenic treatments. Immunohistochemical analysis of human tumor tissues showed VEGFR-2 expression in glioma cells in 19% of specimens examined, mainly in the infiltration zone. Glioma cell VEGFR-2 positivity was restricted to PTEN-deficient tumor specimens. PTEN overexpression reduced VEGFR-2 expression in vitro, as well as knock-down of raptor or rictor. Genetic interference with VEGFR-2 revealed proproliferative, antiinvasive and chemoprotective functions for VEGFR-2 in glioma cells. VEGFR-2-dependent cellular effects were concomitant with activation of 'kappa-light-chain-enhancer' of activated B-cells, protein kinase B, and N-myc downstream regulated gene 1. Two-photon in vivo microscopy revealed that expression of VEGFR-2 in glioma cells hampers antiangiogenesis. Bevacizumab induces a proinvasive response in VEGFR-2-positive glioma cells. Patients with PTEN-negative glioblastomas had a shorter survival after initiation of bevacizumab therapy compared with PTEN-positive glioblastomas. Conclusively, expression of VEGFR-2 in glioma cells indicates an aggressive glioblastoma subgroup developing early resistance to temozolomide or bevacizumab. Loss of PTEN may serve as a biomarker identifying those tumors upfront by routine neuropathological methods.

Background and Purpose: Flow-diverter stents are emerging for the endovascular treatment of difficult-to-treat or otherwise untreatable cerebral aneurysms (wide-neck, fusiform, dissecting, blisterlike, or giant). We assessed the clinical safety and efficacy of the Flow-Redirection Endoluminal Device., Materials and Methods: This was an institutional review board-approved single-center observational clinical study in 29 patients with 34 aneurysms elected to be treated by endovascular intervention. After providing informed consent, patients were included according to the following criteria: aneurysm fundus-to-neck ratio <2 or neck diameter >4 mm, fusiform, dissecting, or giant aneurysms. The primary end point for clinical safety was the absence of death, absence of major or minor stroke, and absence of transient ischemic attack. The primary end point for treatment efficacy was complete angiographic occlusion according to the O'Kelly Marotta grading scale immediately after the procedure and at follow-up after 3 and 6 months (O'Kelly Marotta D: complete occlusion)., Results: The Flow-Redirection Intraluminal Device deployment was technically successful in all cases. In 26/29 (89%) of patients, the primary end point of safety was reached; in the 3 remaining patients, 1 disabling ischemic stroke and 2 minor strokes with complete recovery at follow-up were observed. Angiographic (DSA and MRA) and clinical follow-up were available after 3 months in 29/29 (100%) and after 6 months in 25/29 (86%) patients (after 6 months, only MRA follow-up was performed according to our study protocol and institutional standard). At 3-month follow-up, complete occlusion was reached in 19/34 aneurysms (O'Kelly Marotta D: 19/34; 56%). At 6-month follow-up, aneurysm occlusion was complete in 22/30 aneurysms (O'Kelly Marotta D: 22/30; 73%)., Conclusions: Deployment of the Flow-Redirection Intraluminal Device flow-diverter stent is safe and effective in the treatment of difficult-to-treat or otherwise untreatable intracranial aneurysms., (© 2015 by American Journal of Neuroradiology.)

Human glioblastomas may be hierarchically organized. Within this hierarchy, glioblastoma-initiating cells have been proposed to be more resistant to radiochemotherapy and responsible for recurrence. Here, established stem cell markers and stem cell attributed characteristics such as self-renewal capacity and tumorigenicity have been profiled in primary glioblastoma cultures to predict radiosensitivity. Furthermore, the sensitivity to radiotherapy of different subpopulations within a single primary glioblastoma culture was analyzed by a flow cytometric approach using Nestin, SRY (sex-determining region Y)-box 2 (SOX2) and glial fibrillary acidic protein. The protein expression of Nestin and SOX2 as well as the mRNA levels of Musashi1, L1 cell adhesion molecule, CD133, Nestin, and pleiomorphic adenoma gene-like 2 inversely correlated with radioresistance in regard to the clonogenic potential. Only CD44 protein expression correlated positively with radioresistance. In terms of proliferation, Nestin protein expression and Musashi1, pleiomorphic adenoma gene-like 2, and CD133 mRNA levels are inversely correlated with radioresistance. Higher expression of stem cell markers does not correlate with resistance to radiochemotherapy in the cancer genome atlas glioblastoma collective. SOX2 expressing subpopulations exist within single primary glioblastoma cultures. These subpopulations predominantly form the proliferative pool of the primary cultures and are sensitive to irradiation. Thus, profiling of established stem cell markers revealed a surprising result. Except CD44, the tested stem cell markers showed an inverse correlation between expression and radioresistance. Markers used to define glioma-initiating cells (GIC) are generally not defining a more resistant, but rather a more sensitive group of glioma cells. An exemption is CD44 expression. Also proliferation of the GIC culture itself was not systematically associated with radiosensitivity or - resistance, but a SOX-2 positive, proliferative subgroup within a GIC culture is showing the highest radiosensitivity., (© 2014 International Society for Neurochemistry.)

Cancer stem cells (CSCs) have been suggested as potential therapeutic targets for treating malignant tumors, but the in vivo supporting evidence is still missing. Using a GFP reporter driven by the promoter of the nuclear receptor tailless (Tlx), we demonstrate that Tlx(+) cells in primary brain tumors are mostly quiescent. Lineage tracing demonstrates that single Tlx(+) cells can self-renew and generate Tlx(-) tumor cells in primary tumors, suggesting that they are brain tumor stem cells (BTSCs). After introducing a BTSC-specific knock-out of the Tlx gene in primary mouse tumors, we observed a loss of self-renewal of BTSCs and prolongation of animal survival, accompanied by induction of essential signaling pathways mediating cell-cycle arrest, cell death, and neural differentiation. Our study demonstrates the feasibility of targeting glioblastomas and indicates the suitability of BTSCs as therapeutic targets, thereby supporting the CSC hypothesis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To compare conventional magnetic resonance imaging (MRI) techniques (T2-w and Gadolinium-DTPA-enhanced T1-w images) and Gadofluorine-M (GfM), a novel contrast agent in MRI, in murine gliomas., Materials and Methods: Growth monitoring of murine gliomas (induced in mice) was performed on a 2.3 Tesla Bruker Biospec MRI unit. First all animals were investigated with conventional MRI techniques. In group I GfM was applied at an early stage of disease, in group II at a later stage. After injection of GfM follow-up MRI was performed without further injection of contrast agent. On MR images tumor size and signal intensities were assessed. Animals were killed for histological evaluation., Results: In both groups GfM delineated tumor extents larger and more precisely than conventional MRI techniques. The difference between GfM and conventional MRI techniques reached level of significance at both tumor stages. Follow-up MRI after singular injection of GfM showed persistence of GfM in tumor tissue. On tissue sections GfM-enhancing areas corresponded closely to vital tumor tissue. GfM showed a mainly intracellular accumulation., Conclusion: Application of GfM resulted in superior delineation of experimental glioma compared with conventional MRI techniques. Thus, GfM bears a high potential in clinical application., (Copyright © 2011 Wiley-Liss, Inc.)

Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.

Inflammation plays a central role in the development of numerous disorders of the central nervous system (CNS) such as multiple sclerosis (MS). For a long time it was assumed that recruitment of macrophages into the CNS and breakdown of the blood-brain barrier (BBB) are closely linked. In the present study we challenge this concept. We used small superparamagnetic iron oxide particles (SPIO)-enhanced T2-weighted (T2-w) magnetic resonance imaging (MRI) on a routine 1.5 T MRI unit to follow macrophage infiltration in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. After an initial SPIO-enhanced MRI, gadofluorine M (Gf), an experimental contrast agent which proved to be more sensitive in detecting BBB leakage than gadolinium (Gd)-DTPA (Bendszus, M., Ladewig, G., Jestaedt, L., Misselwitz, B., Solymosi, L., Toyka, K.V., Stoll, G., Gadofluorine-M enhancement allows more sensitive detection of inflammatory CNS lesions than T2-w imaging: a quantitative MRI study. Brain 2008; 1-12), was applied to the same animals followed by a second scan. Areas with SPIO-induced signal loss on T2-w MRI indicative of recent macrophage infiltration were matched with areas showing Gf enhancement as a measure of BBB disturbance. Overall 87 EAE lesions showed iron-related signal loss, while 57 lesions showed Gf enhancement. By direct comparison we could detect concomitant SPIO-induced signal loss and Gf enhancement only in a small minority of lesions. In conclusion, our findings show macrophage infiltration in the CNS during EAE in areas with a closed BBB for humoral factors. This holds true despite the use of a more sensitive MR contrast agent for BBB disruption than Gd-DTPA. Our experimental observations may have implications for disease monitoring in MS patients by MRI which guides treatment decisions.

Objective: Vasospasm of the cerebral vessels remains a major source for morbidity and mortality after aneurysmal subarachnoid hemorrhage. The purpose of this study was to evaluate the frequency of infarction after transluminal balloon angioplasty (TBA) in patients with severe subarachnoid hemorrhage-related vasospasm., Methods: We studied 38 patients (median Hunt and Hess Grade II and median Fisher Grade 4) with angiographically confirmed severe vasospasm (>70% vessel narrowing). A total of 118 vessels with severe vasospasm in the anterior circulation were analyzed. Only the middle cerebral artery, including the terminal internal carotid artery, was treated with TBA (n = 57 vessel segments), whereas the anterior cerebral artery was not treated (n = 61 vessel segments). For both the treated and the untreated vessel territories, infarction on unenhanced computed tomographic scan was assessed as a marker for adverse outcome., Results: Infarction after TBA occurred in four middle cerebral artery territories (four out of 57 [7%]), whereas the infarction rate was 23 out of 61 (38%) in the anterior cerebral artery territories not subjected to TBA (P < 0.001, Fisher exact test). Three procedure-related complications occurred during TBA (dissection, n = 1; temporary vessel occlusions, n = 2). One of these remained asymptomatic, whereas this may have contributed to the development of infarction on follow-up computed tomographic scans in two cases., Conclusion: In a population of patients with a high risk of infarction resulting from vasospasm after subarachnoid hemorrhage, the frequency of infarction in the distribution of vessels undergoing TBA amounts to 7% and is significantly lower than in vessels not undergoing TBA despite some risk inherent to the procedure.

Nerve imaging by magnetic resonance imaging (MRI) is an emerging tool for the diagnostic work-up of patients with PNS disorders. We have recently shown that the experimental MR contrast agent gadofluorine M (Gf, Bayer Schering Pharma AG, Berlin) accumulates in nerves undergoing Wallerian degeneration and in areas of acute focal demyelination allowing in-vivo assessment of nerve pathology. The exact pathomechanism underlying Gf accumulation in peripheral nerve disorders is unknown so far. In the present study we compared nerve signal alterations on T2-w and Gf-enhanced T1-w MRI in two different models of acute inflammatory and chronic degenerative demyelination: experimental autoimmune neuritis (EAN) induced by immunization with PNS myelin and experimental Charcot-Marie-Tooth (CMT) disease in rats overexpressing the myelin protein PMP22. During the acute stage of inflammation and demyelination, strong Gf enhancement on T1-w MRI was seen in nerve roots and peripheral nerves in EAN, which resolved with completed remyelination. Similarly, Gf accumulation was seen in CMT rats during early stages with active demyelination at 6 weeks while at chronic stages (9 months) Gf enhancement decreased despite numerous demyelinated axons and onion bulb formation. At all disease stages no signal alterations were seen on T2-w MRI. In conclusion, our data show that the novel MR contrast agent Gf, but not Gadolinium (Gd)-DTPA, facilitates detection of ongoing demyelination by MR neurography independent from the underlying pathology. It appears that the extent of Gf enhancement depends on the acuity of demyelination and is probably related to a transient disturbance of the blood-nerve barrier. Clinical development of Gf may help to further improve the sensitivity of nerve lesion assessment by MRI in patients with peripheral neuropathies.