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Magnetic resonance (MR) relaxometry is a quantitative imaging method that measures tissue relaxation properties. This review discusses the state of the art of clinical proton MR relaxometry for glial brain tumors. Current MR relaxometry technology also includes MR fingerprinting and synthetic MRI, which solve the inefficiencies and challenges of earlier techniques. Despite mixed results regarding its capability for brain tumor differential diagnosis, there is growing evidence that MR relaxometry can differentiate between gliomas and metastases and between glioma grades. Studies of the peritumoral zones have demonstrated their heterogeneity and possible directions of tumor infiltration. In addition, relaxometry offers T2* mapping that can define areas of tissue hypoxia not discriminated by perfusion assessment. Studies of tumor therapy response have demonstrated an association between survival and progression terms and dynamics of native and contrast-enhanced tumor relaxometric profiles. In conclusion, MR relaxometry is a promising technique for glial tumor diagnosis, particularly in association with neuropathological studies and other imaging techniques., Competing Interests: Declaration of conflicting interestsOC is an inventor on patents for MR fingerprinting technology and receives royalties from Siemens Healthineers. RO has research collaboration agreements with GE Healthcare and Philips Healthcare, all unrelated to this work. RJY has consulted for Agios, Puma, NordicNeuroLab and ICON plc, and received research funding from Agios, all unrelated to this work. AIH is Owner/President of fMRI Consultants, LLC, a purely educational entity. The other authors report no conflict of interest.

(1) Purpose: To determine the borders of malignant gliomas with diffusion kurtosis and perfusion MRI biomarkers. (2) Methods: In 50 high-grade glioma patients, diffusion kurtosis and pseudo-continuous arterial spin labeling (pCASL) cerebral blood flow (CBF) values were determined in contrast-enhancing area, in perifocal infiltrative edema zone, in the normal-appearing peritumoral white matter of the affected cerebral hemisphere, and in the unaffected contralateral hemisphere. Neuronavigation-guided biopsy was performed from all affected hemisphere regions. (3) Results: We showed significant differences between the DKI values in normal-appearing peritumoral white matter and unaffected contralateral hemisphere white matter. We also established significant ( p < 0.05) correlations of DKI with Ki-67 labeling index and Bcl-2 expression activity in highly perfused enhancing tumor core and in perifocal infiltrative edema zone. CBF correlated with Ki-67 LI in highly perfused enhancing tumor core. One hundred percent of perifocal infiltrative edema tissue samples contained tumor cells. All glioblastoma samples expressed CD133. In the glioblastoma group, several normal-appearing white matter specimens were infiltrated by tumor cells and expressed CD133. (4) Conclusions: DKI parameters reveal changes in brain microstructure invisible on conventional MRI, e.g., possible infiltration of normal-appearing peritumoral white matter by glioma cells. Our results may be useful for plotting individual tumor invasion maps for brain glioma surgery or radiotherapy planning.

The aim of the study was to evaluate the relationship between tumor blood flow (TBF) measured by the pseudo-continuous arterial spin labeling (PCASL) method and IDH1 mutation status of gliomas as well as Ki-67 proliferative index. Methods. The study included 116 patients with newly diagnosed gliomas of various grades. They received no chemotherapy or radiotherapy before MRI. IDH1 status assessment was performed after tumor removal in 106 cases—48 patients were diagnosed with wildtype gliomas (Grade 1−2—6 patients, Grade 3−4—42 patients) and 58 patients were diagnosed with mutant forms of gliomas (Grade 1−2—28 patients, Grade 3−4—30 patients). In 64 cases out of 116 Ki-67 index was measured. Absolute and normalized tumor blood flow values were measured on 3D PCASL maps. Results. TBF and normalized TBF (nTBF) in wildtype gliomas were significantly higher than in IDH1-mutant gliomas (p < 0.001). ASL perfusion showed high values of sensitivity and specificity in the differential diagnosis of gliomas with distinct IDH1 status (for TBF: specificity 75%, sensitivity 77.6%, AUC 0.783, cutoff 80.57 mL/100 g/min, for nTBF: specificity 77.1%, sensitivity 79.3%, AUC 0.791, cutoff 4.7). TBF and nTBF in wildtype high-grade gliomas (HGG) were significantly higher than in mutant forms (p < 0.001). ASL perfusion showed the following values of sensitivity and specificity in the diagnosis of mutant HGG and wildtype HGG (for TBF: specificity 83.3%, sensitivity 60%, AUC 0.719, cutoff 84.18 mL/100 g/min, for nTBF: specificity 88.1%, sensitivity 60%, AUC 0.729, cutoff 4.7). There was a significant positive correlation between tumor blood flow and Ki-67 (for TBF Rs = 0.63, for nTBF Rs = 0.61). Conclusion. ASL perfusion may be an informative factor in determining the IDH1 status in brain gliomas preoperative and tumor proliferative activity.

Objective: To analyze the differences of high-grade glioma subregions using magnetic resonance relaxometry with compilation of images (MAGiC) and arterial spin labeling (ASL), as well as to compare quantitative measurements of these techniques with morphological data., Material and Methods: The study enrolled 35 patients with newly diagnosed supratentorial gliomas (23 - grade IV, 12 - grade III). We measured relaxometric values (T1, T2, proton density), tumor blood flow (TBF) in glioma subregions and normal-appearing brain matter. Neuronavigation was intraoperatively used to obtain tissue samples from active tumor growth zone, perifocal infiltrative edema zone and adjacent brain matter along surgical approach., Results: ASL perfusion revealed higher tumor blood flow (TBF) in active tumor growth region compared to perifocal infiltrative edema zone ( p <0.01). Relaxometric values (T1, T2, proton density) in perifocal zone were higher ( p <0.01) compared to adjacent intact white matter along surgical approach. However, there were no differences in TBF between these zones. Proton density in tumor-adjacent intact white matter was higher ( p <0.01) compared to normal-appearing white matter in ipsilateral hemisphere. There was inverse correlation between T2 and TBF in active tumor growth zone (Spearman rank R= -0.58; p =0.0016). We found inverse correlation between T2 and Ki67 proliferative index and direct correlation between TBF and Ki67 in this zone. Nevertheless, these relationships were insignificant after multiple test adjustment., Conclusion: Our study advocates for complementary power of ASL perfusion and MR relaxometry in assessment of high-grade brain glioma subregions. More malignant tumor zones tend to have higher TBF and shorter T2. Further investigation is needed to prove the capability of MAGiC to reveal foci of increased relaxometric values in tumor-adjacent normal-appearing white matter.

The brain has an exceptionally high requirement for energy metabolism, with glucose serving as the exclusive energy source. Cancers, including glioblastoma, have a high glucose uptake and rely on aerobic glycolysis for energy metabolism. The alternation of high-efficiency oxidative phosphorylation to a low-efficiency aerobic glycolysis pathway (Warburg effect) provides macromolecules for biosynthesis and proliferation. Current research indicates that the specific metabolism in the tumor tissue and normal brain tissue in the glioma allows the use of 5-aminolevulinic acid (5 ALA)-induced protoporphyrin IX (PpIX) and methylene blue (MB) to monitor and correct the development of the tumor. The focus is on the detection of the differences between tumor cells and tumor-associated macrophages/microglia using spectroscopic and microscopic methods, based on the fluorescent signals and the difference in the drug accumulation of photosensitizers (PSs). Since 5 ALA has long been used effectively in the clinic for fluorescent surgical navigation, it was employed as an agent to identify the localization of tumor tissue and study its composition, particularly tumor and immune cells (macrophages), which have also been shown to actively accumulate PpIX. However, since PpIX is photodynamically active, it can be considered effective as the main target of tumor tissue for further successful photodynamic therapy. MB was employed to visualize resident microglia, which is important for their activation/deactivation to prevent the reprogramming of the immune cells by the tumor. Thus, using two drugs, it is possible to prevent crosstalk between tumor cells and the immune cells of different geneses., (© 2020. Higher Education Press.)

Dendritic cell-based vaccines are an intensively studied active immunotherapy technology. Aim of this article is to review the results of the key clinical studies of such vaccines in the treatment of neuro-oncological diseases. Their effectiveness was studied most widely in the treatment of malignant glial tumors, the study went from experimental work to phase III clinical studies, preliminary results of which indicate some positive results of this immunotherapy method in adults. Currently, emphasis is also being placed on the identification of clinical and immunological correlates of the patient's response to therapy and on the search for new antigens for sensitization of dendritic cells Studies of dendritic cell vaccines also include a number of other neuro-oncological diseases. A separate part of this article is devoted to the treatment of intracerebral tumors in children, for example, medulloblastomas and gliomas of the pons. In addition, the potential use of dendritic cell vaccines for intracerebral metastases is considered.

Maximum resection and preservation of neurological function are main principles in surgery of brain tumors, especially glial neoplasms with diffuse growth. Therefore, exact localizing of eloquent brain areas is an important component in surgical planning ensuring optimal resection with minimal postoperative neurological deficit. Functional MRI is used to localize eloquent brain areas adjacent to the tumor. This paper is an initial stage in analysis of resting-state fMRI in assessment of functional changes of neuronal activity caused by brain gliomas of different localization. We report two patients with glial tumors localized within the precentral gyrus of the left hemisphere and near speech area. Considering data of task-based and resting-state fMRI, as well as direct cortical stimulation, we propose a methodology for assessing the overlap of activations obtained by these methods.

The pathological processes developing after spinal cord injuries often lead to formation of cysts. Existing surgical and medical methods are insufficient for treatment of post-traumatic spinal cord cysts. One of the emerging tools is cell therapy. Olfactory ensheathing cells (OECs) are perspective cells for cell therapy. In this study, we demonstrated that human OEC transplantation is effective in experimental spinal cysts. For our experiments, we selected animals only at the intermediate stage of recovery with scores from 8 to 13 according to the Basso, Beattie, and Bresnahan (BBB) scale. Cells were transplanted in different quantities (0.75 and 1.5 million) into the fully formed cysts and in the areas of injury without cysts. Improvement of limb mobility after human OEC transplantation into post-traumatic cysts was shown. In the group of rats with cysts, time-dependent increase in the BBB score was observed in subgroups treated with 0.75 and 1.5 million OECs with no statistically significant time-dependent dynamics of BBB values in the control group. When all three subgroups (control and two OEC doses) were compared, the Kruskal-Wallis test showed the presence of differences between subgroups after 1, 3, and 4 weeks of treatment with evidence of divergence increase. There was no statistically significant difference between the two doses of OEC treatment. The human OECs in the experiments without cysts were not effective. It was also shown that PKH26-labeled human OECs survive throughout the experiment and migrate to nearby areas of the cyst. Therefore, it was found that it is effective to transplant human OECs into fully formed cysts. In the future, autologous OECs can be used to personalize the treatment of patients with spinal cysts.

Astrocytes are a dominant cell type that envelopes the glioma bed. Typically, that is followed by formation of contacts between astrocytes and glioma cells and accompanied by change in astrocyte phenotype, a phenomenon known as a 'reactive astrogliosis.' Generally considered glioma-promoting, astrocytes have many controversial peculiarities in communication with tumor cells, which need thorough examination in vitro. This review is devoted to in vitro co-culture studies of glioma cells and astrocytes. Firstly, we list several fundamental works which allow understanding the modalities of co-culturing. Cell-to-cell interactions between astrocytes and glioma cells, the roles of astrocytes in tumor metabolism, and glioma-related angiogenesis are reviewed. In the review, we also discuss communications between glioma stem cells and astrocytes. Co-cultures of glioma cells and astrocytes are used for studying anti-glioma treatment approaches. We also enumerate surgical, chemotherapeutic, and radiotherapeutic methods assessed in co-culture experiments. In conclusion, we underline collisions in the field and point out the role of the co-cultures for neurobiological studies.

In epithelial tumors, the epidermal growth factor receptor (EGFR) controls key signaling pathways responsible for growth, proliferation, migration, and survival of tumor cells. The epidermal growth factor receptor variant III (EGFRvIII) is the most common EGFR mutation that occurs in up to 30% of high-grade gliomas especially glioblastoma multiforme (GBM). EGFRvIII arises from the deletion of exon 2-7 that leads to the formation of the constitutively activated mutant receptor incapable of binding any known ligand. EGFRvIII-expressing cells are resistant to EGFR inhibitors and therefore take advantage in survival. Furthermore, EGFRvIII expression in tumors is often correlates with poor prognosis. Indeed, EGFRvIII targeting is of great therapeutic value in order to inhibit GBM progression and invasion. The presence of the unique glycine site in EGFRvIII provides an option to develop EGFRvIII-specific monoclonal antibodies (MAbs). These antibodies are used for detection of EGFRvIII and immunotherapy. Peptide CDX-110 derived from EGFRvIII has high immunogenicity. This peptide was used for the development of anti-EGFRvIII MAbs with improved specificity to the mutant receptor, EGFRvIII-specific dendritic cell vaccine, and CDX-110-KLH peptide vaccine. These immune reagents were successfully tested in preclinical and clinical studies for GBM treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We obtained the morphologically, cytofluorometrically, and functionally mature dendritic cells from rats that were pulsed with antigens of the C6 glioma tissue extract. The concentrations of angiogenesis antigens (VEGF, VEGFR-1, and VEGFR-2) and periglioma zone proteins (GFAP, connexin 43, and BSAT1) in the pulsing extract were measured by ELISA. Our results drove us to a conclusion that despite mature phenotype of pulsed dendritic cell, the antigenic composition of glioma tissue extracts should be modified.

High grade gliomas (HGGs) are the most frequent and highly invasive type of brain tumors, which arise from glial cells. Among HGGs, glioblastoma multiforme (GBM) is the commonest and deadliest tumor type. Standard HGG therapy that involves tumor resection followed by concomitant treatment with radiation exposure and temozolomide (TMZ) cannot prevent recurrent tumor. The median survival of treated patients after surgery does not exceed 1.5 years. Vaccination with autologous dendritic cells (DCs) pulsed with tumor-specific peptides, antigens, or lysates is considered as a promising option to induce a potent anti-tumor immune response and cytotoxicity against GBM cells. However, since the tumor microenvironment is highly immunosuppressive and immunotolerant, specialized approaches should be applied to protect DC transplants against tumor-induced functional impairment and inhibition. So far, many phase I-III clinical trials utilizing DC vaccines for HGG treatment were completed or are underway. In summary, DC vaccination was safe and well tolerated by patients. DC-induced anti-tumor immune responses correlated with prolonged overall and progression- free survival. Combination of DC therapy with other interventional strategies (i.e., radiotherapy, chemotherapy, antibodies, etc.) and multimodal approaches should improve HGG treatment outcomes. In this review, we consider strategies that provide an option to override the immune inhibitory tumor microenvironment and boost DC vaccine-based antitumor immune response.

The review is devoted to a relatively young direction in therapy of malignant gliomas, which is based on applying monoclonal antibodies against tumour-associated antigens. The current data on efficacy of main therapeutic agents in clinical practice or clinical trials concerning high-grade gliomas, especially glioblastoma multiforme, is summarized. Of particular interest is bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (anti-VEGF), which is widely used in glioblastoma. Major clinical trials devoted to bevacizumab monotherapy and combinations of bevacizumab with other therapeutic modalities in primary and recurrent glioblastoma conducted since 2006 till now are reviewed. The results ofexperimental and clinical application ofmonoclonal antibodies against epidermal growth factor receptor (EGFR) and its mutant variant EGFRvIII are analyzed, showing the most significant clinical effectiveness of nimotuzumab--a humanized monoclonal antibody. Significant part of the review is devoted to discussion of experimental and clinical data concerning efficacy of antibodies against VEGF receptor 2, platelet-derived growth factor receptor α, hepatocyte growth factor and its receptor c-Met. Unbiassed analysis of clinical trials on monoclonal antibodies does not allow us to conclude that passive immunotherapy directed against antigens listed above can significantly improve the overall survival of patients suffering from glioblastoma multiforme. This finding has encouraged us to mention several alternative approaches to passive immunotherapy and to list several prospective antigens for developing monoclonal antibodies.