In theory, in vitro and in vivo models for human gliomas have great potential to not only enhance our understanding of glioma biology, but also to facilitate the development of novel treatment strategies for these tumors. For reliable prediction and validation of the effects of different therapeutic modalities, however, glioma models need to comply with specific and more strict demands than other models of cancer, and these demands are directly related to the combination of genetic aberrations and the specific brain micro-environment gliomas grow in. This review starts with a brief introduction on the pathological and molecular characteristics of gliomas, followed by an overview of the models that have been used in the last decades in glioma research. Next, we will discuss how these models may play a role in better understanding glioma development and especially in how they can aid in the design and optimization of novel therapies. The strengths and weaknesses of the different models will be discussed in light of genotypic, phenotypic and metabolic characteristics of human gliomas. The last part of this review provides some examples of how therapy experiments using glioma models can lead to deceptive results when such characteristics are not properly taken into account.

Cerebral blood flow (CBF) is regulated by vasomotor, chemical, metabolic, and neurogenic mechanisms. Even though the innervation of cerebral arteries is quite extensively described and reviewed in the literature, its role in regulation of CBF in humans remains controversial. We believe that insufficient attention has so far been focused on the potential role of the innervation of the cerebral vasculature in cerebral autoregulation in humans. We have performed an extensive search and selection of available literature on electrical, chemical, and surgical manipulations of the sympathetic innervation of cerebral arteries, and the effects of circulation sympathetically active agents on CBF. Studies on (surgical) ganglion block show a role of sympathetic tone in preventing increases in CBF in humans, which are consistent with the view based on animal studies. Both direct innervation of the cerebral arteries from cervical ganglia and stimulation of adrenergic receptors by circulating sympathomimetics prevent sudden increases of CBF associated with hypertension and hypercapnia. We postulate that under normal physiological conditions neurogenic control has little influence on cerebral autoregulation as other methods of control (vasomotor, chemical, and metabolic) are dominant. In severely challenging circumstances, such as delayed cerebral ischaemia after subarachnoid haemorrhage, these methods might be overwhelmed, increasing the relative importance of neurogenic, sympathetic control of CBF. This insight might lead to future therapeutic possibilities.

Background Myeloid-derived suppressor cells (MDSC) are a functional myeloid cell subset that includes myeloid cells with immune suppressive properties. The presence of MDSC has been reported in the peripheral blood of patients with several malignant and non-malignant diseases. So far, direct comparison of MDSC across different diseases and Centers is hindered by technical pitfalls and a lack of standardized methodology. To overcome this issue, we formed a network through the COST Action Mye-EUNITER (www.mye-euniter.eu) with the goal to standardize and facilitate the comparative analysis of human circulating MDSC in cancer, inflammation and infection. In this manuscript, we present the results of the multicenter study Mye-EUNITER MDSC Monitoring Initiative, that involved 13 laboratories and compared circulating MDSC subsets across multiple diseases, using a common protocol for the isolation, identification and characterization of these cells. Methods We developed, tested, executed and optimized a standard operating procedure for the isolation and immunophenotyping of MDSC using blood from healthy donors. We applied this procedure to the blood of almost 400 patients and controls with different solid tumors and non-malignant diseases. The latter included viral infections such as HIV and hepatitis B virus, but also psoriasis and cardiovascular disorders. Results We observed that the frequency of MDSC in healthy donors varied substantially between centers and was influenced by technical aspects such as the anticoagulant and separation method used. Expansion of polymorphonuclear (PMN)-MDSC exceeded the expansion of monocytic MDSC (M-MDSC) in five out of six solid tumors. PMN-MDSC expansion was more pronounced in cancer compared with infection and inflammation. Programmed death-ligand 1 was primarily expressed in M-MDSC and e-MDSC and was not upregulated as a consequence of disease. LOX-1 expression was confined to PMN-MDSC. Conclusions This study provides improved technical protocols and workflows for the multi-center analysis of circulating human MDSC subsets. Application of these workflows revealed a predominant expansion of PMN-MDSC in solid tumors that exceeds expansion in chronic infection and inflammation.

Gliomas are primary brain tumors that are associated with a poor prognosis. The introduction of new treatment modalities (including immunotherapy) for these neoplasms in the last 3 decades has resulted in only limited improvement in survival. Gliomas are known to create an immunosuppressive microenvironment that hampers the efficacy of (immuno)therapy. One component of this immunosuppressive environment is the myeloid-derived suppressor cell (MDSC). We set out to analyze the presence and activation state of MDSCs in blood (n = 41) and tumor (n = 20) of glioma patients by measuring S100A8/9 and arginase using flow cytometry and qPCR. Inhibition of T cell proliferation and cytokine production after stimulation with anti-CD3/anti-CD28 coated beads was used to measure in vitro MDSC suppression capacity. We report a trend toward a tumor grade-dependent increase of both monocytic (M-) and polymorphonuclear (PMN-) MDSC subpopulations in the blood of patients with glioma. M-MDSCs of glioma patients have increased levels of intracellular S100A8/9 compared with M-MDSCs in healthy controls (HCs). Glioma patients also have increased S100A8/9 serum levels, which correlates with increased arginase activity in serum. PMN-MDSCs in both blood and tumor tissue demonstrated high expression of arginase. Furthermore, we assessed blood-derived PMN-MDSC function and showed that these cells have potent T cell suppressive function in vitro. These data indicate a tumor grade-dependent increase of MDSCs in the blood of patients with a glioma. These MDSCs exhibit an increased activation state compared with MDSCs in HCs, independent of tumor grade.

Myeloid-derived suppressor cells (MDSCs), defined as CD33-positive major histocompatibility complex class II–negative cells, are increased in a varie

Patients with cancer need high-quality information about disease stage, treatment options, and side effects. High-quality information can also improve health literacy, shared decision making, and satisfaction. We created patient-specific three-dimensional (3D) models of tumors including surrounding functional areas and assessed what patients with glioma value (or fear) about the models when they are used to educate them about the relationship between their tumor and specific brain parts, the surgical procedure, and risks. This exploratory study included adult patients with glioma who underwent functional magnetic resonance imaging and diffusion tensor imaging as part of preoperative work-up. All participants received an actual-size 3D model printed based on functional magnetic resonance imaging and diffusion tensor imaging. Semistructured interviews were conducted to identify facilitators and barriers for using the model and perceived effects. Models were successfully created for all 11 participants. There were 18 facilitators and 8 barriers identified. The model improved patients' understanding about their situation; patients reported that it was easier to ask their neurosurgeon questions based on their model and that it supported their decision about preferred treatment. A perceived barrier for using the 3D model was that it could be emotionally confronting, particularly in an early phase of the disease. Positive effects were related to psychological domains, including coping, learning effects, and communication. Patient-specific 3D models are promising and simple tools that could help patients with glioma better understand their situation, treatment options, and risks. These models have the potential to improve shared decision making.