bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2021‒12‒12
eighteen papers selected by
Oltea Sampetrean
Keio University

  1. Cancers (Basel). 2021 Nov 25. pii: 5939. [Epub ahead of print]13(23):
      BACKGROUND: Previous data on glycogen synthase kinase 3 (GSK-3) inhibition in cancer models support a cytotoxic effect with selectivity for tumor cells compared to normal tissue but the effect of these inhibitors in glioma has not been widely studied. Here, we investigate their potential as cytotoxics in glioma.METHODS: We assessed the effect of pharmacologic GSK-3 inhibition on established (U87, U251) and patient-derived (GBM1, GBM4) glioblastoma (GBM) cell lines using cytotoxicity assays as well as undertaking a detailed investigation of the effect on cell cycle, mitosis, and centrosome biology. We also assessed drug uptake and efficacy of GSK-3 inhibition alone and in combination with radiation in xenograft models.
    RESULTS: Using the selective GSK-3 inhibitor AZD2858, we demonstrated single agent cytotoxicity in two patient-derived glioma cell lines (GBM1, GBM4) and two established cell lines (U251 and U87) with IC50 in the low micromolar range promoting centrosome disruption, failed mitosis, and S-phase arrest. Glioma xenografts exposed to AZD2858 also showed growth delay compared to untreated controls. Combined treatment with radiation increased the cytotoxic effect of clinical radiation doses in vitro and in orthotopic glioma xenografts.
    CONCLUSIONS: These data suggest that GSK-3 inhibition promotes cell death in glioma through disrupting centrosome function and promoting mitotic failure and that AZD2858 is an effective adjuvant to radiation at clinical doses.
    Keywords:  GSK-3; centrosome; cytotoxicity; glioblastoma; radiation
  2. Am J Cancer Res. 2021 ;11(11): 5543-5558
      Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. This cancer shows rapid, highly infiltrative growth, that invades individually or in small groups the surrounding tissue. The aggressive tumor biology of GBM has devastating consequences with a median survival of 15 months. GBM often has Epidermal Growth Factor Receptor (EGFR) abnormalities. Despite recent advances in the study of GBM tumor biology, it is unclear whether mutations in GBM are related to EGFR amplification and relevant phenotypes like tumor infiltration. This study aimed to perform whole-exome sequencing analysis in 30 human GBM samples for identifying mutational portraits associated with EGFR amplification and infiltrative patterns. Our results show that EGFR-amplified tumors have overall higher mutation rates than EGFR-no-amplified. Six genes out of 2029 candidate genes show mutations associated with EGFR amplification status. Mutations in these genes for GBM are novel, not previously reported in GBM, and with little presence in the TCGA database. GPR179, USP48, and BLK show mutation only in EGFR-amplified cases, and all the affected cases exhibit diffuse infiltrative patterns. On the other hand, mutations in ADGB, EHHADH, and PTPN13, were present only in the EGFR-no-amplified group with a more diverse infiltrative phenotype. Overall, our work identified different mutational portraits of GBM related to well-established features like EGFR amplification and tumor infiltration.
    Keywords:  EGFR amplification; FISH; Glioblastoma (GBM); infiltration patterns; somatic mutation; whole exome sequencing
  3. Adv Healthc Mater. 2021 Dec 08. e2101956
      Glioblastoma (GBM) is a stage IV astrocytoma that carries a dismal survival rate of ∼10 months post-diagnosis and treatment. The highly invasive capacity of GBM and its ability to to escape therapeutic challenges are key factors contributing to the poor overall survival rate. While current treatments aim to target the cancer cell itself, they fail to consider the significant role that the GBM tumor microenvironment (TME) plays in promoting tumor progression and therapeutic resistance. The GBM tumor glycocalyx and glycan-rich extracellular matrix (ECM), which are important constituents of the TME have received little attention as therapeutic targets. A wide array of aberrantly modified glycans in the GBM TME mediate tumor growth, invasion, therapeutic resistance, and immunosuppression. Here, we provide an overview of the landscape of aberrant glycan modifications in GBM, and discuss the design and utility of three-dimensional glycomaterials as a tool to evaluate glycan mediated GBM progression and therapeutic efficacy. The development of alternative strategies to target glycans in the TME can potentially unveil broader mechanisms of restricting tumor growth and enhancing the efficacy of tumor-targeting therapeutics. This article is protected by copyright. All rights reserved.
    Keywords:  Extracellular Matrix; Glioblastoma; Glycomaterials; Immunosuppression
  4. Int J Mol Sci. 2021 Nov 26. pii: 12810. [Epub ahead of print]22(23):
      Despite extensive preclinical research on immunotherapeutic approaches, malignant glioma remains a devastating disease of the central nervous system for which standard of care treatment is still confined to resection and radiochemotherapy. For peripheral solid tumors, immune checkpoint inhibition has shown substantial clinical benefit, while promising preclinical results have yet failed to translate into clinical efficacy for brain tumor patients. With the advent of high-throughput sequencing technologies, tumor antigens and corresponding T cell receptors (TCR) and antibodies have been identified, leading to the development of chimeric antigen receptors (CAR), which are comprised of an extracellular antibody part and an intracellular T cell receptor signaling part, to genetically engineer T cells for antigen recognition. Due to efficacy in other tumor entities, a plethora of CARs has been designed and tested for glioma, with promising signs of biological activity. In this review, we describe glioma antigens that have been targeted using CAR T cells preclinically and clinically, review their drawbacks and benefits, and illustrate how the emerging field of transgenic TCR therapy can be used as a potent alternative for cell therapy of glioma overcoming antigenic limitations.
    Keywords:  CAR; TCR; adoptive T cell transfer; brain tumor; glioblastoma; glioma
  5. Mol Oncol. 2021 Dec 07.
      Glioblastoma (GBM) is the most common type of glioma and is uniformly fatal. Currently, tumour heterogeneity and mutation acquisition are major impedances for tailoring personalized therapy. We collected blood and tumour tissue samples from 25 GBM patients, and 25 blood samples from healthy controls. Cell-free DNA (cfDNA) was extracted from the plasma of GBM patients and from healthy controls. Tumour DNA was extracted from fresh tumour samples. Extracted DNA was sequenced using a whole-genome sequencing procedure. We also collected 180 tumour DNA datasets from GBM patients publicly available at the TCGA/PANCANCER project. These data were analyzed for mutations and gene-gene fusions that could be potential druggable targets. We found that plasma cfDNA concentrations in GBM patients were significantly elevated (22.6±5 ng/mL), as compared to healthy controls (1.4±0.4 ng/mL) of the same average age. We identified unique mutations in the cfDNA and tumour DNA of each GBM patient, including some of the most frequently mutated genes in GBM according to the COSMIC database (TP53, 18.75%; EGFR, 37.5%; NF1, 12.5%; LRP1B, 25%; IRS4, 25%). Using our gene-gene fusion database, ChiTaRS 5.0, we identified gene-gene fusions in cfDNA and tumour DNA, such as KDR-PDGFRA and NCDN-PDGFRA, that correspond to previously reported alterations of PDGFRA in GBM (44% of all samples). Interestingly, the PDGFRA protein fusions can be targeted by tyrosine kinase inhibitors such as imatinib, sunitinib and sorafenib. Moreover, we identified BCR-ABL1 (in 8% of patients), COL1A1-PDGFB (8%), NIN-PDGFRB (8%) and FGFR1-BCR (4%) in cfDNA of patients, which can be targeted by analogues of imatinib. ROS1 fusions (CEP85L-ROS1 and GOPC-ROS1), identified in 8% of patient cfDNA, might be targeted by crizotinib, entrectinib or larotrectinib. Thus, our study suggests that integrated analysis of cfDNA plasma concentration, gene mutations and gene-gene fusions can serve as a diagnostic modality for distinguishing GBM patients who may benefit from targeted therapy. These results open new avenues for precision medicine in GBM, using non-invasive liquid biopsy diagnostics to assess personalized patient profiles. Moreover, repeated detection of druggable targets over the course of the disease may provide real-time information on the evolving molecular landscape of the tumour.
    Keywords:  Circulating cell-free DNA; druggable; gene mutation; gene-gene fusion; glioblastoma; liquid biopsy
  6. Trends Mol Med. 2021 Dec 02. pii: S1471-4914(21)00295-1. [Epub ahead of print]
      Tumor blood vessels create optimal conditions for glioblastoma (GBM) growth and therapy resistance. Therefore, tissue engineering techniques evolved towards allowing its inclusion in preclinical in vitro GBM models. In comparison with conventional ones, less representative of tumor biology, these new tools might significantly improve GBM treatment, contributing to a higher throughput screening in drug research and to the clinical translation of these therapies.
    Keywords:  glioblastoma; in vitro models; neovascularization; perivascular niche; tissue engineering
  7. Acta Neuropathol Commun. 2021 Dec 04. 9(1): 191
      Knowledge of 1p/19q-codeletion and IDH1/2 mutational status is necessary to interpret any investigational study of diffuse gliomas in the modern era. While DNA sequencing is the gold standard for determining IDH mutational status, genome-wide methylation arrays and gene expression profiling have been used for surrogate mutational determination. Previous studies by our group suggest that 1p/19q-codeletion and IDH mutational status can be predicted by genome-wide somatic copy number alteration (SCNA) data alone, however a rigorous model to accomplish this task has yet to be established. In this study, we used SCNA data from 786 adult diffuse gliomas in The Cancer Genome Atlas (TCGA) to develop a two-stage classification system that identifies 1p/19q-codeleted oligodendrogliomas and predicts the IDH mutational status of astrocytic tumors using a machine-learning model. Cross-validated results on TCGA SCNA data showed near perfect classification results. Furthermore, our astrocytic IDH mutation model validated well on four additional datasets (AUC = 0.97, AUC = 0.99, AUC = 0.95, AUC = 0.96) as did our 1p/19q-codeleted oligodendroglioma screen on the two datasets that contained oligodendrogliomas (MCC = 0.97, MCC = 0.97). We then retrained our system using data from these validation sets and applied our system to a cohort of REMBRANDT study subjects for whom SCNA data, but not IDH mutational status, is available. Overall, using genome-wide SCNAs, we successfully developed a system to robustly predict 1p/19q-codeletion and IDH mutational status in diffuse gliomas. This system can assign molecular subtype labels to tumor samples of retrospective diffuse glioma cohorts that lack 1p/19q-codeletion and IDH mutational status, such as the REMBRANDT study, recasting these datasets as validation cohorts for diffuse glioma research.
    Keywords:  Adult diffuse glioma; Astrocytoma; Copy number; GLASS; Glioblastoma; IDH; Isocitrate dehydrogenase; Oligodendroglioma; REMBRANDT; TCGA
  8. Neuro Oncol. 2021 Dec 02. pii: noab276. [Epub ahead of print]
      BACKGROUND: Diffusion MRI estimates of the apparent diffusion coefficient (ADC) have been shown to be useful in predicting treatment response in patients with glioblastoma (GBM), with ADC elevations indicating tumor cell death. We aimed to investigate whether the ADC values measured before and after treatment with immune checkpoint inhibitors (ICIs) and the changes in these ADC values could predict overall survival (OS) in patients with recurrent IDH wild-type GBM.METHODS: Forty-four patients who met the following inclusion criteria were included in this retrospective study: (i) diagnosed with recurrent IDH wild-type GBM and treated with either pembrolizumab or nivolumab and (ii) availability of diffusion data on pre- and post-ICI MRI. Tumor volume and the median relative ADC (rADC) with respect to the normal-appearing white matter within the enhancing tumor were calculated.
    RESULTS: Median OS among all patients was 8.1 months (range, 1.0-22.5 months). Log-rank test revealed that higher post-treatment rADC was associated with a significantly longer OS (median, 10.3 months for rADC ≧ 1.63 versus 6.1 months for rADC < 1.63; P = 0.02), whereas tumor volume, pre-treatment rADC, and changes in rADC after treatment were not significantly associated with OS. Cox regression analysis revealed that post-treatment rADC significantly influenced OS (P = 0.02, univariate analysis), even after controlling for age and sex (P =0.01, multivariate analysis), and additionally controlling for surgery after ICI treatment (P = 0.045, multivariate analysis).
    CONCLUSIONS: Elevated post-treatment rADC may be an early imaging biomarker for OS benefits in GBM patients receiving ICI treatment.
    Keywords:  ADC; ICI; IDH wild-type; MRI; recurrent glioblastoma
  9. Cancers (Basel). 2021 Nov 29. pii: 6001. [Epub ahead of print]13(23):
      Cancer stem-like cells mediate tumor initiation, progression, and therapy resistance; however, their identification and selective eradication remain challenging. Herein, we analyze the metabolic dependencies of glioblastoma stem-like cells (GSCs) with high-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy. We stratify our in vitro GSC models into two subtypes primarily based on their relative amount of glutamine in relationship to glutamate (Gln/Glu). Gln/GluHigh GSCs were found to be resistant to glutamine deprivation, whereas Gln/GluLow GSCs respond with significantly decreased in vitro clonogenicity and impaired cell growth. The starvation resistance appeared to be mediated by an increased expression of the glutamate/cystine antiporter SLC7A11/xCT and efficient cellular clearance of reactive oxygen species (ROS). Moreover, we were able to directly correlate xCT-dependent starvation resistance and high Gln/Glu ratios with in vitro clonogenicity, since targeted differentiation of GSCs with bone morphogenic protein 4 (BMP4) impaired xCT expression, decreased the Gln/Glu ratio, and restored the sensitivity to glutamine starvation. Moreover, significantly reduced levels of the oncometabolites lactate (Lac), phosphocholine (PC), total choline (tCho), myo-inositol (Myo-I), and glycine (Gly) were observed in differentiated GSCs. Furthermore, we found a strong association between high Gln/Glu ratios and increased expression of Zinc finger E-box-binding homeobox 1 (ZEB1) and xCT in primary GBM tumor tissues. Our analyses suggest that the inhibition of xCT represents a potential therapeutic target in glioblastoma; thus, we could further extend its importance in GSC biology and stress responses. We also propose that monitoring of the intracellular Gln/Glu ratio can be used to predict nutrient stress resistance.
    Keywords:  NMR spectroscopy; ZEB1; cancer stem cells; glioblastoma; glutamine; metabolism; oncometabolites; xCT
  10. Int J Mol Sci. 2021 Dec 06. pii: 13160. [Epub ahead of print]22(23):
      Glioblastoma multiforme (GBM) is the most common form of primary brain cancer and has the highest morbidity rate and current treatments result in a bleak 5-year survival rate of 5.6%. Interstitial therapy is one option to increase survival. Drug delivery by interstitial therapy most commonly makes use of a polymer implant encapsulating a drug which releases as the polymer degrades. Interstitial therapy has been extensively studied as a treatment option for GBM as it provides several advantages over systemic administration of chemotherapeutics. Primarily, it can be applied behind the blood-brain barrier, increasing the number of possible chemotherapeutic candidates that can be used and reducing systemic levels of the therapy while concentrating it near the cancer source. With interstitial therapy, multiple drugs can be released locally into the brain at the site of resection as the polymer of the implant degrades, and the release profile of these drugs can be tailored to optimize combination therapy or maintain synergistic ratios. This can bypass the blood-brain barrier, alleviate systemic toxicity, and resolve drug resistance in the tumor. However, tailoring drug release requires appropriate consideration of the complex relationship between the drug, polymer, and formulation method. Drug physicochemical properties can result in intermolecular bonding with the polymeric matrix and affect drug distribution in the implant depending on the formulation method used. This review is focused on current works that have applied interstitial therapy towards GBM, discusses polymer and formulation methods, and provides design considerations for future implantable biodegradable materials.
    Keywords:  chemotherapy; compression molding; drug delivery; electrospun fibers; glioma; hydrogel; local delivery; release rate; wafer
  11. Front Oncol. 2021 ;11 774017
      Background: Prostate specific membrane antigen (PSMA) PET imaging has recently gained attention in glioblastoma (GBM) patients as a potential theranostic target for PSMA radioligand therapy. However, PSMA PET has not yet been established in a murine GBM model. Our goal was to investigate the potential of PSMA PET imaging in the syngeneic GL261 GBM model and to give an outlook regarding the potential of PMSA radioligand therapy in this model.Methods: We performed an 18F-PSMA-1007 PET study in the orthotopic GL261 model (n=14 GBM, n=7 sham-operated mice) with imaging at day 4, 8, 11, 15, 18 and 22 post implantation. Time-activity-curves (TAC) were extracted from dynamic PET scans (0-120 min p. i.) in a subset of mice (n=4 GBM, n=3 sham-operated mice) to identify the optimal time frame for image analysis, and standardized-uptake-values (SUV) as well as tumor-to-background ratios (TBR) using contralateral normal brain as background were calculated in all mice. Additionally, computed tomography (CT), ex vivo and in vitro 18F-PSMA-1007 autoradiographies (ARG) were performed.
    Results: TAC analysis of GBM mice revealed a plateau of TBR values after 40 min p. i. Therefore, a 30 min time frame between 40-70 min p. i. was chosen for PET quantification. At day 15 and later, GBM mice showed a discernible PSMA PET signal on the inoculation site, with highest TBRmean in GBM mice at day 18 (7.3 ± 1.3 vs. 1.6 ± 0.3 in shams; p=0.024). Ex vivo ARG confirmed high tracer signal in GBM compared to healthy background (TBRmean 26.9 ± 10.5 vs. 1.6 ± 0.7 in shams at day 18/22 post implantation; p=0.002). However, absolute uptake values in the GL261 tumor remained low (e.g., SUVmean 0.21 ± 0.04 g/ml at day 18) resulting in low ratios compared to dose-relevant organs (e.g., mean tumor-to-kidney ratio 1.5E-2 ± 0.5E-2).
    Conclusions: Although 18F-PSMA-1007 PET imaging of GL261 tumor-bearing mice is feasible and resulted in high TBRs, absolute tumoral uptake values remained low and hint to limited applicability of the GL261 model for PSMA-directed therapy studies. Further investigations are warranted to identify suitable models for preclinical evaluation of PSMA-targeted theranostic approaches in GBM.
    Keywords:  18F-PSMA-1007 PET; GL261; Prostate specific membrane antigen (PSMA); glioblastoma; mouse; preclinical
  12. Neuro Oncol. 2021 Dec 08. pii: noab282. [Epub ahead of print]
      BACKGROUND: Targeted gene NGS testing is available through many academic institutions and commercial entities and is increasingly incorporated in practice guidelines for glioblastoma (GBM). This single-center retrospective study aimed to evaluate the clinical utility of incorporating NGS results in the management of GBM patients at a clinical trials-focused academic center.METHODS: We identified 1,011 consecutive adult patients with pathologically confirmed GBM (IDHwt or IDHmut) who had somatic tumor sequencing (Oncopanel, ~500 cancer gene panel) at DFCI from 2013-2019. Clinical records of all IDHwt GBM patients were reviewed to capture clinical trial enrollment and off-label targeted therapy use based on NGS results.
    RESULTS: Of the 557 IDHwt GBM patients with sequencing, 182 entered clinical trials at diagnosis (32.7%) and 213 (38.2%) entered after recurrence. Sequencing results for 130 patients (23.3%) were utilized for clinical trial enrollment for either targeted therapy indications (6.9 % upfront and 27.7% at recurrent clinical trials and 3.1% for off-label targeted therapy) or exploratory studies (55.4% upfront and 6.9% recurrent clinical trials). Median overall survival was 20.1 months with no survival difference seen between patients enrolled in clinical trials compared to those who were not, in a post hoc analysis.
    CONCLUSIONS: While NGS testing has become essential for improved molecular diagnostics, our study illustrates that targeted gene panels remain underutilized for selecting therapy in GBM-IDHwt. Targeted therapy and clinical trial design remain to be improved to help leverage the potential of NGS in clinical care.
    Keywords:  GBM; next generation sequencing; targeted therapy
  13. J Clin Invest. 2021 Dec 09. pii: e151239. [Epub ahead of print]
      BACKGROUND: Long-term prognosis of WHO grade II low-grade glioma (LGG) is poor secondary to risk of recurrence and malignant transformation into high-grade glioma. Given the relatively intact immune system of patients with LGG and the slow tumor growth rate, vaccines are an attractive treatment strategy.METHODS: We conducted a pilot study to evaluate the safety and immunological effects of vaccination with GBM6-AD, lysate of an allogeneic glioblastoma stem cell line, with poly-ICLC in patients with LGG. Patients were randomized to receive the vaccines before surgery (Arm 1) or not (Arm 2) and all patients received adjuvant vaccine. Co-primary outcomes were to evaluate the safety and immune response in the tumor.
    RESULTS: A total of 17 eligible patients were enrolled - nine into Arm 1 and eight into Arm 2. This regimen was well-tolerated with no regimen-limiting toxicity. Neoadjuvant vaccination induced upregulation of type-1 cytokines and chemokines, and increased activated CD8+ T-cells in peripheral blood. Single-cell RNA/TCR-sequencing detected CD8+ T-cell clones that expanded with effector phenotype and migrated into tumor microenvironment (TME) in response to neoadjuvant vaccination. Mass cytometric analyses detected increased tissue resident-like CD8+ T-cells with effector memory phenotype in TME following the neoadjuvant vaccination.
    CONCLUSION: The current regimen induces effector CD8+ T-cell response in peripheral blood and enables vaccine-reactive CD8+ T-cells to migrate into TME. Further refinements of the regimen may have to be integrated into future strategies.
    FUNDING: NIH (1R35NS105068, 1R21CA233856), Dabbiere Foundation, Parker Institute for Cancer Immunotherapy, and Daiichi Sankyo Foundation of Life Science.
    Keywords:  Brain cancer; Cancer immunotherapy; Oncology; T cells; Vaccines
  14. Cancers (Basel). 2021 Nov 25. pii: 5943. [Epub ahead of print]13(23):
      The high expression of MEOX2 transcription factor is closely associated with poor overall survival in glioma. MEOX2 has recently been described as an interesting prognostic biomarker, especially for lower grade glioma. MEOX2 has never been studied in glioma stem-like cells (GSC), responsible for glioma recurrence. The aim of our study was to investigate the role of MEOX2 in GSC. Loss of function approach using siRNA was used to assess the impact of MEOX2 on GSC viability and stemness phenotype. MEOX2 was localized in the nucleus and its expression was heterogeneous between GSCs. MEOX2 expression depends on the methylation state of its promoter and is strongly associated with IDH mutations. MEOX2 is involved in cell proliferation and viability regulation through ERK/MAPK and PI3K/AKT pathways. MEOX2 loss of function correlated with GSC differentiation and acquisition of neuronal lineage characteristics. Besides, inhibition of MEOX2 is correlated with increased expression of CDH10 and decreased pFAK. In this study, we unraveled, for the first time, MEOX2 contribution to cell viability and proliferation through AKT/ERK pathway and its potential involvement in phenotype and adhesion properties of GSC.
    Keywords:  CDH10; ERK; MEOX2; differentiation; glioma stem-like cells
  15. Nat Commun. 2021 Dec 08. 12(1): 7122
      To elucidate the mechanisms underlying the reduced incidence of brain tumors in children with Neurofibromatosis type 1 (NF1) and asthma, we leverage Nf1 optic pathway glioma (Nf1OPG) mice, human and mouse RNAseq data, and two different experimental asthma models. Following ovalbumin or house dust mite asthma induction at 4-6 weeks of age (WOA), Nf1OPG mouse optic nerve volumes and proliferation are decreased at 12 and 24 WOA, indicating no tumor development. This inhibition is accompanied by reduced expression of the microglia-produced optic glioma mitogen, Ccl5. Human and murine T cell transcriptome analyses reveal that inhibition of microglia Ccl5 production results from increased T cell expression of decorin, which blocks Ccl4-mediated microglia Ccl5 expression through reduced microglia NFκB signaling. Decorin or NFκB inhibitor treatment of Nf1OPG mice at 4-6 WOA inhibits tumor formation at 12 WOA, thus establishing a potential mechanistic etiology for the attenuated glioma incidence observed in children with asthma.
  16. J Vis Exp. 2021 Nov 17.
      Pediatric high-grade gliomas (pHGG) represent childhood and adolescent brain cancers that carry a rapid dismal prognosis. Since there is a need to overcome the resistance to current treatments and find a new way of cure, modeling the disease as close as possible in an in vitro setting to test new drugs and therapeutic procedures is highly demanding. Studying their fundamental pathobiological processes, including glutamatergic neuron hyperexcitability, will be a real advance in understanding interactions between the environmental brain and pHGG cells. Therefore, to recreate neurons/pHGG cell interactions, this work shows the development of a functional in vitro model co-culturing human-induced Pluripotent Stem (hiPS)-derived cortical glutamatergic neurons pHGG cells into compartmentalized microfluidic devices and a process to record their electrophysiological modifications. The first step was to differentiate and characterize human glutamatergic neurons. Secondly, the cells were cultured in microfluidic devices with pHGG derived cell lines. Brain microenvironment and neuronal activity were then included in this model to analyze the electrical impact of pHGG cells on these micro-environmental neurons. Electrophysiological recordings are coupled using multielectrode arrays (MEA) to these microfluidic devices to mimic physiological conditions and to record the electrical activity of the entire neural network. A significant increase in neuron excitability was underlined in the presence of tumor cells.
  17. Cancers (Basel). 2021 Nov 25. pii: 5921. [Epub ahead of print]13(23):
      Machine learning (ML) integrated with medical imaging has introduced new perspectives in precision diagnostics of high-grade gliomas, through radiomics and radiogenomics. This has raised hopes for characterizing noninvasive and in vivo biomarkers for prediction of patient survival, tumor recurrence, and genomics and therefore encouraging treatments tailored to individualized needs. Characterization of tumor infiltration based on pre-operative multi-parametric magnetic resonance imaging (MP-MRI) scans may allow prediction of the loci of future tumor recurrence and thereby aid in planning the course of treatment for the patients, such as optimizing the extent of resection and the dose and target area of radiation. Imaging signatures of tumor genomics can help in identifying the patients who benefit from certain targeted therapies. Specifying molecular properties of gliomas and prediction of their changes over time and with treatment would allow optimization of treatment. In this article, we provide neuro-oncology, neuropathology, and computational perspectives on the promise of radiomics and radiogenomics for allowing personalized treatments of patients with gliomas and discuss the challenges and limitations of these methods in multi-institutional clinical trials and suggestions to mitigate the issues and the future directions.
    Keywords:  GBM; imaging; radiogenomics; radiomics