Applications of Radiomics and Radiogenomics in High-Grade Gliomas in the Era of Precision Medicine

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.

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Navigated versus Non-Navigated Intraoperative Ultrasound: Is There Any Impact on the Extent of Resection of High-Grade Gliomas? A Retrospective Clinical Analysis

Journal of Neurological Surgery Part A Central European Neurosurgery ◽

10.1055/s-0033-1356486 ◽

2014 ◽

Vol 75 (03) ◽

pp. 224-230 ◽

Cited By ~ 16

Author(s):

Anne-Katrin Hickmann ◽

Christine Henkel ◽

Minou Nadji-Ohl ◽

Nikolai Hopf ◽

Mirjam Renovanz

Keyword(s):

Intraoperative Ultrasound ◽

Extent Of Resection ◽

Clinical Analysis ◽

High Grade ◽

High Grade Gliomas

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The natural compound obtusaquinone targets pediatric high-grade gliomas through ROS-mediated ER stress

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa106 ◽

2020 ◽

Vol 2 (1) ◽

Cited By ~ 1

Author(s):

Jian Teng ◽

Ghazal Lashgari ◽

Elie I Tabet ◽

Bakhos A Tannous

Keyword(s):

Er Stress ◽

Cell Survival ◽

Natural Compound ◽

Therapeutic Option ◽

High Grade ◽

Intrinsic Resistance ◽

Clinical Prognosis ◽

Cancer Cell Survival ◽

High Grade Gliomas

Abstract Background Pediatric high-grade gliomas (pHGGs) are aggressive primary brain tumors with local invasive growth and poor clinical prognosis. Treatment of pHGGs is particularly challenging given the intrinsic resistance to chemotherapy, an absence of novel therapeutics, and the difficulty of drugs to reach the tumor beds. Accumulating evidence suggests that production of reactive oxygen species (ROS) and misfolded proteins, which typically leads to endoplasmic reticulum (ER) stress, is an essential mechanism in cancer cell survival. Methods Several cell viability assays were used in 6 patient-derived pHGG cultures to evaluate the effect of the natural compound obtusaquinone (OBT) on cytotoxicity. Orthotopic mouse models were used to determine OBT effects in vivo. Immunoblotting, immunostaining, flow cytometry, and biochemical assays were used to investigate the OBT mechanism of action. Results OBT significantly inhibited cell survival of patient-derived pHGG cells in culture. OBT inhibited tumor growth and extended survival in 2 different orthotopic xenograft models. Mechanistically, OBT induced ER stress through abnormal ROS accumulation. Conclusion Our data demonstrate the utility and feasibility of OBT as a potential therapeutic option for improving the clinical treatment of pHGGs.

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Targeting reduced mitochondrial DNA quantity as a therapeutic approach in pediatric high-grade gliomas

Neuro-Oncology ◽

10.1093/neuonc/noz140 ◽

2019 ◽

Vol 22 (1) ◽

pp. 139-151 ◽

Cited By ~ 10

Author(s):

Han Shen ◽

Man Yu ◽

Maria Tsoli ◽

Cecilia Chang ◽

Swapna Joshi ◽

...

Keyword(s):

Mitochondrial Dna ◽

Glucose Metabolism ◽

Mitochondrial Function ◽

Copy Number ◽

Pyruvate Dehydrogenase Kinase ◽

High Grade ◽

Mtdna Copy Number ◽

Mitochondrial Oxidation ◽

High Grade Gliomas

Abstract Background Despite increased understanding of the genetic events underlying pediatric high-grade gliomas (pHGGs), therapeutic progress is static, with poor understanding of nongenomic drivers. We therefore investigated the role of alterations in mitochondrial function and developed an effective combination therapy against pHGGs. Methods Mitochondrial DNA (mtDNA) copy number was measured in a cohort of 60 pHGGs. The implication of mtDNA alteration in pHGG tumorigenesis was studied and followed by an efficacy investigation using patient-derived cultures and orthotopic xenografts. Results Average mtDNA content was significantly lower in tumors versus normal brains. Decreasing mtDNA copy number in normal human astrocytes led to a markedly increased tumorigenicity in vivo. Depletion of mtDNA in pHGG cells promoted cell migration and invasion and therapeutic resistance. Shifting glucose metabolism from glycolysis to mitochondrial oxidation with the adenosine monophosphate–activated protein kinase activator AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) or the pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA) significantly inhibited pHGG viability. Using DCA to shift glucose metabolism to mitochondrial oxidation and then metformin to simultaneously target mitochondrial function disrupted energy homeostasis of tumor cells, increasing DNA damage and apoptosis. The triple combination with radiation therapy, DCA and metformin led to a more potent therapeutic effect in vitro and in vivo. Conclusions Our results suggest metabolic alterations as an onco-requisite factor of pHGG tumorigenesis. Targeting reduced mtDNA quantity represents a promising therapeutic strategy for pHGG.

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TH-E-ValB-06: Quantitative Characterization of Tumor Vascular Dysfunction in High-Grade Gliomas Prior to and During Radiotherapy

Medical Physics ◽

10.1118/1.2241947 ◽

2006 ◽

Vol 33 (6Part23) ◽

pp. 2290-2290

Author(s):

V Nagesh ◽

T Chenevert ◽

L Junck ◽

C Tsien ◽

T Lawrence ◽

...

Keyword(s):

Vascular Dysfunction ◽

High Grade ◽

Quantitative Characterization ◽

High Grade Gliomas

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Study of the biodistribution of fluorescein in glioma-infiltrated mouse brain and histopathological correlation of intraoperative findings in high-grade gliomas resected under fluorescein fluorescence guidance

Journal of Neurosurgery ◽

10.3171/2015.2.jns132507 ◽

2015 ◽

Vol 122 (6) ◽

pp. 1360-1369 ◽

Cited By ~ 77

Author(s):

Roberto Jose Diaz ◽

Roberto Rey Dios ◽

Eyas M. Hattab ◽

Kelly Burrell ◽

Patricia Rakopoulos ◽

...

Keyword(s):

Tumor Cell ◽

Low Dose ◽

Glioma Cells ◽

High Grade ◽

Fluorescein Sodium ◽

Tumor Margins ◽

Histopathological Correlation ◽

High Grade Gliomas

OBJECT Intravenous fluorescein sodium has been used during resection of high-grade gliomas to help the surgeon visualize tumor margins. Several studies have reported improved rates of gross-total resection (GTR) using high doses of fluorescein sodium under white light. The recent introduction of a fluorescein-specific camera that allows for high-quality intraoperative imaging and use of very low dose fluorescein has drawn new attention to this fluorophore. However, the ability of fluorescein to specifically stain glioma cells is not yet well understood. METHODS The authors designed an in vitro model to assess fluorescein uptake in normal human astrocytes and U251 malignant glioma cells. An in vivo experiment was also subsequently designed to study fluorescein uptake by intracranial U87 malignant glioma xenografts in male nonobese diabetic/severe combined immunodeficient mice. A genetically induced mouse glioma model was used to adjust for the possible confounding effect of an inflammatory response in the xenograft model. To assess the intraoperative application of this technology, the authors prospectively enrolled 12 patients who underwent fluorescein-guided resection of their high-grade gliomas using low-dose intravenous fluorescein and a microscope-integrated fluorescence module. Intraoperative fluorescent and nonfluorescent specimens at the tumor margins were randomly analyzed for histopathological correlation. RESULTS The in vitro and in vivo models suggest that fluorescein demarcation of glioma-invaded brain is the result of distribution of fluorescein into the extracellular space, most likely as a result of an abnormal blood-brain barrier. Glioblastoma tumor cell–specific uptake of fluorescein was not observed, and tumor cells appeared to mostly exclude fluorescein. For the 12 patients who underwent resection of their high-grade gliomas, the histopathological analysis of the resected specimens at the tumor margin confirmed the intraoperative fluorescent findings. Fluorescein fluorescence was highly specific (up to 90.9%) while its sensitivity was 82.2%. False negatives occurred due to lack of fluorescence in areas of diffuse, low-density cellular infiltration. Margins of contrast enhancement based on intraoperative MRI–guided StealthStation neuronavigation correlated well with fluorescent tumor margins. GTR of the contrast-enhancing area as guided by the fluorescent signal was achieved in 100% of cases based on postoperative MRI. CONCLUSIONS Fluorescein sodium does not appear to selectively accumulate in astrocytoma cells but in extracellular tumor cell-rich locations, suggesting that fluorescein is a marker for areas of compromised blood-brain barrier within high-grade astrocytoma. Fluorescein fluorescence appears to correlate intraoperatively with the areas of MR enhancement, thus representing a practical tool to help the surgeon achieve GTR of the enhancing tumor regions.

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Minimally Invasive Resection of Deep-seated High-grade Gliomas Using Tubular Retractors and Exoscopic Visualization

Journal of Neurological Surgery Part A Central European Neurosurgery ◽

10.1055/s-0038-1641738 ◽

2018 ◽

Vol 79 (04) ◽

pp. 330-336 ◽

Cited By ~ 16

Author(s):

Rajiv Iyer ◽

Kaisorn Chaichana

Keyword(s):

Minimally Invasive ◽

Hospital Stay ◽

Length Of Hospital Stay ◽

Extent Of Resection ◽

Karnofsky Performance Score ◽

High Grade ◽

Subcortical Structures ◽

Surgical Morbidity ◽

Tubular Retractor ◽

High Grade Gliomas

Background and Study Aims/Objective Deep-seated high-grade gliomas (HGGs) represent a unique surgical challenge because they reside deep to critical cortical and subcortical structures and infiltrate functional areas of the brain. Therefore, accessing and resecting these tumors can often be challenging and associated with significant morbidity. We describe the use of minimally invasive approaches to access deep-seated HGGs to achieve extensive resections while minimizing surgical morbidity. Materials and Methods All patients who underwent resection of a deep-seated intraparenchymal HGG with the use of a tubular retractor with exoscopic visualization from January 2016 to May 2017 were identified prospectively at a single institution. Variables evaluated included tumor location, pre- and postoperative neurologic function, extent of resection, and length of hospital stay. Results Overall, 14 patients underwent resection of an HGG (11 glioblastomas, 3 anaplastic astrocytomas) with a tubular retractor under exoscopic visualization. Seven tumors (50%) involved the thalamus, three (21%) the motor corticospinal tract, two (14%) the inferior frontal occipital fasciculus, one (7%) each the basal ganglia and optic pathway. The median preoperative Karnofsky Performance Score (KPS) was 70 (interquartile range: 55–80), where the major presenting symptom was motor weakness in seven (50%). The average plus or minus the standard error of the mean percentage resection was 97.0 ± 1.2%. The median hospital stay was 4 days (range: 2–7). At 1 month postoperatively, median postoperative KPS (within 30 days) was 87 (range: 77–90), where eight (57%) were improved, five (36%) were stable, and one (7%) was worse postoperatively. Conclusions Deep-seated HGGs can be accessed, visualized, and resected using tubular retractors and exoscopic visualization with minimal morbidity.

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