Evaluation of Eight Plasma Proteins as Candidate Blood-Based Biomarkers for Malignant Gliomas

Lange, R.; Dulloor, Pratima; Korley, Frederick K.; Bettegowda, Chetan; Blair, Cheríe; Grossman, Stuart A.; Holdhoff, Matthias

doi:10.3109/07357907.2014.933237

Cited by 23 publications

(20 citation statements)

References 55 publications

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“…We found that NSE and NRGN were elevated, and MT3 decreased, in mTBI patients compared to controls. This is consistent with other data in the literature for all three markers ( 1 , 2 , 27 , 42 ). The decrease detected for MT3 may be related to the sequestering of this protein at the injury site in bound protein complexes, as reported in experimental models ( 32 ).…”

Section: Discussionsupporting

confidence: 93%

Derivation of a Three Biomarker Panel to Improve Diagnosis in Patients with Mild Traumatic Brain Injury

Peacock

Meter²,

Mirshahi³

et al. 2017

Front. Neurol.

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BackgroundNearly 5 million emergency department (ED) visits for head injury occur each year in the United States, of which <10% of patients show abnormal computed tomography (CT) findings. CT negative patients frequently suffer protracted somatic, behavioral, and neurocognitive dysfunction. Our goal was to evaluate biomarkers to identify mild TBI (mTBI) in patients with suspected head injury.MethodsAn observational ED study of head-injured and control patients was conducted at Johns Hopkins University (HeadSMART). Head CT was obtained (ACEP criteria) in patients with Glasgow Coma Scale scores of 13–15 and aged 18–80. Three candidate biomarker proteins, neurogranin (NRGN), neuron-specific enolase (NSE), and metallothionein 3 (MT3), were evaluated by immunoassay (samples <24 h from injury). American Congress of Rehabilitation Medicine (ACRM) criteria were used for diagnosis of mTBI patients for model building. Univariate analysis, logistic regression, and random forest (RF) algorithms were used for data analysis in R. Overall, 662 patients were studied. Statistical models were built using 328 healthy controls and 179 mTBI patients.ResultsMedian time from injury was 5.9 h (IQR, 4.0; range 0.8–24 h). mTBI patients had elevated NSE, but decreased MT3 versus controls (p < 0.01 for each). NRGN was also elevated but within 2–6 h after injury. In the derivation set, the best model to distinguish mTBI from healthy controls used three markers, age, and sex as covariates (C-statistic = 0.91, sensitivity 98%, specificity 72%). Panel test accuracy was validated with the 155 remaining ACRM+ mTBI patients. Applying the RF model to the ACRM+ mTBI validation set resulted in 78% correctly classified as mTBI (119/153). CT positive and CT negative validation subsets were 91% and 75% correctly classified. In samples taken <2 h from injury, 100% (10/10) samples classified correctly, indicating that hyperacute testing is possible with these biomarker assays. The model accuracy varied from 72–100% overall, and had greater accuracy with increasing severity, as shown by comparing CT+ with CT− (91% versus 75%), and Injury Severity Score ≥16 versus <16 (88% versus 72%, respectively). Objective blood tests, detecting NRGN, NSE, and MT3, can be used to identify mTBI, irrespective of neuroimaging findings.

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Section: Discussionsupporting

confidence: 93%

Derivation of a Three Biomarker Panel to Improve Diagnosis in Patients with Mild Traumatic Brain Injury

Peacock

Meter²,

Mirshahi³

et al. 2017

Front. Neurol.

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“…Similarly, GFAP positive exosome numbers are increased in grade III and IV astrocytoma compared to healthy controls (Galbo et al, ). Two of the 12 studies report on higher GFAP levels in plasma of grade IV patients, but no statistics were performed (Vietheer et al, ) or no statistical significance was reached (Lange et al, ). High GFAP levels in blood of grade IV astrocytoma patients is in contrast with the most often described lower GFAP levels in higher grade astrocytoma tissue (Tables ).…”

Section: Resultsmentioning

confidence: 99%

“…No Lange et al, 2014 Grade I (n = 3), Grade II (n = 5), Grade III (n = 3), Grade IV (n = 25), Brain metastasis (n = 24), Healthy individuals (n = 132) GFAP levels in serum determined by ELISA and immunohistochemistry of tumor tissue.…”

Section: Yesmentioning

confidence: 99%

Importance of GFAP isoform‐specific analyses in astrocytoma

Bodegraven

Asperen

Robe

et al. 2019

Glia

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Gliomas are a heterogenous group of malignant primary brain tumors that arise from glia cells or their progenitors and rely on accurate diagnosis for prognosis and treatment strategies. Although recent developments in the molecular biology of glioma have improved diagnosis, classical histological methods and biomarkers are still being used. The glial fibrillary acidic protein (GFAP) is a classical marker of astrocytoma, both in clinical and experimental settings. GFAP is used to determine glial differentiation, which is associated with a less malignant tumor. However, since GFAP is not only expressed by mature astrocytes but also by radial glia during development and neural stem cells in the adult brain, we hypothesized that GFAP expression in astrocytoma might not be a direct indication of glial differentiation and a less malignant phenotype. Therefore, we here review all existing literature from 1972 up to 2018 on GFAP expression in astrocytoma patient material to revisit GFAP as a marker of lower grade, more differentiated astrocytoma. We conclude that GFAP is heterogeneously expressed in astrocytoma, which most likely masks a consistent correlation of GFAP expression to astrocytoma malignancy grade. The GFAP positive cell population contains cells with differences in morphology, function, and differentiation state showing that GFAP is not merely a marker of less malignant and more differentiated astrocytoma. We suggest that discriminating between the GFAP isoforms GFAPδ and GFAPα will improve the accuracy of assessing the differentiation state of astrocytoma in clinical and experimental settings and will benefit glioma classification.

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“…Plasma GFAP may, together with plasma placental growth factor (PlGF), differentiate between radiologically suspected high-grade glioma and brain metastases [ 73 ]. Obviously, the fact that not only GFAP, but also other markers such as brain-derived neurotrophic factor (BDNF) and S100 calcium binding protein B (S100B), can be detected in the circulation of healthy controls negatively influences the specificity of such protein markers for detection of disease processes [ 91 ]. Finally, urine protein levels of 2-hydroxyglutarate (2-HG) may aid in distinguishing IDH1 mutant glioma patients from those with IDH1 wild-type glioma [ 98 ].…”

Section: Circulating Proteins (Cps)mentioning

confidence: 99%

Liquid biopsies in patients with diffuse glioma

et al. 2015

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Diffuse gliomas are the most common malignant primary tumors of the central nervous system. Like other neoplasms, these gliomas release molecular information into the circulation. Tumor-derived biomarkers include proteins, nucleic acids, and tumor-derived extracellular vesicles that accumulate in plasma, serum, blood platelets, urine and/or cerebrospinal fluid. Recently, also circulating tumor cells have been identified in the blood of glioma patients. Circulating molecules, vesicles, platelets, and cells may be useful as easily accessible diagnostic, prognostic and/or predictive biomarkers to guide patient management. Thereby, this approach may help to circumvent problems related to tumor heterogeneity and sampling error at the time of diagnosis. Also, liquid biopsies may allow for serial monitoring of treatment responses and of changes in the molecular characteristics of gliomas over time. In this review, we summarize the literature on blood-based biomarkers and their potential value for improving the management of patients with a diffuse glioma. Incorporation of the study of circulating molecular biomarkers in clinical trials is essential for further assessment of the potential of liquid biopsies in this context.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1399-y) contains supplementary material, which is available to authorized users.

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Evaluation of Eight Plasma Proteins as Candidate Blood-Based Biomarkers for Malignant Gliomas

Cited by 23 publications

References 55 publications

Derivation of a Three Biomarker Panel to Improve Diagnosis in Patients with Mild Traumatic Brain Injury

Derivation of a Three Biomarker Panel to Improve Diagnosis in Patients with Mild Traumatic Brain Injury

Importance of GFAP isoform‐specific analyses in astrocytoma

Liquid biopsies in patients with diffuse glioma

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