Grading Of Primary Brain Tumors Research Articles

Molecular imaging of gliomas.

Molecular characterization has become a key diagnostic tool for the classification and grading of primary brain tumors. Molecular markers, such as isocitrate dehydrogenase (IDH) mutation status, 1p/19q codeletion, methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter, or CDKN2A/B homozygous deletion discriminate different tumor entities and grades, and play a crucial role for treatment response and prognosis. In recent years, magnetic resonance imaging (MRI), whose main functions has been to detect a tumor, to provide spatial information for neurosurgical and radiotherapy planning, and to monitor treatment response, has shown potential in assessing molecular features of gliomas from image-based biomarkers. As an outstanding example, numerous studies have proven that the T2/FLAIR mismatch sign can identify IDH-mutant, 1p/19q non-codeleted astrocytomas with a specificity of up to 100%. For other purposes, multiparametric MRI, often coupled with machine learning methods, seems to achieve the highest accuracy in predicting molecular markers. Relevant future applications might be anticipating changes in the molecular composition of gliomas and providing useful information about the cellular and genetic heterogeneity of gliomas, especially in the non-resected tumor parts.

Correlation between hypoxic area in primary brain tumors and WHO grade: differentiation from malignancy using 18F-fluoromisonidazole positron emission tomography.

Background 18F-fluoromisonidazole positron emission tomography (FMISO-PET) has been used for identification of hypoxic areas in tumors, and since hypoxia causes hypoxia-inducible factor-1 and enhancement of tumor growth, identifying the hypoxic area in the tumor tissue is important. Purpose To evaluate the usefulness of FMISO-PET in the grading of primary brain tumors. Material and Methods FMISO-PET was performed preoperatively on 41 consecutive patients with pathologically confirmed brain tumor. A neuroradiologist retrospectively measured both maximum standardized uptake value (SUVmax) and mean SUV (SUVmean) in the tumor and normal cerebellar parenchyma. Maximum tumor/normal control ratio (T/Nmax) and mean tumor/normal control ratio (T/Nmean) were calculated and analyzed. Results There was a positive correlation between World Health Organization (WHO) grade and both T/Nmax and T/Nmean (r = 0.731 and 0.713, respectively). When all cases were divided into benign (WHO grade II) and malignant groups (III and IV), there were significant differences between the two groups in both T/Nmax and T/Nmean ( P < 0.001). If the cutoff value was defined as T/Nmax = 1.25 and T/Nmean = 1.23, T/Nmax had a sensitivity of 90.0% and a specificity of 90.9% while T/Nmean had a sensitivity of 93.3% and a specificity of 90.9% in differentiating the benign group from the malignant group. Conclusion Both T/Nmax and T/Nmean in FMISO-PET have a positive correlation with primary brain tumor grading, making FMISO-PET useful in diagnosing the malignancy of primary brain tumors.

Role of magnetic resonance spectroscopy in grading of primary brain tumors

ObjectiveTo assess the usefulness of MR spectroscopy (MRS) in grading of primary brain tumors. MethodsMRS was performed in 22 patients with primary brain tumors. Metabolite ratios of Choline (Cho)/N-acetylaspartate (NAA), Cho/Creatine (Cr), Cho+Cr/NAA as well as lipids and lactate (LL)/Cr were calculated at short and intermediate echo times (TEs). Additionally, myo-inositol (mI)/Cr was calculated at short TE. Tumors were subdivided into low grades and high grade on the basis of histopathology. Receiver operating characteristic analysis of metabolite ratios was performed to find cutoff values between high and low grade tumors. The resulting sensitivity, specificity and accuracy were calculated. ResultsAt intermediate TE, Cho/NAA, Cho+Cr/NAA and Cho/Cr were significantly higher in high grade tumors than in low grade tumor. At short TE, Cho/Cr and LL/Cr ratios were significantly higher in high grade tumors than in low grade tumor. The diagnostic accuracy of metabolite ratios at intermediate TE was 86% whereas at short TE, the diagnostic accuracy was 75%. Combination of both TEs revealed a diagnostic accuracy of 88%. ConclusionCho/NAA, Cho+Cr/NAA and Cho/Cr are reliable in determining the tumor grade. LL/Cr is highly related to high grade tumors. Combination of both short and intermediate TEs provides better accuracy, in grading of brain neoplasm, compared to that when using each TE separately.

Factors affecting 18 F FDOPA standardized uptake value in patients with primary brain tumors after treatment

AimTo investigate the factors affecting 18F FDOPA uptake in patients with primary brain tumors (PBT) after treatment. Materials and methods97 patients with PBT (6 were grade I, 40 were grade II, 29 were grade III and 22 were grade IV) underwent 18F FDOPA positron emission tomography/computed tomography (PET/CT) after treatment. Intervals from surgery, chemotherapy (CHT) and radiotherapy (RT) were 41.48 (±42.27), 16.04 (±29.08) and 28.62 (±34.49) months respectively. Results18F FDOPA uptake in the site of recurrence was not related to the interval from surgery and CHT while a significant relationship has been found with the interval from RT and tumor grade. ConclusionsThe results of our study show that the interval from RT and the grade of PBT should be considered carefully when evaluating brain PET/CT scans since these factors could directly affect 18F FDOPA uptake.

MTSS1 suppresses cell migration and invasion by targeting CTTN in glioblastoma.

Glioblastomas (GBMs) are the highest grade of primary brain tumors with astrocytic similarity and are characterized dispersal of tumor cell. Metastasis suppressor 1 (MTSS1) play an important role in cancer metastasis. Recent studies indicating that MTSS1 as a potential tumor suppressor and its reduced expression associated with poor prognosis in many cancer types. However, the relationship with the prognosis of patients and the molecular mechanism of MTSS1 renders a tumor suppressor effect in GBM is unknown. Here, we showed that low MTSS1 gene expression is associated with poor outcomes in patients with GBM. Overexpression of MTSS1 in U-87 MG cells exhibited inhibited glioma cell growth, colony formation, migration and invasion. Mechanistically, we found that high MTSS1 expression in U-87 MG reduced expression of CTTN. These results implicate that the role of MTSS1 suppresses cell migration and invasion by inhibiting expression of CTTN and as a prognosis biomarker in GBM.

Primary brain tumors: Proton magnetic resonance spectroscopic analysis and histopathological correlation

Objective: Recent advances in treatment of primary brain tumors have increased the interest in radiological imaging in respect to both the diagnosis of tumor and the evaluation of the efficiency of therapy. Conventional Magnetic Resonance (MR) imaging is commonly used for diagnosis and follows up of the primary brain tumors, but it fails in grading of the tumors. MR spectroscopy permits in-vivo biochemical evaluation of brain lesions. Methods: Twenty three patients with histopathologic diagnosis of primary brain tumor and control group consisting of 23 healthy volunteers were investigated. In addition to conventional MR imaging of all patients were underwent point resolved spectroscopy (PRESS) sequence via single voxel MR spectroscopy. Using MR spectroscopy, metabolites [N-acetyl aspartate (NAA), choline (Cho), myo-inositol (mI), lipid, lactate and alanine] and their ratio to creatine (Cr) were measured quantitatively. Results: MR spectroscopic imaging of neuroglial primary brain tumors revealed that the NAA/Cr and mI/Cr ratios were decreased. In extra axial primary brain tumors, which consist of meningioma, NAA wasn’t detected, Cho/Cr ratio was remarkably increased, mI/Cr, lipid/Cr and lactate/Cr ratios were mildly increased. Alanine peak was detected only in meningioma. In high grade neuroglial tumors in proportion to low grade ones NAA/Cr and mI/Cr ratios were decreased, Cho/Cr, lipid/Cr and lactate/Cr ratios were remarkably increased. Conclusion: MR spectroscopy provides extra information in classification of primary brain tumors as intra-axial and extra-axial, and in grading of neuroglial primary brain tumors as high grade or low grade. It was concluded that using conventional MR imaging in cooperation with MR spectroscopy is beneficial in differential diagnosis and in grading of primary brain tumors.

Regulation of Actin Filament Turnover in Brain Tumor Cell Motility

Cell migration and invasion is driven by turnover of the actin cytoskeleton, a process initiated by cofilin activation. Active cofilin concentrations correlate with the grade of primary brain tumors, tumor cell migration and brain invasion (Nagai S, Moreno O, Smith CA, Ivanchuk S, Romagnuolo R, Golbourn B, Weeks A, Seol HJ, and Rutka JT. 2011, Genes Cancer. Sep;2(9):859-69). To investigate how cell migration and invasion is enhanced in high grade brain tumors by cofilin we have developed a physical model based on the molecular mechanisms for actin turnover already known to be enhanced by cofilin. The model is then used to fit actin distributions in eGFP-actin transfected U251 brain tumor cells using model convolution microscopy. The best fits of the model yield estimates for the kinetic parameters for actin turnover in high grade brain tumor cells. These parameters are similar to isolated in vitro measurements made in the presence of cofilin and suggest that actin turnover is stimulated throughout the cell by cofilin. Further analysis of the model is used to elucidate potential mechanisms to regulate brain tumor cell motility.

Assessment of blood-brain barrier disruption using dynamic contrast-enhanced MRI. A systematic review.

There is increasing recognition of the importance of blood–brain barrier (BBB) disruption in aging, dementia, stroke and multiple sclerosis in addition to more commonly-studied pathologies such as tumors. Dynamic contrast-enhanced MRI (DCE-MRI) is a method for studying BBB disruption in vivo. We review pathologies studied, scanning protocols and data analysis procedures to determine the range of available methods and their suitability to different pathologies. We systematically review the existing literature up to February 2014, seeking studies that assessed BBB integrity using T1-weighted DCE-MRI techniques in animals and humans in normal or abnormal brain tissues. The literature search provided 70 studies that were eligible for inclusion, involving 417 animals and 1564 human subjects in total. The pathologies most studied are intracranial neoplasms and acute ischemic strokes. There are large variations in the type of DCE-MRI sequence, the imaging protocols and the contrast agents used. Moreover, studies use a variety of different methods for data analysis, mainly based on model-free measurements and on the Patlak and Tofts models. Consequently, estimated KTrans values varied widely. In conclusion, DCE-MRI is shown to provide valuable information in a large variety of applications, ranging from common applications, such as grading of primary brain tumors, to more recent applications, such as assessment of subtle BBB dysfunction in Alzheimer's disease. Further research is required in order to establish consensus-based recommendations for data acquisition and analysis and, hence, improve inter-study comparability and promote wider use of DCE-MRI.

PTPμ suppresses glioma cell migration and dispersal

The cell-surface receptor protein tyrosine phosphatase mu (PTPmu) is a homophilic cell adhesion molecule expressed in CNS neurons and glia. Glioblastomas (GBMs) are the highest grade of primary brain tumors with astrocytic similarity and are characterized by marked dispersal of tumor cells. PTPmu expression was examined in human GBM, low-grade astrocytoma, and normal brain tissue. These studies revealed a striking loss of PTPmu protein expression in highly dispersive GBMs compared to less dispersive low-grade astrocytomas and normal brain. We hypothesized that PTPmu contributes to contact inhibition of glial cell migration by transducing signals in response to cell adhesion. Therefore, loss of PTPmu may contribute to the extensive dispersal of GBMs. The migration of brain tumor cells was assessed in vitro using a scratch wound assay. Parental U-87 MG cells express PTPmu and exhibited limited migration. However, short-hairpin RNA (shRNA)-mediated knockdown of PTPmu induced a morphological change and increased migration. Next, a brain slice assay replicating the three-dimensional environment of the brain was used. To assess migration, labeled U-87 MG glioma cells were injected into adult rat brain slices, and their movement was followed over time. Parental U-87 MG cells demonstrated limited dispersal in this assay. However, PTPmu shRNA induced migration and dispersal of U-87 MG cells in the brain slice. Finally, in a mouse xenograft model of intracranially injected U-87 MG cells, PTPmu shRNA induced morphological heterogeneity in these xenografts. Together, these data suggest that loss of PTPmu in human GBMs contributes to tumor cell migration and dispersal, implicating loss of PTPmu in glioma progression.

Cerebral Blood Volume Measurements by Perfusion-Weighted MR Imaging in Gliomas: Ready for Prime Time in Predicting Short-Term Outcome and Recurrent Disease?

Current classification and grading of primary brain tumors has significant limitations. Our aim was to determine whether the relative cerebral volume (rCBV) measurements in gliomas may serve as an adjunct to histopathologic grading, with a hypothesis that rCBV values are more accurate in predicting 1-year survival and recurrence. Thirty-four patients with gliomas (WHO grade I-IV, 27 astrocytomas, 7 tumors with oligodendroglial components) underwent contrast-enhanced MR rCBV measurements before treatment. The region of interest and the single pixel with the maximum CBV value within the tumors were normalized relative to the contralateral normal tissue (rCBV(mean) and rCBV(max), respectively). Karnofsky performance score and progression-free survival (PFS) were recorded. Receiver operating characteristic curves and Kaplan-Meier survival analysis were conducted for CBV and histologic grade (WHO grade). Significant correlations were detected only when patients with oligodendrogliomas and oligoastrocytomas were excluded. The rCBV(mean) and rCBV(max) in the astrocytomas were 3.5 +/- 2.9 and 3.7 +/- 2.7. PFS correlated with rCBV parameters (r = -0.54 to -0.56, P < or = .009). WHO grade correlated with rCBV values (r = 0.65, P < or = .0002). rCBV(max) > 4.2 was found to be a significant cutoff value for recurrence prediction with 77.8% sensitivity and 94.4% specificity (P = .0001). rCBV(max) < or = 3.8 was a significant predictor for 1-year survival (93.7% sensitivity, 72.7% specificity, P = .0002). The relative risk for shorter PFS was 11.1 times higher for rCBV(max) > 4.2 (P = .0006) and 6.7 times higher for WHO grade > II (P = .05). The combined CBV-WHO grade classification enhanced the predictive value for recurrence/progression (P < .0001). rCBV values in astrocytomas but not tumors with oligodendroglial components are predictive for recurrence and 1-year survival and may be more accurate than histopathologic grading.

Usefulness of preoperative grading of primary brain tumors using F-18 FDG and C-11 methionine PET

Objectives: On the determination of treatment for preoperative primary brain tumors, it is very important for the neurosurgeons to predict the grade of malignancy or the extent of the tumors. The aim of this study is to evaluate the usefulness of FDG PET and MET PET when considering the plan of operation for the primary brain tumors. Methods: We examined 12 patients with preoperative brain tumors who underwent FDG PET and MET PET. Moreover, we estimated the correlations between WHO grading and the tumor/normal brain uptake ratios (T/N ratio). Results: The T/N ratios of FDG in GIV were significantly higher than that in GII ( p<0.01) or GIII ( p<0.01), but there was not a significant difference in the T/N ratio between GII and GIII ( p=0.11). There was not a significant correlation between WHO grading and T/N ratio of MET. F/M ratio in GII was significantly lower than that in GIII ( p<0.05) or GIV ( p<0.05). Discussion: In a plan to treat glioma, it is very important to suppose its histology. In this study, FDG was useful for differentiating between glioblastoma (GIV) and other graded brain tumors (excluding malignant lymphoma). In regard to the use of MET PET, the tumors can be detected and differentiated with high sensitivity and good contrast. On the occasion of planning the operation, it may be helpful to comprehend the malignancy and the location of the tumors. Conclusions: FDG PET was useful for grading the primary brain tumor, especially differentiating between glioblastoma and the other brain tumors. MET PET was not useful for evaluating the grade but was sensitive to detect the location. A combination of FDG PET with MET PET is very useful as an auxiliary examination when neurosurgeons are deciding on the treatment strategy.