DZIP3 is a key factor to stratify IDH1 wild-type lower-grade gliomas.

BACKGROUND: Malignant glioma is the most common form of primary malignant brain cancer. Heterogeneity is the hallmark of glioma. DAZ-interacting zinc finger 3 (DZIP3), acts as an RNA-binding RING-type ubiquitin ligase; however, its function in glioma is yet unclear. RESULTS: The DZIP3 expression was related to the World Health Organization (WHO) grade and isocitrate dehydrogenase 1(IDH1) status, as well as the clinical outcome. Malignant cases exhibit lower DZIP3 expression. DZIP3 was an independent predictive factor of good prognosis in all grade and lower grade gliomas (p < 0.0001). Gene enrichment analysis and immunohistochemistry indicated that DZIP3 affected the biological behavior of glioma through the angiogenesis pathway. Moreover, based on DZIP3 expression, IDH1 wild-type lower-grade gliomas could be divided into two groups with different survival time. CONCLUSION: In conclusion, the loss of DZIP3 may be involved in the mechanism of angiogenesis in the invasive biological process of glioma. These findings laid an understanding of DZIP3-specific clinical features in glioma. METHODS: A total of 325 glioma patients from the Chinese Glioma Genome Atlas (CGGA) RNA-seq cohort comprised the training cohort, while 265 patients from the GSE 16011 array cohort formed the validation cohort. The mRNA expression of DZIP3 and clinical characteristics was assessed. DZIP3 protein expression and microvessel density (MVD) were evaluated by immunohistochemistry (IHC).

Bevacizumab in treating the cystic components of pediatric low-grade gliomas: A report of four patients.

Low-grade gliomas (LGG) are among the most common types of brain tumors in children and young adults. These tumors often consist of solid and cystic components. Bevacizumab is a documented treatment for progressive LGG, yet the impact of therapy on the cystic component of these tumors is unknown. We present four patients with prominently cystic LGG treated with bevacizumab at the time of progression. In each case, the cystic component responded to treatment. This is the first known study to investigate bevacizumab's impact on the cystic component of low-grade gliomas.

Regorafenib in patients with recurrent high-grade astrocytoma.

PURPOSE: Antiangiogenic treatment approaches have failed to improve outcome in randomized trials of high-grade astrocytoma. One key mechanism of resistance to antiangiogenic treatment may concern the upregulation of alternative pro-angiogenic pathways. Regorafenib is a potent multikinase inhibitor that may alter some of those pathways. In this retrospective study, we investigated efficacy and radiographic tumor growth patterns of regorafenib in recurrent high-grade astrocytoma. METHODS: We screened for patients with high-grade astrocytoma in whom regorafenib was administered for at least 4 weeks. We assessed treatment efficacy in terms of progression-free survival (PFS), overall survival, and adverse events defined by Common Toxicity Criteria (CTC). In addition, radiographic tumor growth patterns were determined at baseline and recurrence. RESULTS: A total of 6 patients met eligibility criteria. The number of recurrences prior to regorafenib varied between 2 and 6. Patients were on regorafenib treatment for at least 4 weeks and maximally 14 weeks. Median PFS was 3.5 months and ranged from 2.0 to 4.0 months. Radiographic response was progressive disease in all patients with an objective response rate of 0%. CTC°3 adverse events were observed in all but one patient. The most common radiographic growth pattern was local with no change in growth pattern at recurrence. An infiltrative tumor growth was not induced in any patient. CONCLUSIONS: This retrospective study indicates a very poor performance of regorafenib in recurrent high-grade astrocytoma with a fairly high number of CTC°3 adverse events. In addition, regorafenib does not seem to bear a potential for infiltrative tumor growth promotion.

Microvascular characteristics of lower-grade diffuse gliomas: investigating vessel size imaging for differentiating grades and subtypes.

OBJECTIVES: Vessel size imaging (VSI) could reveal average microvessel diameter. The aim was to investigate microvascular characteristics and the efficacy of VSI in lower-grade glioma (LGG) grading and subtype differentiation based on 2016 classification of central nervous system tumours. METHODS: Fifty-seven LGG (grade II/III, 36/21) patients who received VSI examination before surgery were retrospectively analysed. The average (Rmean) and maximum (Rmax) vessel size indexes were obtained. The long (VDmax) and short (VDmin) vascular diameter, microvascular area (MVA) and density (MVD) were obtained using paraffin specimens. The patients were divided into grades II and III, and histological and molecular subtypes. The differences among microvascular parameters of different subtypes and grades were compared. Two-sample t-test, analysis of variance test, Mann-Whitney test, the Kruskal-Wallis test and Pearson correlation analysis were used for statistics. RESULTS: Rmean, Rmax, VDmin, VDmax, and MVA were higher in grade-III than in grade-II LGGs (p < 0.05) in each type except the isocitrate dehydrogenase (IDH) mutant with 1p/19q-intact type. For grade II, the IDH mutant with 1p/19q co-deleted and IDH wildtype possessed more dominant angiogenesis than IDH mutant with 1p/19q-intact type, revealed by lower Rmean, Rmax and VDmin while higher MVD for the former (p < 0.05), the same as oligodendroglioma versus astrocytoma. Rmean and Rmax correlated with VDmin (r = 0.804, 0.815, p < 0.05), VDmax (r = 0.766, 0.774, p < 0.05) and MVA (r = 0.755, 0.759, p < 0.05), respectively, while they had no correlation with MVD (r = -0.085, -0.080, p > 0.05). CONCLUSIONS: VSI holds great potential for non-invasively revealing microvascular characteristics of LGGs pre-surgery and differentiating their grades and molecular subtypes. KEY POINTS: • VSI can assist in differentiating grade-II and -III gliomas. • The IDH gene and 1p/19q chromosome may influence the angiogenesis in grade-II gliomas. • VSI is valuable for differentiating the molecular subtypes of grade-II gliomas.

Utility of arterial spin labelling MRI for discriminating atypical high-grade glioma from primary central nervous system lymphoma.

AIM: To evaluate the ability of arterial spin labelling (ASL) magnetic resonance imaging (MRI) in differentiating primary central nervous system lymphoma (PCNSL) from atypical high-grade glioma (HGG), as well as exploring the underlying pathological mechanisms. METHODS AND MATERIALS: Twenty-three patients with PCNSL and 17 patients with atypical HGG who underwent ASL-MRI were identified retrospectively. Absolute cerebral blood flow (aCBF) and normalised cerebral blood flow (nCBF) values were obtained, and were compared between PCNSL and atypical HGG using the Mann-Whitney U-test. The performance in discriminating between PCNSL and atypical HGG was evaluated using receiver-operating characteristics analysis and area-under-the-curve (AUC) values for aCBF and nCBF. The correlation between microvessel density (MVD) and aCBF was determined by Spearman's correlation analysis. RESULTS: Atypical HGG demonstrated significantly higher aCBF, nCBF, and MVD values than PCNSL (p<0.05). The diagnostic accuracy of discriminating PCNSL from atypical HGG showed AUC=0.877 (95% confidence interval [CI] 0.735-0.959) for aCBF, and AUC=0.836 (95% confidence interval [CI] 0.685-0.934) for nCBF. There was a moderate positive correlation between aCBF values of region of interest (ROI >30 mm2) in the enhanced area and MVD values (rho=0.579, p=0.0001), and a strong positive correlation between aCBF values MVD based on "point-to-point biopsy" (rho=0.83, p=0.0029). Interobserver agreements for aCBF and nCBF were excellent (ICC >0.75). CONCLUSIONS: ASL perfusion MRI is a useful imaging technique for the discrimination between atypical HGG and PCNSL, which may be determined by the difference of MVD between them.

Vessel Morphologies of the Brain in Cytological Squash Preparations Are Useful for Intraoperative Diagnosis of High-Grade Astrocytomas.

OBJECTIVE: The aim of this study was to determine whether intraoperative cytological evaluation of squash preparations is of benefit for differentiating high-grade from low-grade astrocytomas. METHODS: Squash preparations of 42 astrocytomas were classified histologically according to the World Health Organization (WHO) 2007 classification system as grade II (n = 12), grade III (n = 11), and grade IV (n = 19) and were divided into 2 groups, namely a low-grade group (grade II) and a high-grade group (grades III and IV). The focus was on morphological cell and vessel characteristics, namely nuclear atypia, chromatin pattern, nuclear enlargement, variation in nuclear size, the presence of nucleoli, mitosis, tumor necrosis, cell density, multibranched vessels, and vascular dilatation, and these characteristics were compared between the low- and high-grade groups. RESULTS: Nuclear atypia, the presence of coarse chromatin, variations in nuclear size, and cell density ≥200 per high-power field were significantly more prevalent in high- than in low-grade astrocytomas (p = 0.0407, p < 0.01, p < 0.01, and p < 0.01, respectively). Vessels with > 3 branches and a mean vessel diameter ≥20 µm were more prevalent in high- than in low-grade astrocytomas (p < 0.01). CONCLUSION: Squash preparation cytology provides added benefit for the intraoperative identification of high-grade astrocytoma.

Differentiation of grade II and III oligodendrogliomas from grade II and III astrocytomas: a histogram analysis of perfusion parameters derived from dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) MRI.

Background Since oligodendroglial tumors are sensitive to chemotherapy and have a better prognosis, the differentiation of oligodendroglial tumors (OT) from astrocytic tumors (AT) is important. Purpose To investigate the perfusion and permeability parameters that differentiate grade II and III OT from AT, using dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI). Material and Methods We retrospectively reviewed the DCE and DSC MRIs of 39 patients with OT (OTs, n = 19; grade II, n = 12 and grade III, n = 7) and AT (ATs, n = 20; grade II, n = 7 and grade III, n = 13). Glioblastomas were not included. Various histogram parameters of relative cerebral blood volume, volume transfer constant (Ktrans), flux rate constant (Kep), plasma volume fraction (Vp), and extravascular extracellular volume fraction (Ve) from DSC and DCE MRI, were compared between the two groups. Univariable and multivariable logistic regression were used to distinguish OT from AT. Receiver operating characteristic (ROC) curve analysis was performed. Results On the results of DCE MRI, most of the histogram parameters of Ktrans, Kep, and Ve showed tendencies toward higher values in OT than AT. Multivariable logistic regression revealed that the 50th Kep and 95th Ktrans were the most significant parameters predictive of OT, with an odds ratio of 3.7 and 2.5, respectively ( P = 0.004 and 0.03). The area under the curve from the ROC curve analysis for the 50th Kep and the 95th Ktrans were 0.81 and 0.80, respectively. Conclusion The DCE MRI-derived parameters of Ktrans and Kep could facilitate differentiation of OT from AT.

Diagnostic Performance of Arterial Spin Labeling for Grading Nonenhancing Astrocytic Tumors.

PURPOSE: We evaluated the utility of arterial spin labeling (ASL) imaging of tumor blood flow (TBF) for grading non-enhancing astrocytic tumors. MATERIALS AND METHODS: Thirteen non-enhancing astrocytomas were divided into high-grade (n = 7) and low-grade (n = 6) groups. Both ASL and conventional sequences were acquired using the same magnetic resonance machine. Intratumoral absolute maximum TBF (TBFmax), absolute mean TBF (TBFmean), and corresponding values normalized to cerebral blood flow (TBFmax and TBFmean ratios) were measured. The Mann-Whitney U test and receiver operating characteristic (ROC) curve analysis were used to assess the accuracy of TBF variables for tumor grading. RESULTS: Compared with low-grade astrocytoma, high-grade astrocytoma exhibited significantly greater absolute TBFmax (90.93 ± 24.96 vs 46.94 ± 20.97 ml/100 g/min, P < 0.001), TBFmean (58.75 ± 19.89 vs 31.16 ± 17.63 ml/100 g/min, P < 0.001), TBFmax ratio (3.34 ± 1.22 vs 1.35 ± 0.5, P < 0.001), and TBFmean ratio (2.15 ± 0.94 vs 0.88 ± 0.41, P < 0.001). The TBFmax ratio yielded the highest diagnostic accuracy (sensitivity 100%, specificity 86.3%), while absolute TBFmean yielded the lowest accuracy (sensitivity 85.7%, specificity 70.1%) by ROC analysis. CONCLUSION: Parameters from ASL perfusion imaging, particularly TBFmax ratio, may be useful for distinguishing high-grade from low-grade astrocytoma in cases with equivocal conventional MRI findings.

Radiation-Induced Large Vessel Cerebral Vasculopathy in Pediatric Patients With Brain Tumors Treated With Proton Radiation Therapy.

PURPOSE: The purpose of this research was to evaluate the incidence, time to development, imaging patterns, risk factors, and clinical significance of large vessel cerebral vasculopathy in pediatric patients with brain tumors treated with proton radiation therapy. METHODS AND MATERIALS: A retrospective study was performed on 75 consecutive pediatric patients with primary brain tumors treated with proton radiation therapy. Radiation-induced large vessel cerebral vasculopathy (RLVCV) was defined as intracranial large vessel arterial stenosis or occlusion confirmed on magnetic resonance angiography, computed tomographic angiography, catheter angiography, or a combination of these within an anatomic region with previous exposure to proton beam therapy and not present before radiation therapy. Clinical records were used to determine the incidence, timing, radiation dose to the large vessels, and clinical significance associated with the development of large vessel vasculopathy in these patients. RESULTS: RLVCV was present in 5 of 75 (6.7%) patients and included tumor pathologic features of craniopharyngioma (n=2), ATRT (n=1), medulloblastoma (n=1), and anaplastic astrocytoma (n=1). The median time from completion of radiation therapy to development was 1.5 years (mean, 3.0 years; range, 1.0-7.5 years). Neither mean age at the time of radiation therapy (5.1 years) nor mean radiation therapy dose to the large vessels (54.5 Gy) was a statistically significant risk factor. Four of the 5 patients with RLVCV presented with acute stroke and demonstrated magnetic resonance imaging evidence of acute infarcts in the expected vascular distributions. Angiography studies demonstrated collateral vessel formation in only 2 of the patients with RLVCV. No patients demonstrated acute hemorrhage or aneurysm. Two patients were treated with pial synangiomatosis surgery. CONCLUSIONS: RLVCV can occur in pediatric patients with brain tumors treated with proton radiation therapy. Further studies are necessary to determine potential risk factors for large vessel vasculopathy with proton radiation therapy in comparison with conventional photon radiation therapy.

Post-treatment changes of tumour perfusion parameters can help to predict survival in patients with high-grade astrocytoma.

OBJECTIVES: Vascular characteristics of tumour and peritumoral volumes of high-grade gliomas change with treatment. This work evaluates the variations of T2*-weighted perfusion parameters as overall survival (OS) predictors. METHODS: Forty-five patients with histologically confirmed high-grade astrocytoma (8 grade III and 37 grade IV) were included. All patients underwent pre- and post-treatment T2*-weighted contrast-enhanced magnetic resonance (MR) imaging. Tumour, peritumoral and control volumes were segmented. Relative variations of cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), Ktrans-T2*, kep-T2*, ve-T2* and vp-T2* were calculated. Differences regarding tumour grade and surgical resection extension were evaluated with ANOVA tests. For each parameter, two groups were defined by non-supervised clusterisation. Survival analysis were performed on these groups. RESULTS: For the tumour region, the 90th percentile increase or stagnation of CBV was associated with shorter survival, while a decrease related to longer survival (393 ± 189 vs 594 ± 294 days; log-rank p = 0.019; Cox hazard-ratio, 2.31; 95% confidence interval [CI], 1.12-4.74). Ktrans-T2* showed similar results (414 ± 177 vs 553 ± 312 days; log-rank p = 0.037; hazard-ratio, 2.19; 95% CI, 1.03-4.65). The peritumoral area values showed no relationship with OS. CONCLUSIONS: Post-treatment variations of the highest CBV and Ktrans-T2* values in the tumour volume are predictive factors of OS in patients with high-grade gliomas. KEY POINTS: • Vascular characteristics of high-grade glioma tumour and peritumoral regions change with treatment. • Quantitative assessment of MRI perfusion provides valuable information regarding tumour aggressiveness. • Quantitative T2*-weighted perfusion parameters can help to predict overall survival. • Post-treatment variations of CBV and K trans-T2 values are predictive factors of OS. • Increased values may justify treatment intensification in these patients.

Improving the Grading Accuracy of Astrocytic Neoplasms Noninvasively by Combining Timing Information with Cerebral Blood Flow: A Multi-TI Arterial Spin-Labeling MR Imaging Study.

BACKGROUND AND PURPOSE: Systematic and accurate glioma grading has clinical significance. We present the utility of multi-TI arterial spin-labeling imaging and provide the bolus arrival time maps for grading astrocytomas. MATERIALS AND METHODS: Forty-three patients with astrocytomas (21 men; mean age, 51 years) were recruited. The classification abilities of conventional MR imaging features, normalized CBF value derived from multi-TI arterial spin-labeling imaging, normalized bolus arrival time, and normalized CBF derived from single-TI arterial spin-labeling were compared in patients with World Health Organization (WHO) grade II, III, and IV astrocytomas. RESULTS: The normalized CBF value derived from multi-TI arterial spin-labeling imaging was higher in patients with higher grade astrocytoma malignancies compared with patients with lower grade astrocytomas, while the normalized bolus arrival time showed the opposite tendency. The normalized CBF value derived from the multi-TI arterial spin-labeling imaging showed excellent performance with areas under the receiver operating characteristic curve of 0.813 (WHO II versus III), 0.964 (WHO II versus IV), 0.872 (WHO III versus IV), and 0.883 (low-grade-versus-high-grade gliomas). The normalized CBF value derived from single-TI arterial spin-labeling imaging could statistically differentiate the WHO II and IV groups (area under the receiver operating characteristic curve = 0.826). The normalized bolus arrival time effectively identified the WHO grades II and III with an area under the receiver operating characteristic curve of 0.836. Combining the normalized CBF value derived from multi-TI arterial spin-labeling imaging and normalized bolus arrival time improved the diagnostic accuracy from 65.10% to 72.10% compared with the normalized CBF value derived from multi-TI arterial spin-labeling imaging being applied independently. The combination of multi-TI arterial spin-labeling imaging and conventional MR imaging had the best performance, with a diagnostic accuracy of 81.40%. CONCLUSIONS: Multi-TI arterial spin-labeling imaging can evaluate perfusion dynamics by combining normalized bolus arrival time and normalized CBF values derived from multiple TIs. It is superior to single-TI arterial spin-labeling imaging and conventional MR imaging features when applied independently and can improve the diagnostic accuracy when combined with conventional MR imaging for grading astrocytomas.

miR-21 Is Linked to Glioma Angiogenesis: A Co-Localization Study.

MicroRNA-21 (miR-21) is the most consistently over-expressed microRNA (miRNA) in malignant gliomas. We have previously reported that miR-21 is upregulated in glioma vessels and subsets of glioma cells. To better understand the role of miR-21 in glioma angiogenesis and to characterize miR-21-positive tumor cells, we systematically stained consecutive serial sections from ten astrocytomas for miR-21, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), phosphatase and tensin homolog (PTEN), octamer-binding transcription factor 4 (Oct4), sex-determining region Y box 2 (Sox2) and CD133. We developed an image analysis-based co-localization approach allowing global alignment and quantitation of the individual markers, and measured the miR-21 in situ hybridization signal against the immunohistochemical staining of the six different markers. miR-21 significantly co-localized with the hypoxia- and angiogenesis-associated markers HIF-1α (p=0.0020) and VEGF (p=0.0096), whereas the putative miR-21 target, PTEN, was expressed independently of miR-21. Expression of stem cell markers Oct4, Sox2 and CD133 was not associated with miR-21. In six glioblastoma cultures, miR-21 did not correlate with the six markers. These findings suggest that miR-21 is linked to glioma angiogenesis, that miR-21 is unlikely to regulate PTEN, and that miR-21-positive tumor cells do not possess stem cell characteristics.

High accuracy of arterial spin labeling perfusion imaging in differentiation of pilomyxoid from pilocytic astrocytoma.

INTRODUCTION: Pilomyxoid astrocytoma (PMA) is a relatively new tumor entity which has been added to the 2007 WHO Classification of tumors of the central nervous system. The goal of this study is to utilize arterial spin labeling (ASL) perfusion imaging to differentiate PMA from pilocytic astrocytoma (PA). METHODS: Pulsed ASL and conventional MRI sequences of patients with PMA and PA in the past 5 years were retrospectively evaluated. Patients with history of radiation or treatment with anti-angiogenic drugs were excluded. RESULTS: A total of 24 patients (9 PMA, 15 PA) were included. There were statistically significant differences between PMA and PA in mean tumor/gray matter (GM) cerebral blood flow (CBF) ratios (1.3 vs 0.4, p < 0.001) and maximum tumor/GM CBF ratio (2.3 vs 1, p < 0.001). Area under the receiver operating characteristic (ROC) curves for differentiation of PMA from PA was 0.91 using mean tumor CBF, 0.95 using mean tumor/GM CBF ratios, and 0.89 using maximum tumor/GM CBF. Using a threshold value of 0.91, the mean tumor/GM CBF ratio was able to diagnose PMA with 77 % sensitivity, 100 % specificity, and a threshold value of 0.7, provided 88 % sensitivity and 86 % specificity. There was no statistically significant difference between the two tumors in enhancement pattern (p = 0.33), internal architecture (p = 0.15), or apparent diffusion coefficient (ADC) values (p = 0.07). CONCLUSION: ASL imaging has high accuracy in differentiating PMA from PA. The result of this study may have important applications in prognostication and treatment planning especially in patients with less accessible tumors such as hypothalamic-chiasmatic gliomas.

La heterogeneidad del flujo sanguíneo en resonancia magnética, biomarcador para clasificar por grados los astrocitomas cerebrales / The heterogeneity of blood flow on magnetic resonance imaging: a biomarker for grading cerebral astrocytomas

Objetivos: Estudiar si los histogramas de los parámetros cuantitativos de perfusión por RM obtenidos a partir de los volúmenes tumoral y peritumoral permiten clasificar in vivo el grado de los astrocitomas. Material y métodos: Se incluyen 61 pacientes diagnosticados histológicamente de astrocitoma grado II, III o IV, estudiados mediante RM de perfusión T2* con contraste intravenoso, seleccionando manualmente los volúmenes tumoral y peritumoral, cuantificándose vóxel a vóxel diferentes parámetros de perfusión: volumen sanguíneo (VS), flujo sanguíneo (FS), tiempo de tránsito medio (TTM), constante de transferencia (Ktrans), coeficiente de lavado, volumen intersticial y volumen vascular. Para cada volumen se obtuvo el histograma correspondiente con su media, desviación típica y curtosis, estas últimas como medidas de heterogeneidad, comparándose las diferencias por parámetro y grado tumoral. También se calcularon la media y desviación del 10% de los valores máximos. Finalmente se realizó un análisis discriminante multiparamétrico para mejorar la clasificación. Resultados: En el volumen tumoral se obtuvieron diferencias estadísticamente significativas entre los 3 grados tumorales para la media y la desviación de VS, FS y Ktrans, tanto para la distribución completa, como para el 10% máximo. En la región peritumoral no se obtuvieron diferencias significativas para ningún parámetro. El análisis discriminante mejoró ligeramente la clasificación. Conclusiones: La cuantificación de parámetros del volumen total de la región tumoral con VS, FS y Ktrans es útil para establecer el grado de los astrocitomas. La heterogeneidad, representada por la desviación típica del FS, es el parámetro con mayor fiabilidad diagnóstica para separar los tumores de bajo y alto grado (AU)

Objectives: To study whether the histograms of quantitative parameters of perfusion in MRI obtained from tumor volume and peritumor volume make it possible to grade astrocytomas in vivo. Material and methods: We included 61 patients with histological diagnoses of grade II, III, or IV astrocytomas who underwent T2*-weighted perfusion MRI after intravenous contrast agent injection. We manually selected the tumor volume and peritumor volume and quantified the following perfusion parameters on a voxel-by-voxel basis: blood volume (BV), blood flow (BF), mean transit time (TTM), transfer constant (Ktrans), washout coefficient, interstitial volume, and vascular volume. For each volume, we obtained the corresponding histogram with its mean, standard deviation, and kurtosis (using the standard deviation and kurtosis as measures of heterogeneity) and we compared the differences in each parameter between different grades of tumor. We also calculated the mean and standard deviation of the highest 10% of values. Finally, we performed a multiparametric discriminant analysis to improve the classification. Results: For tumor volume, we found statistically significant differences among the three grades of tumor for the means and standard deviations of BV, BF, and Ktrans, both for the entire distribution and for the highest 10% of values. For the peritumor volume, we found no significant differences for any parameters. The discriminant analysis improved the classification slightly. Conclusions: The quantification of the volume parameters of the entire region of the tumor with BV, BF, and Ktrans is useful for grading astrocytomas. The heterogeneity represented by the standard deviation of BF is the most reliable diagnostic parameter for distinguishing between low grade and high grade lesions (AU)

[The heterogeneity of blood flow on magnetic resonance imaging: a biomarker for grading cerebral astrocytomas]. / La heterogeneidad del flujo sanguíneo en resonancia magnética, biomarcador para clasificar por grados los astrocitomas cerebrales.

OBJECTIVES: To study whether the histograms of quantitative parameters of perfusion in MRI obtained from tumor volume and peritumor volume make it possible to grade astrocytomas in vivo. MATERIAL AND METHODS: We included 61 patients with histological diagnoses of grade II, III, or IV astrocytomas who underwent T2*-weighted perfusion MRI after intravenous contrast agent injection. We manually selected the tumor volume and peritumor volume and quantified the following perfusion parameters on a voxel-by-voxel basis: blood volume (BV), blood flow (BF), mean transit time (TTM), transfer constant (K(trans)), washout coefficient, interstitial volume, and vascular volume. For each volume, we obtained the corresponding histogram with its mean, standard deviation, and kurtosis (using the standard deviation and kurtosis as measures of heterogeneity) and we compared the differences in each parameter between different grades of tumor. We also calculated the mean and standard deviation of the highest 10% of values. Finally, we performed a multiparametric discriminant analysis to improve the classification. RESULTS: For tumor volume, we found statistically significant differences among the three grades of tumor for the means and standard deviations of BV, BF, and K(trans), both for the entire distribution and for the highest 10% of values. For the peritumor volume, we found no significant differences for any parameters. The discriminant analysis improved the classification slightly. CONCLUSIONS: The quantification of the volume parameters of the entire region of the tumor with BV, BF, and K(trans) is useful for grading astrocytomas. The heterogeneity represented by the standard deviation of BF is the most reliable diagnostic parameter for distinguishing between low grade and high grade lesions.

Correlation between cerebral blood volume measurements by perfusion-weighted magnetic resonance imaging and two-year progression-free survival in gliomas.

Our goal was to determine whether relative cerebral blood volume (rCBV) can serve as an adjunct to histopathologic grading in the assessment of gliomas, with the hypothesis that rCBV can predict two-year survival. We evaluated 29 newly diagnosed gliomas (13 WHO grade II, seven grade III, nine grade IV; 17 astrocytomas, 12 oligodendroglial tumors). Dynamic susceptibility-weighted contrast-enhanced perfusion MR images and CBV maps were obtained. rCBVmax measurements (maximum tumor CBV/contralateral normal tissue CBV) and progression-free survival (PFS) were recorded. Receiver operating characteristic curves and Kaplan-Meier survival curves were calculated for rCBVmax and histologic grade. rCBVmax measurements differed between gliomas without (2.38 +/- 1.22) and with progression (5.57 +/- 2.84) over two years. The optimal rCBVmax cut-off value to predict progression was 2.95. rCBVmax < 2.95 was a significant predictor of two-year PFS, almost as accurate as WHO grade II. In the pure astrocytoma subgroup, the optimal rCBVmax cut-off value to predict progression was 2.85. In this group rCBVmax < 2.85 was a significant predictor of two-year PFS, an even better predictor of two-year PFS than WHO grade II. rCBVmax can be used to predict two-year PFS in patients with gliomas, independent of pathologic findings, especially in tumors without oligodendroglial components.

Tumor blood flow from arterial spin labeling perfusion MRI: a key parameter in distinguishing high-grade gliomas from primary cerebral lymphomas, and in predicting genetic biomarkers in high-grade gliomas.

PURPOSE: To evaluate the usefulness of pseudo-continuous arterial spin labeling (pCASL) imaging in differentiating high-grade gliomas from lymphomas and in noninvasively predicting genetic biomarkers in high-grade gliomas. MATERIALS AND METHODS: Twelve glioblastoma multiforme (GBM), 3 anaplastic astrocytoma (AA), 5 recurred GBM, and 9 lymphoma patients underwent conventional MR and pCASL imaging. On pCASL perfusion map, mean absolute tumor blood flow (mTBF) was calculated from five regions of interest (ROIs) within the enhancing portion of the tumor. Relative TBF (rTBF = mTBF/mBFgm × 100) was also calculated. mTBF and rTBF of high-grade gliomas and lymphomas were compared using unpaired Student's t-test and receiver operating characteristic (ROC) analysis. Additionally, the association of TBF and six immunohistochemically confirmed genetic biomarkers was analyzed by Pearson correlation analysis in the group of high-grade gliomas. RESULTS: Both mTBF and rTBF of the high-grade gliomas were significantly higher than those of the lymphomas: 92.1 ± 34.7 versus 53.6 ± 30.5 mL/min/100 mg (P = 0.008) and 182.3 ± 69.5 versus 92.5 ± 44.9 (P = 0.002), respectively. Only epidermal growth factor receptor (EGFR) expression status showed a significant positive correlation with mTBF(P = 0.015) and rTBF(P = 0.007). CONCLUSION: pCASL imaging may facilitate differentiation of high-grade gliomas from lymphomas and prediction of EGFR expression status in high-grade gliomas.

Correlation of aquaporin-1 water channel protein expression with tumor angiogenesis in human astrocytoma.

Aquaporin-1 (AQP1) is a water channel protein, widely expressed in epithelial and endothelial cells, known to be associated with invasion, angiogenesis, cell migration and formation of tumour oedema in several malignancies. We investigated the pattern of immunohistochemical expression of AQP1 in human astrocytomas and its role in tumour angiogenesis and infiltration. Immunohistochemical staining of AQP1 was performed in astrocytomas of grade II, III and IV. Intensity and pattern of expression were analysed. Non-neoplastic brain tissues served as control. There was a significant increase in the intensity of AQP1 expression from low-grade to high-grade astrocytomas (p<0.0001). Despite intense expression of AQP1 in astrocytoma grade IV, we observed strong regional differences. AQP1 up-regulation was predominantly located perivascularly, in areas of tumour infiltration, distant from the necrotic tumour core. AQP1 expression correlates with the grade of malignancy and is associated with angiogenesis, as well as with invasion of grade IV tumour in areas of tumour infiltration. Suppression of AQP1 expression could be a potential means of reducing invasion of glioma cells.

Phosphorylated 4E-binding protein 1 (p-4E-BP1): a novel prognostic marker in human astrocytomas.

AIMS: To investigate the significance of the mammalian target of rapamycin (mTOR) pathway in astrocytic tumours, published information in this context being limited, especially regarding phosphorylated 4E-binding protein (p-4E-BP) 1. METHODS AND RESULTS: Paraffin-embedded tissue from 111 patients with astroglial tumours (grades II-IV) was investigated for the association of phosphorylated mTOR (p-mTOR) signalling components with phosphorylated extracellular signal-related kinase 1/2 (p-ERK1/2) and phosphorylated AKT (p-AKT) expression, clinicopathological features, angiogenesis, isocitrate dehydrogenase 1 (IDH1)-R132H, and survival. Expression was also quantified by western blot analysis in 12 cases and in three primary glioma cell cultures following rapamycin treatment. p-mTOR expression correlated with p-4E-BP1 expression and marginally with p-p70S6K expression. p-4E-BP1 expression increased with tumour grade. Rapamycin induced a decline in phosphorylation levels of all three proteins. Nuclear p-AKT and cytoplasmic p-ERK1/2 immunoexpression correlated with p-4E-BP1 expression, whereas cytoplasmic p-AKT expression correlated with p-p70S6K expression. All three proteins were associated with increased angiogenesis but not with IDH1-R132H expression status. p-mTOR adversely affected overall and disease-free survival in univariate analysis. In multivariate survival analysis, the presence of p-4E-BP1 predicted shortened overall survival in the entire cohort and glioblastomas. CONCLUSIONS: mTOR signalling components are differentially involved in the acquisition of a more aggressive and angiogenic phenotype in astrocytic tumours. Moreover, p-4E-BP1 emerges as a novel prognostic marker, which might aid in the selection of patients who are more likely to benefit from therapy with mTOR inhibitors.