Rationale and Objectives
The aim of this study was to investigate the effect of perfusion computed tomography (PCT) with acetazolamide (ACZ) challenge and compare it to 10% carbon dioxide (CO 2 ) challenge in rat C6 glioma.
Materials and Methods
PCT was performed on 32 rats, including 20 with orthotopically implanted C6 gliomas and 12 serving as controls. Ten rats with gliomas and six normal rats underwent PCT with ACZ challenge. The other 10 rats with gliomas and six normal rats underwent PCT with 10% CO 2 challenge. The raw data were processed using Philips computed tomographic brain perfusion software. Perfusion parameters before and after the challenge were recorded. Percentage changes due to ACZ administration and 10% CO 2 challenge were calculated. Pearson’s correlation coefficients were used to investigate relationships between percentage changes in perfusion parameters and vascular endothelial growth factor and microvessel density.
Results
In C6 gliomas, percentage change in cerebral blood flow was significantly different between ACZ (72.73%) and 10% CO 2 (28.47%) challenge ( P < .01). Percentage change in cerebral blood volume was 37.85% with ACZ and 24.69% with 10% CO 2 challenge ( P = .02). In controls, percentage change in cerebral blood flow was significantly different between ACZ (117.42%) and 10% CO 2 (65.86%) challenge ( P < .01). For percentage change in cerebral blood volume, there was no significant difference between ACZ (107.51%) and 10% CO 2 (92.95%) challenge. Significant correlations were observed among percentage changes in vascular endothelial growth factor, microvessel density, and cerebral blood volume ( P < .01). Percentage change in cerebral blood flow correlated well with vascular endothelial growth factor.
Conclusions
The results of this study indicate that PCT with ACZ challenge is a more reliable technique compared to 10% CO 2 challenge for the quantitative evaluation of microcirculation in gliomas.
Glioma is one of the most prevalent primary brain tumors in adults. The growth and metastasis of glioma require adequate vascularization . The intensity of angiogenesis is a determinant of tumor aggression. Highly vascularized gliomas are associated with a poor prognosis, because they consist of elevated expression levels of vascular endothelial growth factor (VEGF), which is an important mediator of angiogenesis . Assessment of angiogenesis is therefore a key element in diagnosis of glioma and is still an open field of research . Cerebrovascular reactivity is expressed as change in cerebral blood flow (CBF) from baseline under a vasodilatory stimuli and serves as a marker of cerebral microcirculation function . Normally, the challenge will result in a robust increase in CBF. If the CBF response is muted or absent, preexisting cerebral vasodilation or dysfunction of cerebral vessel is inferred . A mixture of 10% carbon dioxide (CO 2 ) and 90% air and acetazolamide (ACZ) are increasingly being used as vasodilators. ACZ is an inhibitor of the enzyme carbonic anhydrase that catalyzes the reversible reaction involving the hydration of CO 2 and the dehydration of carbonic acid . Although biopsy and histology remain the gold standard to characterize brain tumor microvascularity, there is a possibility of sampling errors. Additionally, the functionality of blood vessels cannot be estimated by histology. Hence, intense research is conducted to develop noninvasive imaging methods that can afford a comprehensive evaluation of glioma vascular supply.
Perfusion computed tomography (PCT) has become a promising tool for a quick and inexpensive evaluation of the cerebral circulation . Although positron emission tomography (PET) and magnetic resonance (MR) imaging are not available at smaller centers and hospitals, the advantage of PCT over positron emission tomographic and MR perfusion methods are that PCT is relatively simple and straightforward and provides quantitative measures of perfusion parameters, which are difficult to obtain using MR imaging or PET . Thus, in this study, PCT was used to investigate cerebral and C6 glioma perfusion changes induced by challenge with ACZ and with a mixture of 10% CO 2 and 90% air. Correlations were investigated between PCT with ACZ and VEGF and microvessel density (MVD).
Materials and methods
Research Subjects
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Animal Preparation
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Perfusion Computed Tomographic (CT) and Challenge Procedure
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Histologic Analysis
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Data Processing
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Statistical Analysis
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Results
Perfusion CT Parameters of Different Areas of Rat C6 Glioma
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Table 1
Perfusion Parameters in Controls, Tumor Central Parenchyma, and Periphery
Variable Controls Central Parenchyma Periphery ( n = 12) ( n = 20) ( n = 20) Cerebral blood flow (mL/100 g/min) 54.37 ± 11.40 89.33 ± 21.80 ∗ 109.68 ± 22.11 ∗,† Cerebral blood volume (mL/100 g) 8.68 ± 1.06 43.06 ± 10.75 ∗ 51.60 ± 10.20 ∗,† Mean transit time (s) 9.06 ± 1.89 14.02 ± 12.07 14.97 ± 12.15 Time to peak (s) 21.14 ± 1.82 20.68 ± 15.00 21.75 ± 15.67 Permeability (mL/100 g/min) 1.18 ± 0.18 15.68 ± 2.62 ∗ 17.88 ± 2.59 ∗,†
Data are expressed as mean ± standard deviation.
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Comparison of Percentage Changes in Perfusion CT Parameters with ACZ or 10% CO 2 Challenge in Controls
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Comparison between ACZ and 10% CO 2 Challenge in Rat C6 Glioma
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Table 2
Perfusion Data of Perfusion Computed Tomography Performed with ACZ and CO 2
Variable_n_ Cerebral Blood Flow (mL/100 g/min) Cerebral Blood Volume (mL/100 g) Controls before ACZ 6 56.01 ± 4.71 8.66 ± 0.76 Controls after ACZ 6 86.88 ± 11.08 ∗ 20.66 ± 9.58 ∗ Controls before 10% CO 2 6 52.74 ± 15.61 8.71 ± 1.32 Controls after 10% CO 2 6 62.26 ± 24.20 ∗ 14.82 ± 8.77 ∗ Gliomas before ACZ 10 80.56 ± 10.33 38.07 ± 11.50 Gliomas after ACZ 10 159.40 ± 10.32 ∗ 60.69 ± 15.05 ∗ Gliomas before 10% CO 2 10 52.74 ± 15.61 8.71 ± 1.33 Gliomas after 10% CO 2 10 125.15 ± 22.98 ∗ 51.04 ± 10.76 ∗
ACZ, acetazolamide; CO 2 , carbon dioxide.
Data are expressed as mean ± standard deviation.
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Correlation in C6 Tumor of Percentage Change Induced by ACZ and VEGF and MVD
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Table 3
Pearson’s Correlations in C6 Tumors of Percentage Change Induced by Acetazolamide and Microvessel Density and Vascular Endothelial Growth Factor
Variable_r_ (CBF Percentage Change)r (CBV Percentage Change) Microvessel density 0.458 0.931 ‡ Vascular endothelial growth factor 0.516 ∗ 0.724 †
CBF, cerebral blood flow; CBV, cerebral blood volume.
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Table 4
Microvessel Density and Vascular Endothelial Growth Factor in Controls and Tumor Central Parenchyma
Variable Controls Tumor Central Parenchyma_P_ ( n = 6) ( n = 10) Microvessel density 2.09 ± 0.35 6.48 ± 1.93 .02 Vascular endothelial growth factor 3.13 ± 1.04 8.04 ± 2.69 .01
Data are expressed as mean ± standard deviation.
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Discussion
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Conclusions
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Acknowledgments
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