This study demonstrates that a dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) perfusion parameter may indicate vascular abnormality in a brain tumor model and reflects an effect of dexamethasone treatment. In addition, X-ray computed tomography (CT) measurements of vascular tortuosity and tissue markers of vascular morphology were performed to investigate the underpinnings of tumor response to dexamethasone.
One cohort of Fisher 344 rats (N = 13), inoculated intracerebrally with 9L gliosarcoma cells, was treated with dexamethasone (i.p. 3 mg/kg/day) for five consecutive days, and another cohort (N = 11) was treated with equal volume of saline. Longitudinal DSC-MRI studies were performed at the first (baseline), third and fifth day of treatments. Relative cerebral blood volume (rCBV) was significantly reduced on the third day of dexamethasone treatment (0.65±.13) as compared to the fifth day during treatment (1.26±.19, p<0.05). In saline treated rats, relative CBV gradually increased during treatment (0.89±.13, 1.00±.21, 1.13±.23) with no significant difference on the third day of treatment (p>0.05). In separate serial studies, microfocal X-ray CT of ex vivo brain specimens (N = 9) and immunohistochemistry for endothelial cell marker anti-CD31 (N = 8) were performed. Vascular morphology of ex vivo rat brains from micro-CT analysis showed hypervascular characteristics in tumors, and both vessel density (41.32±2.34 branches/mm3, p<0.001) and vessel tortuosity (p<0.05) were significantly reduced in tumors of rats treated with dexamethasone compared to saline (74.29±3.51 branches/mm3). The vascular architecture of rat brain tissue was examined with anti-CD31 antibody, and dexamethasone treated tumor regions showed reduced vessel area (16.45±1.36 µm2) as compared to saline treated tumor regions (30.83±4.31 µm2, p<0.001) and non-tumor regions (22.80±1.11 µm2, p<0.01).
Increased vascular density and tortuosity are culprit to abnormal perfusion, which is transiently reduced during dexamethasone treatment.
We used dynamic MRI to evaluate the effects of monoclonal antibodies targeting brain tumor vasculature. Female athymic rats with intracerebral human tumor xenografts were untreated or treated with intetumumab, targeting αV-integrins, or bevacizumab, targeting vascular endothelial growth factor (n = 4–6 per group). Prior to treatment and at 1, 3, and 7 days after treatment, we performed standard MRI to assess tumor volume, dynamic susceptibility-contrast MRI with the blood-pool iron oxide nanoparticle ferumoxytol to evaluate relative cerebral blood volume (rCBV), and dynamic contrast-enhanced MRI to assess tumor vascular permeability. Tumor rCBV increased by 27 ± 13% over 7 days in untreated rats; intetumumab increased tumor rCBV by 65 ± 10%, whereas bevacizumab reduced tumor rCBV by 31 ± 10% at 7 days (P < .001 for group and day). Similarly, intetumumab increased brain tumor vascular permeability compared with controls at 3 and 7 days after treatment, whereas bevacizumab decreased tumor permeability within 24 hours (P = .0004 for group, P = .0081 for day). All tumors grew over the 7-day assessment period, but bevacizumab slowed the increase in tumor volume on MRI. We conclude that the vascular targeting agents intetumumab and bevacizumab had diametrically opposite effects on dynamic MRI of tumor vasculature in rat brain tumor models. Targeting αV-integrins increased tumor vascular permeability and blood volume, whereas bevacizumab decreased both measures. These findings have implications for chemotherapy delivery and antitumor efficacy.
bevacizumab; blood–brain barrier; dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging; intetumumab
To determine the usefulness of perfusion MR imaging in assessing the histologic grade of cerebral gliomas.
Materials and Methods
In order to determine relative cerebral blood volume (rCBV), 22 patients with pathologically proven gliomas (9 glioblastomas, 9 anaplastic gliomas and 4 low-grade gliomas) underwent dynamic contrast-enhanced T2*-weighted and conventional T1- and T2-weighted imaging. rCBV maps were obtained by fitting a gamma-variate function to the contrast material concentration versus time curve. rCBV ratios between tumor and normal white matter (maximum rCBV of tumor / rCBV of contralateral white matter) were calculated and compared between glioblastomas, anaplastic gliomas and low-grade gliomas.
Mean rCBV ratios were 4.90°±1.01 for glioblastomas, 3.97°±0.56 for anaplastic gliomas and 1.75°±1.51 for low-grade gliomas, and were thus significantly different; p < .05 between glioblastomas and anaplastic gliomas, p < .05 between anaplastic gliomas and low-grade gliomas, p < .01 between glioblastomas and low-grade gliomas. The rCBV ratio cutoff value which permitted discrimination between high-grade (glioblastomas and anaplastic gliomas) and low-grade gliomas was 2.60, and the sensitivity and specificity of this value were 100% and 75%, respectively.
Perfusion MR imaging is a useful and reliable technique for estimating the histologic grade of gliomas.
Brain neoplasms, MR; Brain, blood flow; Cerebral blood vessels, flow dynamics; Magnetic resonance (MR), contrast enhancement
To assess the capability of perfusion MRI to differentiate between necrosis and tumor recurrence in patients showing radiological progression of cerebral metastases treated with stereotactic radiosurgery (SRS). From 2004 to 2006 dynamic susceptibility-weighted contrast-enhanced perfusion MRI scans were performed on patients with cerebral metastasis showing radiological progression after SRS during follow-up. Several perfusion MRI characteristics were examined: a subjective visual score of the relative cerebral blood volume (rCBV) map and quantitative rCBV measurements of the contrast-enhanced areas of maximal perfusion. For a total of 34 lesions in 31 patients a perfusion MRI was performed. Diagnoses were based on histology, definite radiological decrease or a combination of radiological and clinical follow-up. The diagnosis of tumor recurrence was obtained in 20 of 34 lesions, and tumor necrosis in 14 of 34. Regression analyses for all measures proved statistically significant (χ2 = 11.6–21.6, P < 0.001–0.0001). Visual inspection of the rCBV map yielded a sensitivity and specificity of 70.0 respectively 92.9%. The optimal cutoff point for maximal tumor rCBV relative to white matter was 2.00 (improving the sensibility to 85.0%) and 1.85 relative to grey matter (GM), improving the specificity to 100%, with a corresponding sensitivity of 70.0%. Perfusion MRI seems to be a useful tool in the differentiation of necrosis and tumor recurrence after SRS. For the patients displaying a rCBV-GM greater than 1.85, the diagnosis of necrosis was excluded. Salvage treatment can be initiated for these patients in an attempt to prolong survival.
Cerebral metastases; Stereotactic radiosurgery; Perfusion MRI; Necrosis; Recurrence
A growing body of evidence indicates a role for D3 receptors in L-DOPA-induced dyskinesias. This involvement could be amenable to non-invasive in vivo analysis using functional neuroimaging. With this goal, we examined the hemodynamic response to the dopamine D3-preferring agonist 7-hydroxy-N,N-di-n-propyl-2 aminotetralin (7-OHDPAT) in naïve, parkinsonian and L-DOPA-treated, dyskinetic rodents and primates using pharmacological MRI (phMRI) and relative cerebral blood volume (rCBV) mapping. Administration of 7-OHDPAT induced minor negative changes of rCBV in the basal ganglia in naïve and parkinsonian animals. Remarkably, the hemodynamic response was reversed (increased rCBV) in the striatum of parkinsonian animals rendered dyskinetic by repeated L-DOPA treatment. Such increase in rCBV is consistent with D1 receptor-like signaling occurring in response to D3 stimulation, demonstrates a dysregulation of dopamine receptor function in dyskinesia and provides a potentially novel means for the characterization and treatment of L-DOPA-induced dyskinesia in patients.
Dyskinesia; Parkinson’s disease; Dopamine; Dopamine receptor; D3; Striatum; phMRI; Primate
Although dexamethasone is very effective for controlling peritumoral cerebral edema, it is associated with distressing side effects that decrease the quality of life for many patients. One potential mechanism to explain the ability of dexamethasone to repair blood-brain barrier dysfunction is through the inhibition of cyclooxygenase-2 (COX-2). The purpose of this study was to determine in a rat brain tumor model whether SC-236, a selective COX-2 inhibitor, is as effective as dexamethasone. Twenty-nine adult male Fischer 344 rats were implanted with intracerebral 9L gliosarcomas and divided into 3 treatment groups. One group (n = 9) served as controls, another (n = 9) was treated with dexamethasone (3 mg/kg p.o. daily), and a third group (n = 11) received SC-236 (3 mg/kg p.o. daily). A survival study was performed. The median survival in the control group was 16 days, compared with 23 days for the dexamethasone group and 23 days for the COX-2 inhibitor group. Kaplan-Meier analysis on pairwise group comparisons showed improved survival that was statistically significant for each treatment group compared with the control group (log-rank test P = 0.009 for dexamethasone to control and P = 0.005 for COX-2 to control), and no significant difference in survival for the COX-2 compared with dexamethasone (log-rank test P = 0.2). These results suggest that a selective COX-2 inhibitor appears to be as effective as dexamethasone in prolonging survival in a rat brain tumor model.
Characterization of the ontogeny of the cerebral dopaminergic system is crucial for gaining a greater understanding of normal brain development and its alterations in response to drugs of abuse or conditions such as attention-deficit hyperactivity disorder. Pharmacological MRI (phMRI) was used to determine the response to dopamine transporter (DAT) blockers cocaine and methylphenidate (MPH), the dopamine releaser D-amphetamine (AMPH), the selective D1 agonist dihydrexidine, and the D2/D3 agonist quinpirole in young (<30 days old) and adult (>60 days old) rats. In adult rats, cocaine (0.5 mg/kg i.v.) or MPH (2 mg/kg) induced primarily positive cerebral blood volume (rCBV) changes in the dopaminergic circuitry, but negative rCBV changes in the young animals. Microdialysis measurements in the striatum showed that young rats have a smaller increase in extracellular dopamine in response to cocaine than adults. The young rats showed little rCBV response to the selective D1 agonist dihydrexidine in contrast to robust rCBV increases observed in the adults, whereas there was a similar negative rCBV response in the young and adult rats to the D2 agonist quinpirole. We also performed a meta-analysis of literature data on the development of D1 and D2 receptors and the DAT. These data suggest a predominance of D2-like over D1-like function between 20 and 30 days of age. These combined results suggested that the dopamine D1 receptor is functionally inhibited at young age.
Ontogeny; Dopamine; D1 receptor; D2 receptor; Functional MRI; Pharmacological MRI
To determine the utility of perfusion MR imaging in the differential diagnosis of brain tumors.
Materials and Methods
Fifty-seven patients with pathologically proven brain tumors (21 high-grade gliomas, 8 low-grade gliomas, 8 lymphomas, 6 hemangioblastomas, 7 metastases, and 7 various other tumors) were included in this study. Relative cerebral blood volume (rCBV) and time-to-peak (TTP) ratios were quantitatively analyzed and the rCBV grade of each tumor was also visually assessed on an rCBV map.
The highest rCBV ratios were seen in hemangioblastomas, followed by high-grade gliomas, metastases, low-grade gliomas, and lymphomas. There was no significant difference in TTP ratios between each tumor group (p>0.05). At visual assessment, rCBV was high in 17 (81%) of 21 high-grade gliomas and in 4 (50%) of 8 low-grade gliomas. Hemangioblastomas showed the highest rCBV and lymphomas the lowest.
Perfusion MR imaging may be helpful in the differentiation of thevarious solid tumors found in the brain, and in assessing the grade of the various glial tumors occurring there.
Brain neoplasms, diagnosis; Brain neoplasms, MR; Brain, perfusion; Magnetic resonance (MR), perfusion study
Glioma grading assumes significant importance in that low- and high-grade gliomas display different prognoses and are treated with dissimilar therapeutic strategies. The objective of our study was to retrospectively assess the usefulness of a cumulative normalized cerebral blood volume (nCBV) histogram for glioma grading based on 3 T MRI.
From February 2010 to April 2012, 63 patients with astrocytic tumors underwent 3 T MRI with dynamic susceptibility contrast perfusion-weighted imaging. Regions of interest containing the entire tumor volume were drawn on every section of the co-registered relative CBV (rCBV) maps and T2-weighted images. The percentile values from the cumulative nCBV histograms and the other histogram parameters were correlated with tumor grades. Cochran’s Q test and the McNemar test were used to compare the diagnostic accuracies of the histogram parameters after the receiver operating characteristic curve analysis. Using the parameter offering the highest diagnostic accuracy, a validation process was performed with an independent test set of nine patients.
The 99th percentile of the cumulative nCBV histogram (nCBV C99), mean and peak height differed significantly between low- and high-grade gliomas (P = <0.001, 0.014 and <0.001, respectively) and between grade III and IV gliomas (P = <0.001, 0.001 and <0.001, respectively). The diagnostic accuracy of nCBV C99 was significantly higher than that of the mean nCBV (P = 0.016) in distinguishing high- from low-grade gliomas and was comparable to that of the peak height (P = 1.000). Validation using the two cutoff values of nCBV C99 achieved a diagnostic accuracy of 66.7% (6/9) for the separation of all three glioma grades.
Cumulative histogram analysis of nCBV using 3 T MRI can be a useful method for preoperative glioma grading. The nCBV C99 value is helpful in distinguishing high- from low-grade gliomas and grade IV from III gliomas.
We evaluated dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging (DSC-MRI) using gadoteridol in comparison to the iron oxide nanoparticle blood pool agent, ferumoxytol in patients with glioblastoma multiforme (GBM) who received standard radiochemotherapy (RCT).
Methods and Materials
Fourteen patients with GBM received standard RCT and underwent 19 MRI sessions that included DSC-MRI acquisitions with gadoteridol on day 1 and ferumoxytol on day 2. Relative cerebral blood volume (rCBV) values were calculated from DSC data obtained from each contrast agent. T1-weighted acquisition post-gadoteridol administration was used to identify enhancing regions.
In 7 MRI sessions of clinically presumptive active tumor, gadoteridol-DSC showed low rCBV in 3 and high rCBV in 4, while ferumoxytol-DSC showed high rCBV in all 7 sessions (p=0.002). After RCT, 7 MRI sessions showed increased gadoteridol contrast enhancement on T1-weighted scans coupled with low rCBV without significant differences between contrast agents (p=0.9). Based on post-gadoteridol T1-weighted scans, DSC-MRI, and clinical presentation four patterns of response to RCT were observed: 1) regression, 2) pseudoprogression, 3) true progression, and 4) mixed response.
We conclude that DSC-MRI with a blood-pool agent such as ferumoxytol may provide a better monitor of tumor rCBV than DSC-MRI with gadoteridol. Lesions demonstrating increased enhancement on T1-weighted MRI coupled with low ferumoxytol rCBV, are likely exhibiting pseudoprogression, while high rCBV with ferumoxytol is a better marker than gadoteridol for determining active tumor. These interesting pilot observations suggest that ferumoxytol may differentiate tumor progression from pseudoprogression, and warrant further investigation.
Blood-brain barrier; dynamic susceptibility- weighted contrast-enhanced magnetic resonance imaging; glioblastoma multiforme; pseudoprogression; radiochemotherapy
Gliosarcoma is one of the most common malignant brain tumors, and anti-angiogenesis is a promising approach for the treatment of gliosarcoma. However, chemotherapy is obstructed by the physical obstacle formed by the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). Honokiol has been known to possess potent activities in the central nervous system diseases, and anti-angiogenic and anti-tumor properties. Here, we hypothesized that honokiol could cross the BBB and BCSFB for the treatment of gliosarcoma.
We first evaluated the abilities of honokiol to cross the BBB and BCSFB by measuring the penetration of honokiol into brain and blood-cerebrospinal fluid, and compared the honokiol amount taken up by brain with that by other tissues. Then we investigated the effect of honokiol on the growth inhibition of rat 9L gliosarcoma cells and human U251 glioma cells in vitro. Finally we established rat 9L intracerebral gliosarcoma model in Fisher 344 rats and human U251 xenograft glioma model in nude mice to investigate the anti-tumor activity.
We showed for the first time that honokiol could effectively cross BBB and BCSFB. The ratios of brain/plasma concentration were respectively 1.29, 2.54, 2.56 and 2.72 at 5, 30, 60 and 120 min. And about 10% of honokiol in plasma crossed BCSFB into cerebrospinal fluid (CSF). In vitro, honokiol produced dose-dependent inhibition of the growth of rat 9L gliosarcoma cells and human U251 glioma cells with IC50 of 15.61 µg/mL and 16.38 µg/mL, respectively. In vivo, treatment with 20 mg/kg body weight of honokiol (honokiol was given twice per week for 3 weeks by intravenous injection) resulted in significant reduction of tumor volume (112.70±10.16 mm3) compared with vehicle group (238.63±19.69 mm3, P = 0.000), with 52.77% inhibiting rate in rat 9L intracerebral gliosarcoma model, and (1450.83±348.36 mm3) compared with vehicle group (2914.17±780.52 mm3, P = 0.002), with 50.21% inhibiting rate in human U251 xenograft glioma model. Honokiol also significantly improved the survival over vehicle group in the two models (P<0.05).
This study provided the first evidence that honokiol could effectively cross BBB and BCSFB and inhibit brain tumor growth in rat 9L intracerebral gliosarcoma model and human U251 xenograft glioma model. It suggested a significant strategy for offering a potential new therapy for the treatment of gliosarcoma.
This study aims to compare gadoteridol with ferumoxytol for contrast-enhanced and perfusion-weighted (PW) MRI of intracranial tumors. The final analysis included 26 patients, who underwent 3 consecutive days of 3T MRI. Day 1 consisted of anatomical pre- and postcontrast images, and PW MRI was acquired using gadoteridol (0.1 mmol/kg). On Day 2, the same MRI sequences were obtained with ferumoxytol (510 mg) and on Day 3, the anatomical images were repeated to detect delayed ferumoxytol-induced signal changes. The T1-weighted images were evaluated qualitatively and quantitatively for enhancement volume and signal intensity (SI) changes; PW data were used to estimate the relative cerebral blood volume (rCBV). All 26 lesions showed 24-hour T1-weighted ferumoxytol enhancement; 16 also had T2-weighted hypointensities. In 6 patients, ferumoxytol-induced signal changes were noted in areas with no gadoteridol enhancement. Significantly greater (P< .0001) SI changes were seen with gadoteridol, and qualitative analyses (lesion border delineation, internal morphology, contrast enhancement) also showed significant preferences (P= .0121; P = .0015; P < .0001, respectively) for this agent. There was no significant difference in lesion enhancement volumes between contrast materials. The ferumoxytol-rCBV values were significantly higher (P = .0016) compared with the gadoteridol-rCBV values. In conclusion, ferumoxytol provides important information about tumor biology that complements gadoteridol imaging. The rCBV measurements indicate areas of tumor undergoing rapid growth, whereas the 24-hour scans mark the presence of inflammatory cells. Both of these functions provide useful information about tumor response to treatment. We suggest that dynamic and anatomical imaging with ferumoxytol warrant further assessment in brain tumor therapy.
brain tumors; ferumoxytol; magnetic resonance imaging; ultrasmall superparamagnetic iron oxide nanoparticles
INTRODUCTION: Contrast-enhanced MRI (CE-MRI) represents the current mainstay for monitoring treatment response in glioblastoma multiforme (GBM), based on the premise that enlarging lesions reflect increasing tumor burden, treatment failure, and poor prognosis. Unfortunately, irradiating such tumors can induce changes in CE-MRI that mimic tumor recurrence, so called post treatment radiation effect (PTRE), and in fact, both PTRE and tumor re-growth can occur together. Because PTRE represents treatment success, the relative histologic fraction of tumor growth versus PTRE affects survival. Studies suggest that Perfusion MRI (pMRI)–based measures of relative cerebral blood volume (rCBV) can noninvasively estimate histologic tumor fraction to predict clinical outcome. There are several proposed pMRI-based analytic methods, although none have been correlated with overall survival (OS). This study compares how well histologic tumor fraction and OS correlate with several pMRI-based metrics. METHODS: We recruited previously treated patients with GBM undergoing surgical re-resection for suspected tumor recurrence and calculated preoperative pMRI-based metrics within CE-MRI enhancing lesions: rCBV mean, mode, maximum, width, and a new thresholding metric called pMRI–fractional tumor burden (pMRI-FTB). We correlated all pMRI-based metrics with histologic tumor fraction and OS. RESULTS: Among 25 recurrent patients with GBM, histologic tumor fraction correlated most strongly with pMRI-FTB (r = 0.82; P < .0001), which was the only imaging metric that correlated with OS (P<.02). CONCLUSION: The pMRI-FTB metric reliably estimates histologic tumor fraction (i.e., tumor burden) and correlates with OS in the context of recurrent GBM. This technique may offer a promising biomarker of tumor progression and clinical outcome for future clinical trials.
glioblastoma; histologic tumor fraction; perfusion MRI; pseudoprogression; radiation necrosis; recurrent; relative cerebral blood volume; survival
Here we describe the Parametric Response Map (PRM), a voxel-wise approach for image analysis and quantification of hemodynamic alterations during treatment for 44 patients with high-grade glioma. Relative cerebral blood volume (rCBV) and flow (rCBF) maps were acquired before treatment and after 1 and 3 weeks of therapy. We compared the standard approach using region-of-interest analysis for change in rCBV or rCBF to the change in perfusion parameters on the basis of PRM (PRMrCBV and PRMrCBF) for their accuracy in predicting overall survival. Neither the percentage change of rCBV or rCBF predicted survival, whereas the regional response evaluations based upon PRM were highly predictive of survival. Even when accounting for baseline rCBV, which is prognostic, PRMrCBV proved more predictive of overall survival.
Despite the established role of MRI in the diagnosis of brain tumours, histopathological assessment remains the clinically used technique, especially for the glioma group. Relative cerebral blood volume (rCBV) is a dynamic susceptibility-weighted contrast-enhanced perfusion MRI parameter that has been shown to correlate to tumour grade, but assessment requires a specialist and is time consuming. We developed analysis software to determine glioma gradings from perfusion rCBV scans in a manner that is quick, easy and does not require a specialist operator.
MRI perfusion data from 47 patients with different histopathological grades of glioma were analysed with custom-designed software. Semi-automated analysis was performed with a specialist and non-specialist operator separately determining the maximum rCBV value corresponding to the tumour. Automated histogram analysis was performed by calculating the mean, standard deviation, median, mode, skewness and kurtosis of rCBV values. All values were compared with the histopathologically assessed tumour grade.
A strong correlation between specialist and non-specialist observer measurements was found. Significantly different values were obtained between tumour grades using both semi-automated and automated techniques, consistent with previous results. The raw (unnormalised) data single-pixel maximum rCBV semi-automated analysis value had the strongest correlation with glioma grade. Standard deviation of the raw data had the strongest correlation of the automated analysis.
Semi-automated calculation of raw maximum rCBV value was the best indicator of tumour grade and does not require a specialist operator.
Advances in knowledge
Both semi-automated and automated MRI perfusion techniques provide viable non-invasive alternatives to biopsy for glioma tumour grading.
To assess whether a new method of quantifying therapy-associated hemodynamic alterations may help to distinguish pseudoprogression from true progression in patients with high-grade glioma.
Patients and Methods
Patients with high-grade glioma received concurrent chemoradiotherapy. Relative cerebral blood volume (rCBV) and blood flow (rCBF) maps were acquired before chemoradiotherapy and at week 3 during treatment on a prospective institutional review board–approved study. Pseudoprogression was defined as imaging changes 1 to 3 months after chemoradiotherapy that mimic tumor progression but stabilized or improved without change in treatment or for which resection revealed radiation effects only. Clinical and conventional magnetic resonance (MR) parameters, including average percent change of rCBV and CBF, were evaluated as potential predictors of pseudoprogression. Parametric response map (PRM), an innovative, voxel-by-voxel method of image analysis, was also performed.
Median radiation dose was 72 Gy (range, 60 to 78 Gy). Of 27 patients, stable disease/partial response was noted in 13 patients and apparent progression was noted in 14 patients. Adjuvant temozolomide was continued in all patients. Pseudoprogression occurred in six patients. Based on PRM analysis, a significantly reduced blood volume (PRMrCBV) at week 3 was noted in patients with progressive disease as compared with those with pseudoprogression (P < .01). In contrast, change in average percent rCBV or rCBF, MR tumor volume changes, age, extent of resection, and Radiation Therapy Oncology Group recursive partitioning analysis classification did not distinguish progression from pseudoprogression.
PRMrCBV at week 3 during chemoradiotherapy is a potential early imaging biomarker of response that may be helpful in distinguishing pseudoprogression from true progression in patients with high-grade glioma.
The biological factors responsible for differential chemoresponsiveness in oligodendroglial tumours with or without the −1p/−19q genotype are unknown, but tumour vascularity may contribute. We aimed to determine whether dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) could distinguish molecular subtypes of oligodendroglial tumour, and examined the relationship between relative cerebral blood volume (rCBV) and outcome following procarbazine, lomustine and vincristine (PCV) chemotherapy.
Pretherapy rCBV was calculated and inter- and intraobserver variability assessed. Allelic imbalance in 1p36, 19q13, 17p13, 10p12–15, and 10q22–26 and p53 mutation (exons 5–8) were determined. rCBV was compared with genotype and clinicopathological characteristics (n=37) and outcome following PCV chemotherapy (n=33).
1p/19q loss was seen in 6/9 grade II oligodendrogliomas, 6/14 grade II oligoastrocytomas, 4/4 grade III oligodendrogliomas, and 3/10 grade III oligoastrocytomas. rCBV measurements had good inter- and intraobserver variability, but did not distinguish histology subtype or grade. Tumours with 1p/19q loss had higher rCBV values (Student’s t-test P=0.001). Receiver operating characteristic analysis revealed a cut-off of 1.59 for identifying genotype (sensitivity 92%, specificity 76%). Tumours with high and low rCBV showed response to chemotherapy. The −1p/−19q genotype, but not rCBV, was strongly associated with response, progression-free and overall survival following PCV chemotherapy. Tumours with high rCBV and intact 1p/19q were associated with shorter progression-free and overall patient survival than those with intact 1p/19q and low rCBV or high rCBV and 1p/19q loss.
rCBV identifies oligodendroglial tumours with 1p/19q loss, but does not predict chemosensitivity. The prognostic significance of rCBV may differ in oligodendroglial tumours with or without the −1p/−19q genotype.
Oligodendroglial tumour; rCBV; Chemosensitivity; Outcome
Our purpose was to determine whether perfusion MR imaging can be used to differentiate benign and malignant meningiomas on the basis of the differences in perfusion of tumor parenchyma and/or peritumoral edema.
A total of 33 patients with preoperative meningiomas (25 benign and 8 malignant) underwent conventional and dynamic susceptibility contrast perfusion MR imaging. Maximal relative cerebral blood volume (rCBV) and the corresponding relative mean time to enhance (rMTE) (relative to the contralateral normal white matter) in both tumor parenchyma and peritumoral edema were measured. The independent samples t-test was used to determine whether there was a statistically significant difference in the mean rCBV and rMTE ratios between benign and malignant meningiomas.
The mean maximal rCBV values of benign and malignant meningiomas were 7.16±4.08 (mean±SD) and 5.89±3.86, respectively, in the parenchyma, and 1.05±0.96 and 3.82±1.39, respectively, in the peritumoral edema. The mean rMTE values were 1.16±0.24 and 1.30±0.32, respectively, in the parenchyma, and 0.91±0.25 and 1.24±0.35, respectively, in the peritumoral edema. The differences in rCBV and rMTE values between benign and malignant meningiomas were not statistically significant (P>0.05) in the parenchyma, but both were statistically significant (P<0.05) in the peritumoral edema.
Perfusion MR imaging can provide useful information on meningioma vascularity which is not available from conventional MRI. Measurement of maximal rCBV and corresponding rMTE values in the peritumoral edema is useful in the preoperative differentiation between benign and malignant meningiomas.
Meningioma; Cerebral neoplasm; Magnetic resonance imaging; Perfusion-weighted imaging; Brain
Currently, radiologic response of brain tumors is assessed according to the Macdonald criteria 10 weeks from the start of therapy. There exists a critical need to identify non-responding patients early in the course of their therapy for consideration of alternative treatment strategies. Our study assessed the effectiveness of the Parametric Response Map (PRM) imaging biomarker to provide for an earlier measure of patient survival prediction.
Forty-five high grade glioma patients received concurrent chemoradiation. Quantitative MRI including apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) maps were acquired pre-treatment and 3 weeks mid-treatment on a prospective institutional-approved study. PRM, a voxel-by-voxel image analysis method, was evaluated as an early prognostic biomarker of overall survival. Clinical and conventional MR parameters were also evaluated.
Multivariate analysis showed that PRMADC+ in combination with PRMrCBV- obtained at week 3 had a stronger correlation to one-year and overall survival rates than any baseline clinical or treatment response imaging metric. The composite biomarker identified three distinct patient groups, non-responders (median survival (MS) of 5.5 months CI: 4.4-6.6) months, partial responders (MS of 16 months CI: 8.6-23.4) and responders (MS has not yet been reached.)
Inclusion of PRMADC+ and PRMrCBV- into a single imaging biomarker metric provided early identification of patients resistant to standard chemoradiation. In comparison to the current standard of assessment of response at 10 weeks (MacDonald Criteria) the composite PRM biomarker potentially provides a useful opportunity for clinicians to identify patients who may benefit from alternative treatment strategies.
DW-MRI; DSC-MRI; glioma; prospective trial; treatment response
To demonstrate in the rat 9L cerebral tumor model that repeated MRI measurements can quantitate acute changes in the blood-brain distribution of Gadomer after dexamethasone administration.
Materials and Methods
A total of 16 Fischer 344 rats were studied at 7T, 15 days after cerebral implantation of a 9L tumor. MRI procedures employed a T-One by Multiple Read Out Pulses (TOMROP) sequence to estimate R1 (R1 = 1/T1) at 145-second intervals before and after administration of Gadomer (Bayer), a macromolecular contrast agent (CA). Two baseline studies preceded Gadomer administration and 10 subsequent R1 maps tracked CA concentration in blood and brain for 25 minutes. Thereafter, either dexamethasone (N = 10) or normal saline (N = 6) was administered intravenously. A total of 90 minutes later a second series of 12 TOMROP measurements of Gadomer distribution was performed. The influx constant, K1, plasma distribution volume, vD, backflux constant, kb, and interstitial space, ve, were determined, and the test-retest differences of each of four vascular parameters were calculated.
Dexamethasone decreased K1 approximately 60% (P = 0.02), lowered kb and vD (P = 0.03 and P < 0.01, respectively), and marginally but insignificantly decreased ve.
This noninvasive MRI technique can detect drug effects on blood-brain transfer constants of CAs within two hours of administration.
blood brain barrier (BBB); vascular permeability; dexamethasone; experimental cerebral tumor; MRI
Objective. To search brain perfusion MRI (pMRI) changes in Behcet's disease (BD) with or without neurological involvement. Materials and Method. The pMRI were performed in 34 patients with BD and 16 healthy controls. Based on neurologic examination and post-contrast MRI, 12 patients were classified as Neuro-Behcet (group 1, NBD) and 22 patients as BD without neurological involvement (group 2). Mean transit time (MTT), time to peak (TTP), relative cerebral blood volume (rCBV), and relative cerebral blood flow (rCBF) were obtained and compared to those of healthy control group (group 3). Results. There was a significant difference in the MTT and rCBF within the pons and parietal cortex in groups 1 and 2. rCBV increased in cerebral pedicle in group 1 compared with groups 2 and 3. In the temporal lobe white matter, prolonged MTT and decreased rCBF were found in groups 1 and 2. In the corpus striatum, internal capsule, and periventricular white matter, rCBF increased in group 1 compared with group 3 and decreased in groups 1 and 2. Conclusion. Brain pMRI is a very sensitive method to detect brain involvement in patients with BD and aids the clinical diagnosis of NBD, especially in patients with negative MRI findings.
Ferumoxytol, an iron nanoparticle used as an intravascular contrast agent for perfusion magnetic resonance imaging (MRI), has never been explored the pediatric population. The purpose of this prospective study is to characterize the vascular and permeability properties of pediatric brain tumors using two contrast agents during a single imaging session: ferumoxytol for dynamic susceptibility weighted contrast (DSC) MRI and gadoteridol for dynamic contrast enhanced (DCE) MRI. In a single imaging session, patients received intravenous ferumoxytol for DSC MRI followed by gadolinium for DCE MRI. Relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), transfer coefficient (Ktrans), and extravascular extracellular space volume fraction (ve) of the brain lesions were calculated. Patients underwent serial imaging sessions over the course of two years. Of the seven patients enrolled thus far, none has experienced an adverse event. Two patients with medulloblastoma were enrolled preoperatively. In the first, rCBVmax, rCBF, Ktrans max, and ve max values were 3.74, 3.12, 0.47 min−1, and 0.08, respectively, while in the second patient, rCBVmax, rCBF, Ktrans max, and ve max values were 4.72, 3.47, 0.60 min−1, and 0.05, respectively. Four patients were enrolled after new gadolinium enhancement was noted in the tumor resection cavity. In 80% of these lesions, rCBV was < 1 suggestive of pseudoprogression secondary to radiochemotherapy. These preliminary results demonstrate that use of ferumoxytol and gadoteridol contrast agents during a single imaging session is feasible, safe, and appears useful for assessing tumor perfusion and permeability characteristics in children.
DSC MRI; DCE MRI; ferumoxytol; brain tumor; pediatric
Vincristine is an integral part of the “PCV” regimen that is commonly administered to treat primary brain tumors. The efficacy of vincristine as a single agent in these tumors has been poorly studied. This study was designed to determine whether vincristine enters normal rat brain or an intracranially or subcutaneously implanted glioma and to assess the presence of the efflux pump P-glycoprotein (P-gp) on tumor and vascular endothelial cells. The 9L rat gliosarcoma was implanted intracranially and subcutaneously in three Fischer 344 rats. On day 7, [3H]vincristine (50 μCi, 4.8 μg) was injected into the carotid artery, and the animals were euthanized 10 or 20 min later. Quantitative autoradiography revealed that vincristine levels in the liver were 6- to 11-fold greater than in the i.c. tumor, and 15- to 37-fold greater than in normal brain, the reverse of the expected pattern with intra-arterial delivery. Vincristine levels in the s.c. tumor were 2-fold higher than levels in the i.c. tumor. P-gp was detected with JSB1 antibody in vascular endothelium of both normal brain and the i.c. tumor, but not in the tumor cells in either location, or in endothelial cells in the s.c. tumor. These results demonstrate that vincristine has negligible penetration of normal rat brain or i.c. 9L glioma despite intra-arterial delivery and the presence of blood-brain barrier dysfunction as demonstrated by Evan’s blue. Furthermore, this study suggests that P-gp-mediated efflux from endothelium may explain these findings. The lack of penetration of vincristine into brain tumor and the paucity of single-agent activity studies suggest that vincristine should not be used in the treatment of primary brain tumors.
Perfusion magnetic resonance brain imaging induces temporal signal changes on brain tissues, manifesting distinct blood-supply patterns for the profound analysis of cerebral hemodynamics. We employed independent factor analysis to blindly separate such dynamic images into different maps, that is, artery, gray matter, white matter, vein and sinus, and choroid plexus, in conjunction with corresponding signal-time curves. The averaged signal-time curve on the segmented arterial area was further used to calculate the relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), and mean transit time (MTT). The averaged ratios for rCBV, rCBF, and MTT between gray and white matters for normal subjects were congruent with those in the literature.
Recently, a vascular-space-occupancy (VASO) MRI technique was developed for quantitative assessment of cerebral blood volume (CBV). This method uses the T1-shortening effect of gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) with imaging parameters chosen that null the precontrast blood magnetization but allow the postcontrast blood magnetization to recover to equilibrium. A key advantage of VASO CBV estimation is that it provides a straightforward procedure for converting MR signals to absolute physiologic values. However, as with other T1-based steady-state approaches, several important factors need to be considered that influence the accuracy of CBV values obtained with VASO MRI. Here, the transverse relaxation (
T2/T2∗) effect in VASO MRI was investigated using multiecho spin-echo and gradient-echo experiments, resulting in underestimation of CBV by 14.9% ± 1.1% and 16.0% ± 2.5% for spin echo (TE = 10 ms) and gradient echo (TE = 6 ms), respectively. In addition, the influence of contrast agent clearance was studied by acquiring multiple postcontrast VASO images at 2.2-min intervals, which showed that the concentration of Gd-DTPA in the first 14 min (single dose) was sufficient for the blood magnetization to fully recover to equilibrium. Finally, the effect of vascular Gd-DTPA leakage was assessed for scalp tissue, and signal extrapolation as a function of postinjection time was demonstrated to be useful in minimizing the associated errors. Specific recommendations for VASO MRI acquisition and processing strategies are provided.
cerebral blood volume; brain; perfusion; VASO; MRI