Janine M. Lupo

Differentiation of Glioblastoma Multiforme and Single Brain Metastasis by Peak Height and Percentage of Signal Intensity Recovery Derived from Dynamic Susceptibility-Weighted Contrast-Enhanced Perfusion MR Imaging

BACKGROUND AND PURPOSE: Glioblastoma multiforme (GBM) and single brain metastasis (MET) are the 2 most common malignant brain tumors that can appear similar on anatomic imaging but require vastly different treatment strategy. The purpose of our study was to determine whether the peak height and the percentage of signal intensity recovery derived from dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion MR imaging could differentiate GBM and MET. MATERIALS AND METHODS: Forty-three patients with histopathologic diagnosis of GBM (n = 27) or MET (n = 16) underwent DSC perfusion MR imaging in addition to anatomic MR imaging before surgery. Regions of interest were drawn around the nonenhancing peritumoral T2 lesion (PTL) and the contrast-enhancing lesion (CEL). T2* signal intensity-time curves acquired during the first pass of gadolinium contrast material were converted to the changes in relaxation rate to yield T2* relaxivity (ΔR2*) curve. The peak height of maximal signal intensity drop and the percentage of signal intensity recovery at the end of first pass were measured for each voxel in the PTL and CEL regions of the tumor. RESULTS: The average peak height for the PTL was significantly higher (P = .04) in GBM than in MET. The average percentage of signal intensity recovery was significantly reduced in PTL (78.4% versus 82.8%; P = .02) and in CEL (62.5% versus 80.9%, P < .01) regions of MET compared with those regions in the GBM group. CONCLUSIONS: The findings of our study show that the peak height and the percentage of signal intensity recovery derived from the ΔR2* curve of DSC perfusion MR imaging can differentiate GBM and MET.

Development of a robust method for generating 7.0 T multichannel phase images of the brain with application to normal volunteers and patients with neurological diseases.

The increased susceptibility effects and high signal-to-noise ratio at 7.0 T enable imaging of the brain using the phase of the magnetic resonance signal. This study describes and evaluates a robust method for calculating phase images from gradient-recalled echo (GRE) scans. The GRE scans were acquired at 7.0 T using an eight-channel receive coil at spatial resolutions up to 0.195 x 0.260 x 2.00 mm. The entire 7.0 T protocol took less than 10 min. Data were acquired from forty-seven subjects including clinical patients with multiple sclerosis (MS) or brain tumors. The phase images were post-processed using a fully automated phase unwrapping algorithm that combined the data from the different channels. The technique was used to create the first phase images of MS patients at any field strength and the first phase images of brain tumor patients above 1.5 T. The clinical images showed novel contrast in MS plaques and depicted microhemorrhages and abnormal vasculature in brain tumors with unsurpassed resolution and contrast.

Pulse sequence for dynamic volumetric imaging of hyperpolarized metabolic products

Dynamic nuclear polarization and dissolution of a (13)C-labeled substrate enables the dynamic imaging of cellular metabolism. Spectroscopic information is typically acquired, making the acquisition of dynamic volumetric data a challenge. To enable rapid volumetric imaging, a spectral-spatial excitation pulse was designed to excite a single line of the carbon spectrum. With only a single resonance present in the signal, an echo-planar readout trajectory could be used to resolve spatial information, giving full volume coverage of 32 x 32 x 16 voxels every 3.5s. This high frame rate was used to measure the different lactate dynamics in different tissues in a normal rat model and a mouse model of prostate cancer.

A serial in vivo 7T magnetic resonance phase imaging study of white matter lesions in multiple sclerosis

Background: Magnetic resonance (MR) phase imaging using high field MR scanners has demonstrated excellent contrast in multiple sclerosis (MS) lesions that is thought to be closely correlated to the local iron content. This pilot study acquired serial in vivo MR scans at 7T to track the evolution of phase contrast as MS lesions progress. Methods: Five MS patients with relapsing–remitting MS were serially scanned for about 2.5 years at 7T using a high resolution T2*-weighted gradient-echo sequence. Magnitude and phase images were reconstructed for each scan and co-registered to their baseline study. Results: Five non-enhancing ring and 70 nodular phase lesions were found in the five patients at baseline. None of the baseline phase lesions (including all five ring phase lesions) showed obvious qualitative variation on phase images during the study. Of note, we observed that three magnitude lesions, not initially read as abnormal signal, were either better appreciated using phase contrast imaging (two lesions) or preceded (one lesion) by phase changes. Conclusion: The observation that ring phase lesions remained unchanged over 2.5 years of follow-up challenges the notion that such lesions reveal the presence of acute activated iron-rich macrophages. It suggests that either different phenotypes of macrophages persist longer than previously expected or other mechanisms related to tissue injury contribute to the phase contrast.

Hyperpolarized [1-13C] glutamate: a metabolic imaging biomarker of IDH1 mutational status in glioma

Mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade glioma and secondary glioblastoma, represent an early pathogenic event, and are associated with epigenetically driven modulations of metabolism. Of particular interest is the recently uncovered relationship between the IDH1 mutation and decreased activity of the branched-chain amino acid transaminase 1 (BCAT1) enzyme. Noninvasive imaging methods that can assess BCAT1 activity could therefore improve detection of mutant IDH1 tumors and aid in developing and monitoring new targeted therapies. BCAT1 catalyzes the transamination of branched-chain amino acids while converting α-ketoglutarate (α-KG) to glutamate. Our goal was to use (13)C magnetic resonance spectroscopy to probe the conversion of hyperpolarized [1-(13)C] α-KG to hyperpolarized [1-(13)C] glutamate as a readout of BCAT1 activity. We investigated two isogenic glioblastoma lines that differed only in their IDH1 status and performed experiments in live cells and in vivo in rat orthotopic tumors. Following injection of hyperpolarized [1-(13)C] α-KG, hyperpolarized [1-(13)C] glutamate production was detected both in cells and in vivo, and the level of hyperpolarized [1-(13)C] glutamate was significantly lower in mutant IDH1 cells and tumors compared with their IDH1-wild-type counterparts. Importantly however, in our cells the observed drop in hyperpolarized [1-(13)C] glutamate was likely mediated not only by a drop in BCAT1 activity, but also by reductions in aspartate transaminase and glutamate dehydrogenase activities, suggesting additional metabolic reprogramming at least in our model. Hyperpolarized [1-(13)C] glutamate could thus inform on multiple mutant IDH1-associated metabolic events that mediate reduced glutamate production.

7-Tesla Susceptibility-Weighted Imaging to Assess the Effects of Radiotherapy on Normal-Appearing Brain in Patients With Glioma

PURPOSE To evaluate the intermediate- and long-term imaging manifestations of radiotherapy on normal-appearing brain tissue in patients with treated gliomas using 7T susceptibility-weighted imaging (SWI). METHODS AND MATERIALS SWI was performed on 25 patients with stable gliomas on a 7 Tesla magnet. Microbleeds were identified as discrete foci of susceptibility that did not correspond to vessels. The number of microbleeds was counted within and outside of the T2-hyperintense lesion. For 3 patients, radiation dosimetry maps were reconstructed and fused with the 7T SWI data. RESULTS Multiple foci of susceptibility consistent with microhemorrhages were observed in patients 2 years after chemoradiation. These lesions were not present in patients who were not irradiated. The prevalence of microhemorrhages increased with the time since completion of radiotherapy, and these lesions often extended outside the boundaries of the initial high-dose volume and into the contralateral hemisphere. CONCLUSIONS High-field SWI has potential for visualizing the appearance of microbleeds associated with long-term effects of radiotherapy on brain tissue. The ability to visualize these lesions in normal-appearing brain tissue may be important in further understanding the utility of this treatment in patients with longer survival.

Survival analysis in patients with newly diagnosed glioblastoma using pre- and postradiotherapy MR spectroscopic imaging

BACKGROUND The objective of this study was to examine the predictive value of parameters of 3D (1)H magnetic resonance spectroscopic imaging (MRSI) prior to treatment with radiation/chemotherapy (baseline) and at a postradiation 2-month follow-up (F2mo) in relationship to 6-month progression-free survival (PFS6) and overall survival (OS). METHODS Sixty-four patients with newly diagnosed glioblastoma multiforme (GBM) being treated with radiation and concurrent chemotherapy were involved in this study. Evaluated were metabolite indices and metabolite ratios. Logistic linear regression and Cox proportional hazards models were utilized to evaluate PFS6 and OS, respectively. These analyses were adjusted by age and MR scanner field strength (1.5 T or 3 T). Stepwise regression was performed to determine a subset of the most relevant variables. RESULTS Associated with shorter PFS6 were a decrease in the ratio of N-acetyl aspartate to choline-containing compounds (NAA/Cho) in the region with a Cho-to-NAA index (CNI) >3 at baseline and an increase of the CNI within elevated CNI regions (>2) at F2mo. Patients with higher normalized lipid and lactate at either time point had significantly worse OS. Patients who had larger volumes with abnormal CNI at F2mo had worse PFS6 and OS. CONCLUSIONS Our study found more 3D MRSI parameters that predicted PFS6 and OS for patients with GBM than did anatomic, diffusion, or perfusion imaging, which were previously evaluated in the same population of patients.

Assessment of perfusion MRI-derived parameters in evaluating and predicting response to antiangiogenic therapy in patients with newly diagnosed glioblastoma

The paradigm for treating patients with glioblastoma multiforme (GBM) is shifting from a purely cytotoxic approach to one that incorporates antiangiogenic agents. These are thought to normalize the tumor vasculature and have shown improved disease management in patients with recurrent disease. How this vascular remodeling evolves during the full course of therapy for patients with newly diagnosed GBM and how it relates to radiographic response and outcome remain unclear. In this study, we examined 35 patients who were newly diagnosed with GBM using dynamic susceptibility contrast (DSC) MRI in order to identify early predictors of radiographic response to antiangiogenic therapy and to evaluate changes in perfusion parameters that may be predictive of progression. After surgical resection, patients received enzastaurin and temozolomide, both concurrent with and adjuvant to radiotherapy. Perfusion parameters, peak height (PH) and percent recovery, were calculated from the dynamic curves to assess vascular density and leakage. Six-month radiographic responders showed a significant improvement in percent recovery between baseline and 2 months into therapy, whereas 6-month radiographic nonresponders showed significantly increased PH between baseline and 1 month. At 2 months into therapy, percent recovery was predictive of progression-free survival. Four months prior to progression, there was a significant increase in the standard deviation of percent recovery within the tumor region. DSC perfusion imaging provides valuable information about vascular remodeling during antiangiogenic therapy, which may aid clinicians in identifying patients who will respond at the pretherapy scan and as an early indicator of response to antiangiogenic therapy.

Analysis of hyperpolarized dynamic 13C lactate imaging in a transgenic mouse model of prostate cancer.

This study investigated the application of an acquisition that selectively excites the [1-13C]lactate resonance and allows dynamic tracking of the conversion of 13C-lactate from hyperpolarized 13C-pyruvate at a high spatial resolution. In order to characterize metabolic processes occurring in a mouse model of prostate cancer, 20 sequential 3D images of 13C-lactate were acquired 5 s apart using a pulse sequence that incorporated a spectral-spatial excitation pulse and a flyback echo-planar readout to track the time course of newly converted 13C-lactate after injection of prepolarized 13C-pyruvate. The maximum lactate signal (MLS), full-width half-maximum (FWHM), time to the peak 13C-lactate signal (TTP) and area under the dynamic curve were calculated from the dynamic images of 10 TRAMP mice and two wild-type controls. The regional variation in 13C-lactate associated with the injected pyruvate was demonstrated by the peak of the 13C-lactate signal occurring earlier in the kidney than in the tumor region. The intensity of the dynamic 13C-lactate curves also varied spatially within the tumor, illustrating the heterogeneity in metabolism that was most prominent in more advanced stages of disease development. The MLS was significantly higher in TRAMP mice that had advanced disease.

GRAPPA-based susceptibility-weighted imaging of normal volunteers and patients with brain tumor at 7 T

Susceptibility-weighted imaging (SWI) is a valuable technique for high-resolution imaging of brain vasculature that greatly benefits from the emergence of higher field strength MR scanners. Autocalibrating partially parallel imaging techniques can be employed to reduce lengthy acquisition times as long as the decrease in signal-to-noise ratio does not significantly affect the contrast between vessels and brain parenchyma. This study assessed the feasibility of a Generalized Autocalibrating Partially Parallel Acquisition (GRAPPA)-based SWI technique at 7 T in both healthy volunteers and brain tumor patients. GRAPPA-based SWI allowed a twofold or more reduction in scan time without compromising vessel contrast and small vessel detection. Postprocessing parameters for the SWI needed to be modified for patients where the tumor causes high-frequency phase wrap artifacts but did not adversely affect vessel contrast. GRAPPA-based SWI at 7 T revealed regions of microvascularity, hemorrhage and calcification within heterogeneous brain tumors that may aid in characterizing active or necrotic tumor and monitoring treatment effects.