Tomography, Volume 2, Issue 2 (June 2016) – 9 articles

We present a practical approach for coregistration of bioluminescence tomography (BLT), computed tomography (CT), and magnetic resonance (MR) images. For this, we developed a customized animal shuttle composed of nonfluorescent, MR-compatible Delrin plastic that fits a commercially available MR surface coil. Mouse embryonic stem cells were transfected with the luciferase gene and labeled with superparamagnetic iron oxide nanoparticles. Cells were stereotaxically implanted in the mouse brain and imaged weekly for 4 weeks with bioluminescent imaging (IVIS Spectrum CT scanner) and magnetic resonance imaging (MRI; 11.7 T horizontal bore scanner). Without the use of software coregistration, in vitro phantom studies yielded root-mean-square errors of 7.6 × 10⁻³, 0.93 mm, and 0.78 mm along the medial–lateral (ML), dorsal–ventral (DV), and anterior–posterior (AP) axes, respectively. Rotation errors were negligible. Software coregistration by translation along the DV and AP axes resulted in consistent agreement between the CT and MR images, without the need for rotation or warping. In vivo coregistered BLT/MRI mouse brain data sets showed a single diffuse region of bioluminescent imaging photon signal and MRI hypointensity. Over time, the transplanted cells formed tumors as histopathologically validated. Disagreement between BLT and MRI tumor location was greatest along the DV axis (1.4 ± 0.2 mm) than along the ML (0.5 ± 0.3 mm) and the AP axes (0.6 mm) because of the uncertainty of the depth of origin of the BLT signal. Combining the high spatial anatomical information of MRI with the cell viability/proliferation data from BLT should facilitate preclinical evaluation of novel therapeutic candidate stem cells. Full article

Malignant cells from breast cancer, as well as other common cancers such as prostate and melanoma, may persist in bone marrow as quiescent, nondividing cells that remain viable for years or even decades before resuming proliferation to cause recurrent disease. This phenomenon, referred to clinically as tumor dormancy, poses tremendous challenges to curing patients with breast cancer. Quiescent tumor cells resist chemotherapy drugs that predominantly target proliferating cells, limiting success of neoadjuvant and adjuvant therapies. We recently developed a 3-dimensional spheroid model of quiescent breast cancer cells in bone marrow for mechanistic and drug testing studies. We combined this model with optical imaging methods for label-free detection of cells, preferentially using glycolysis versus oxidative metabolism to investigate the metabolic state of co-culture spheroids with different bone marrow stromal and breast cancer cells. Through imaging and biochemical assays, we identified different metabolic states of bone marrow stromal cells that control metabolic status and flexibilities of co-cultured breast cancer cells. We tested metabolic stresses and targeted inhibition of specific metabolic pathways to identify approaches to preferentially eliminate quiescent breast cancer cells from bone marrow environments. These studies establish an integrated imaging approach to analyze metabolism in complex tissue environments to identify new metabolically targeted cancer therapies. Full article

Sparse recovery algorithms have shown great potential to accurately reconstruct images using limited-view optoacoustic (photoacoustic) tomography data sets, but these are computationally expensive. In this paper, we propose an improvement of the fast converging Split Augmented Lagrangian Shrinkage Algorithm method based on least square QR inversion for improving the reconstruction speed. We further show image fidelity improvement when using a coherence factor to weight the reconstruction result. Phantom and in vivo measurements show that the accelerated Split Augmented Lagrangian Shrinkage Algorithm method with coherence factor weighting offers images with reduced artifacts and provides faster convergence compared with existing sparse recovery algorithms. Full article

In this study, in vivo T2 heterogeneity of hyperpolarized [13C,15N2]urea in rat kidney has been investigated. Selective quenching of the vascular hyperpolarized 13C signal with a macromolecular relaxation agent revealed that a long T2 component of the [13C,15N2]urea signal originated from the renal extravascular space, thus allowing the vascular and renal filtrate contrast agent pools of the [13C,15N2]urea to be distinguished via multiexponential analysis. The T2 response to induced diuresis and antidiuresis was determined using 2 imaging agents—hyperpolarized [13C,15N2]urea and hyperpolarized bis-1,1-(hydroxymethyl)-1-13C-cyclopropane-2H8 (control agent). During antidiuresis, large T2 increases in the inner medulla and papilla were observed using the former agent only. Therefore, [13C,15N2]urea relaxometry is sensitive to the following 2 steps of the renal urea handling process: glomerular filtration process and inner medullary urea transporter-A1- and urea transporter-A3-mediated urea concentrating process. To aid multiexponential data analysis, simple motion correction and subspace denoising algorithms are presented. Furthermore, a T2-edited, ultralong echo time sequence was developed for sub-2 mm3 resolution 3-dimensional encoding of urea by exploiting relaxation differences in the vascular and filtrate pools. Full article

The fast Padé transform (FPT) is a method of spectral analysis that can be used to reconstruct nuclear magnetic resonance spectra from truncated free induction decay signals with superior robustness and spectral resolution compared with conventional Fourier analysis. The aim of this study is to show the utility of FPT in reducing of the scan time required for hyperpolarized 13C chemical shift imaging (CSI) without sacrificing the ability to resolve a full spectrum. Simulations, phantom, and in vivo hyperpolarized [1-13C] pyruvate CSI data were processed with FPT and compared with conventional analysis methods. FPT shows improved stability and spectral resolution on truncated data compared with the fast Fourier transform and shows results that are comparable to those of the model-based fitting methods, enabling a reduction in the needed acquisition time in 13C CSI experiments. Using FPT can reduce the readout length in the spectral dimension by 2-6 times in 13C CSI compared with conventional Fourier analysis without sacrificing the spectral resolution. This increased speed is crucial for 13C CSI because T1 relaxation considerably limits the available scan time. In addition, FPT can also yield direct quantification of metabolite concentration without the additional peak analysis required in conventional Fourier analysis. Full article

The diagnosis, prognosis, and management of patients with gliomas are largely dictated by the pathological analysis of tissue biopsied from a selected region within the lesion. However, the heterogeneous and infiltrative nature of gliomas make it difficult to identify the optimal region for biopsy with conventional magnetic resonance imaging (MRI). This is particularly true for low-grade gliomas, which are often nonenhancing tumors. To improve the management of patients with such tumors, neuro-oncology requires an imaging modality that can specifically identify a tumor's most anaplastic/aggressive region(s) for biopsy targeting. The addition of metabolic mapping using spectroscopic MRI (sMRI) to supplement conventional MRI could improve biopsy targeting and, ultimately, diagnostic accuracy. Here, we describe a pipeline for the integration of state-of-the-art, high-resolution, whole-brain 3-dimensional sMRI maps into a stereotactic neuronavigation system for guiding biopsies in gliomas with nonenhancing components. We also outline a machine-learning method for automated histological analysis that generates normalized, quantitative metrics describing tumor infiltration in immunohistochemically stained tissue specimens. As a proof of concept, we describe the combination of these 2 techniques in a small cohort of patients with grade 3 glioma. With this work, we aim to present a systematic pipeline to stimulate histopathological image validation of advanced MRI techniques, such as sMRI. Full article

2-hydroxyglutarate (2-HG) has emerged as a biomarker of tumor cell isocitrate dehydrogenase mutations that may enable the differential diagnosis of patients with glioma. At 3 T, detection of 2-HG with magnetic resonance spectroscopy is challenging because of metabolite signal overlap and spectral pattern modulation by slice selection and chemical shift displacement. Using density matrix simulations and phantom experiments, an optimized semi-LASER scheme (echo time = 110 milliseconds) considerably improves localization of the 2-HG spin system compared with that of an existing point-resolved spectroscopy sequence. This results in a visible 2-HG peak in the in vivo spectra at 1.9 ppm in the majority of isocitrate dehydrogenase-mutated tumors. Detected concentrations of 2-HG were similar using both sequences, although the use of semi-LASER generated narrower confidence intervals. Signal overlap with glutamate and glutamine, as measured by pairwise fitting correlation, was reduced. Lactate was readily detectable across patients with glioma using the method presented here (mean Cramér–Rao lower bound: 10% ± 2%). Together with more robust 2-HG detection, long-echo time semi-LASER offers the potential to investigate tumor metabolism and stratify patients in vivo at 3 T. Full article

In vivo quantification of CXCR4 expression using [⁶⁸Ga]pentixafor for positron emission tomography (PET) imaging has gained significant clinical interest as CXCR4 plays a fundamental role in oncology and possesses potential prognostic value when overexpressed. To combine the excellent CXCR4-targeting properties of pentixafor-based tracers with the favorable radionuclide properties of ¹⁸F for high-resolution PET imaging, we developed an Al¹⁸F-labeled 1,4,7-triazacyclononane-triacetic acid (NOTA) analog of pentixather. Al¹⁸F-labeling of NOTA-pentixather was performed in aqueous dimethyl sulfoxide (DMSO) at pH = 4 (105 °C, 15 minutes). CXCR4 affinities were determined in competitive binding assays, and both biodistribution and small-animal PET studies were performed in Daudi lymphoma-bearing mice. Under non-optimized conditions, [¹⁸F]AlF-NOTA-pentixather was obtained in radiochemical yields of 45.5% ± 13.3% and specific activities of up to 24.8 GBq/μmol. Compared with [^natGa]pentixafor, [^natF]AlF-NOTA-pentixather showed 1.4-fold higher CXCR4 affinity. [¹⁸F]AlF-NOTA-pentixather displayed high and CXCR4-specific in vivo uptake in Daudi xenografts (13.9% ± 0.8% injected dose per gram [ID/g] at 1 hour post injection [p.i.]). Because of its enhanced lipophilicity (logP = −1.4), [¹⁸F]AlF-NOTA-pentixather showed increased accumulation in the gall bladder and intestines. However, tumor/background ratios of 7.0 ± 1.2, 2.0 ± 0.3, 2.2 ± 0.4, 16.5 ± 6.5, and 29.2 ± 4 for blood, liver, small intestine, gut, and muscle, respectively, allowed for high-contrast visualization of Daudi tumors using PET (1 hour p.i.). The relatively straightforward radiosynthesis and efficient CXCR4 targeting of [¹⁸F]AlF-NOTA-pentixather demonstrate the successful implementation of ¹⁸F-complexation chemistry and pentixather-based CXCR4 targeting. Upon pharmacokinetic optimization, this class of tracers holds great promise for future application in humans. Full article

Dormant cancer cells, also referred to as quiescent, slowly cycling or “nonproliferative” cells, are believed to contribute to tumor recurrence and present a therapeutic problem because they are nonresponsive to current therapies that target proliferating cells. Concomitant tumor resistance (CTR) is the ability of a primary tumor to restrict the growth of secondary metastases. In this paper, we investigate these 2 cancer concepts using cellular magnetic resonance imaging (MRI). A new model for CTR is presented where a primary mammary fat pad tumor is generated using a human breast cancer cell line (231) and breast cancer brain metastases are generated using a cell line derived from 231 to be brain metastatic (231-BR). Iron oxide particles are used to label the 231BR cells to allow for tracking of the proliferating cells, which form metastases, and the nonproliferating cells, which remain dormant in the brain. Bioluminescence and fluorescence-activated cell sorting are used to validate the MRI data. The presence of a primary 231 mammary fat pad tumor inhibited the formation of MRI-detectable 231BR brain metastases. More iron-retaining cells persisted in the brains of mice with a primary tumor. Bioluminescence and fluorescence-activated cell sorting provide evidence that signal voids detectable by MRI on day 0 represent live, iron-labeled cells in the brain. This work shows that retention of iron by nonproliferative cancer cells can be exploited to monitor the fate of this important cell population in vivo, and it points to a new mechanism for CTR, the enhancement of dormancy by a primary tumor. Full article