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Longitudinal and transverse rotating-frame relaxation time constants, T(1) (ρ) and T(2) (ρ) , have previously been successfully applied to detect gene therapy responses and acute stroke in animal models. Those experiments were performed with continuous-wave irradiation or with frequency-modulated pulses operating in an adiabatic regime. The technique called Relaxation Along a Fictitious Field (RAFF) is a recent extension of frequency-modulated rotating-frame relaxation methods. In RAFF, spin locking takes place along a fictitious magnetic field, and the decay rate is a function of both T(1ρ) and T(2ρ) processes. In this work, the time constant characterizing water relaxation with RAFF (T(RAFF) ) was evaluated for its utility as a marker of response to gene therapy in a rat glioma model. To investigate the sensitivity to early treatment response, we measured several rotating-frame and free-precession relaxation time constants and the water apparent diffusion coefficients, and these were compared with histological cell counts in 8 days of treated and control groups of animals. T(RAFF) was the only parameter exhibiting significant association with cell density in three different tumor regions (border, intermediate, and core tissues). These results indicate that T(RAFF) may provide a marker to identify tumors responding to treatment., (Copyright © 2011 Wiley-Liss, Inc.)

Longitudinal and transverse relaxations in the rotating frame, with characteristic time constants T1rho and T2rho, respectively, have potential to provide unique MRI contrast in vivo. On-resonance spin-lock T1rho with different spin-lock field strengths and adiabatic T2rho with different radiofrequency-modulation functions were measured in BT4C gliomas treated with Herpes Simplex Virus thymidine kinase (HVS-tk) gene therapy causing apoptotic cell death. These NMR tools were able to discriminate different treatment responses in tumor tissue from day 4 onward. An equilibrium two-site exchange model was used to calculate intrinsic parameters describing changes in water dynamics. Observed changes included increased correlation time of water associated with macromolecules and a decreased fractional population of this pool. These results are consistent with destructive intracellular processes associated with cell death and the increase of extracellular space during the treatment. Furthermore, association between longer exchange correlation time and decreased pH during apoptosis is discussed. In this study, we demonstrated that T1rho and T2rho MR imaging are useful tools to quantify early changes in water dynamics reflecting treatment response during gene therapy., (Copyright (c) 2008 Wiley-Liss, Inc.)

The aim of this study was to compare the diffusion characteristic of lactate and alanine in a brain tumor model to that of normal brain metabolites known to be mainly intracellular such as N-acetylaspartate or creatine. The diffusion of (13)C-labeled metabolites was measured in vivo with localized NMR spectroscopy at 9.4 T (400 MHz) using a previously described localization and editing pulse sequence known as ACED-STEAM ('adiabatic carbon editing and decoupling'). (13)C-labeled glucose was administered and the apparent diffusion coefficients of the glycolytic products, {(1)H-(13)C}-lactate and {(1)H-(13)C}-alanine, were determined in rat intracerebral 9L glioma. To obtain insights into {(1)H-(13)C}-lactate compartmentation (intra- versus extracellular), the pulse sequence used very large diffusion weighting (50 ms/microm(2)). Multi-exponential diffusion attenuation of the lactate metabolite signals was observed. The persistence of a lactate signal at very large diffusion weighting provided direct experimental evidence of significant intracellular lactate concentration. To investigate the spatial distribution of lactate and other metabolites, (1)H spectroscopic images were also acquired. Lactate and choline-containing compounds were consistently elevated in tumor tissue, but not in necrotic regions and surrounding normal-appearing brain. Overall, these findings suggest that lactate is mainly associated with tumor tissue and that within the time-frame of these experiments at least some of the glycolytic product ([(13)C] lactate) originates from an intracellular compartment.

Purpose: To report a case of anaplastic large cell lymphoma (ALCL) of the central nervous system (CNS) producing an optic neuropathy., Methods: Observational case report., Results: A 29-year-old male presented with new onset headaches. Magnetic resonance imaging (MRI) of the brain revealed a large enhancing parietal lobe mass. Ocular exam at that time was normal. Initial diagnoses included possible bacterial cerebritis and fungal abscess. Serial lumbar punctures showed increased white blood cells but cytology was negative. A brain biopsy was non-diagnostic. The patient then presented with a left optic neuropathy. Repeat MRI of the brain and orbits revealed infiltration of the clivus and left orbital apex including the optic nerve. The patient had elevated liver function studies and an abdominal ultrasound disclosed two hypoechoic lesions. Liver biopsy confirmed the diagnosis of ALK-1 positive ALCL. The patient was treated with chemotherapy but expired seven months after the initial presentation., Conclusion: ALCL should be considered to be a very rare but potential cause of optic neuropathy. To our knowledge, this is the first reported case of ALCL causing an optic neuropathy.

Magnetic resonance imaging relaxation times, T(1rho) and Carr-Purcell T(2) (CP-T(2)), were measured in a glioma herpes simplex virus-thymidine kinase gene therapy model. In treated tumors with >50% cell death by histology, T(1rho) and CP-T(2) measured with short spacing (tau(CP)) between centers of adiabatic refocusing pulses showed similar enhanced sensitivity to cytotoxic cell damage over CP-T(2) measured with long tau(CP) (long-tau(CP) T(2): 54.3 +/- 0.7 and 55.4 +/- 1.2 ms, P = 0.30; short-tau(CP) T(2): 61.3 +/- 1.0 and 64.2 +/- 1.1 ms, P < 0.05 before and day 2 of treatment, respectively). Without treatment, long-tau(CP) T(2) provided the most pronounced contrast between tumor and normal cerebral tissue. These data demonstrate that endogenous T(2) contrast can be modulated and extended in a manner likely to be clinically important.

(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC), was evaluated as a potential treatment for malignant gliomas using the rat 9L brain tumor model. FMdC was shown to be an effective inhibitor of cell proliferation in cultured 9L cells with an EC(50) of 40 ng/ml. In vitro studies also revealed that this compound significantly inhibited incorporation of [(3)H]thymidine in 9L cells. In vivo therapeutic efficacy of FMdC was evaluated in rats harboring intracerebral 9L tumors which were treated daily with 15 mg/kg, i.p. Treatment response was quantified from changes in tumor growth rates as assessed from sequential magnetic resonance imaging (MRI) tumor volume measurements. In vivo tumor cell kill in individual animals was calculated by fitting tumor volume data with an iterative computer routine. It was estimated that therapeutically responsive rats treated with FMdC daily produced a >/= 0.1 log kill per therapeutic dose which resulted in a significant reduction in tumor growth rate. In addition, localized (1)H-MRS of intracerebral 9L tumors revealed changes in metabolite levels which correlated with therapeutic response. These results provide evidence supporting the use of FMdC in clinical trials for the treatment of malignant gliomas and reveals that MR can play an important role in the pre-clinical evaluation of novel compounds using orthotopic tumor models., (Copyright 2003 John Wiley & Sons, Ltd.)

Measurements of tumor blood flow (TBF) are important for understanding tumor physiology and can be valuable in selecting and evaluating therapies. Brain tumors typically present reduced blood flows compared to normal brain tissue. This study shows that the arterial spin labeling (ASL) technique can be used to measure TBF non-invasively in a rat glioma model. Results show that TBF in the core (36.3 +/- 18.9 ml/100g/min, n=4) and peripheral regions (85.3 +/- 26.9 ml/100g/min, n=4) of the tumor are significantly reduced and show considerable heterogeneity compared to cerebral blood flow (CBF) of normal brain tissue (147.7 +/- 31.1 ml/100g/min, n=4), while T(1) in the tumor (2.6 +/- 0.1 sec) is significantly elevated compared to normal tissue T(1) (2.0 +/- 0.0 sec). These results strongly support the feasibility of using the ASL technique to evaluate different cancer treatment strategies, to monitor the effects of agents designed to modulate TBF and oxygenation (e.g., carbogen gas), and to assess and guide the use of anti-angiogenic agents. Magn Reson Med 44:169-173, 2000., (Copyright 2000 Wiley-Liss, Inc.)

Elevated tissue lactate concentrations typically found in tumors can be measured by in vivo nuclear magnetic resonance (NMR) spectroscopy. In this study, lactate turnover in rat C6 glioma was determined from in vivo 1H NMR measurements of [3-13C]lactate buildup during steady-state hyperglycemia with [1-13C]glucose. With this tumor model, a narrow range of values was observed for the first-order rate constant that describes lactate efflux, k2 = 0.043 +/- 0.007 (n = 12) SD min-1. For individual animals, the standard error in k2 was small (< 18%), which indicated that the NMR data fit the kinetic model well. Lactate measurements before and after infusing [1-13C]glucose showed that the majority of the tumor lactate pool was metabolically active. Signals from 13C-labeled glutamate in tumors were at least 10-fold smaller than the [3-13C]lactate signal, whereas spectra of the contralateral hemispheres revealed the expected labeling of [4-13C]glutamate, as well as [2-13C] and [3-13C]glutamate, which indicates that label cycled through the tricarboxylic acid cycle in the brain tissue. Lack of significant 13C labeling of glutamate was consistent with low respiratory metabolism in this glioma. It is concluded that lactate in rat C6 glioma is actively turning over and that the kinetics of lactate efflux can be quantified noninvasively by 1H NMR detection of 13C label. This noninvasive NMR approach may offer a valuable tool to help evaluate tumor growth and metabolic responsiveness to therapies.

A new method for magnetic resonance imaging (MRI) based on the detection of relatively strong signal from intermolecular zero-quantum coherences (iZQCs) is reported. Such a signal would not be observable in the conventional framework of magnetic resonance; it originates in long-range dipolar couplings (10 micrometers to 1 millimeter) that are traditionally ignored. Unlike conventional MRI, where image contrast is based on variations in spin density and relaxation times (often with injected contrast agents), contrast with iZQC images comes from variations in the susceptibility over a distance dictated by gradient strength. Phantom and in vivo (rat brain) data confirm that iZQC images give contrast enhancement. This contrast might be useful in the detection of small tumors, in that susceptibility correlates with oxygen concentration and in functional MRI.

Increased capacity for glycolytic metabolism is a well-known characteristic of neoplastic cells. Because lactic acid is the end product of glycolysis, in vivo MRS measurements of tumor lactate concentration ([lac]t) may provide valuable information about tumor metabolism, which will aid the development of therapies and the clinical diagnosis and treatment of tumors. In the present study, several hemodynamic and histologic parameters were evaluated with respect to their influence on [lac]t. Pronounced differences in [lac]t in two distinct populations of tumors suggested a putative perfusion threshold. Above this threshold, [lac]t was independent of hemodynamic and histologic factors including tumor blood flow (measured using MRS and the method of D2O washout), extent of necrosis and inflammatory cell infiltrate. Thus, for most tumors, [lac]t was not determined by any one single factor such as hypoxia, venous clearance, glucose supply, extent of necrosis or degree of inflammatory cell infiltrate. Rather, [lac]t may be equilibrated, at least in part, by an interplay of forces involving hemodynamics and substrate supply. In general, the data are consistent with the hypothesis that elevated lactate in most tumors is related to the high glycolytic activity of adequately perfused, viable neoplastic cells.

In vivo 1H MRS can be used to detect and quantify the lactate resonance at 1.3 ppm provided that overlapping lipid resonances are eliminated. A homonuclear spectral editing method was developed to acquire uncontaminated 1H spectra of lactate with adiabatic pulses. An advantage of the adiabatic pulse sequence is the ability to induce uniform flip angles and to maximize sensitivity in applications employing surface coil transmitters which produce highly inhomogeneous B1. Glycolytic activity in an intracerebral C6 glioma in rats was monitored by using adiabatic editing sequences to observe [3-13C]lactate produced from infused [1-13C]glucose. Acute hyperglycemia (serum glucose > 22 mM, n = 10) had no significant effect (P = 0.08) on the total ([12C] + [13C]) tumor lactate signal intensity.

Surface coil MRI combined with spatially localized spectroscopy was used to noninvasively detect 1H signals from metabolites within an intracerebral malignant glioma in rats. The MRS pulse sequence was based upon two-dimensional ISIS, which restricted 1H signals to a column-shaped volume, combined with one-dimensional spectroscopic imaging, which further resolved the signals into 8 or 16 slices along the major axis of the column. All experiments were executed with adiabatic pulses which induced uniform spin excitation despite the inhomogeneous radiofrequency field distribution produced by the surface coil transmitter. Surface coil MRI and MRS experiments were performed on phantom samples, normal rat brains, and rat brains harboring malignant gliomas. Spatially resolved in vivo 1H spectra of intracerebral gliomas revealed significantly decreased concentrations of N-acetyl-aspartate and creatine and increased lactic acid (or lipids) as compared to the contralateral hemisphere. These results demonstrate that metabolic abnormalities in intracerebral rat gliomas can be spatially resolved in a noninvasive manner using localized in vivo 1H MRS.

Surface coil NMR spectroscopy was used to monitor the hyperglycemia-induced alterations in pH and blood flow in vivo in C6 gliomas implanted both subcutaneously and intracerebrally in rats. Tumor pH was calculated from the chemical shift difference between PCr and Pi in the 31P NMR spectra. Subcutaneous glioma pH decreased 0.8 units by 1 h after intraperitoneal administration of an aqueous 50% glucose solution (6 g glucose per kg body weight). In contrast, hyperglycemia failed to significantly alter the pH of intracerebral gliomas which were monitored for 90 min following administration of glucose. Tumor blood flow (TBF) was determined both pre- and post-glucose administration using deuterium NMR by monitoring the time course of D2O washout following intratumoral injection of saline D2O. Subcutaneous and intracerebral TBF were found to have an average change of -78.1% (range -47.4 to -93.3%, n = 5) and -21.1% (range +6.0 to -37.8%, n = 9), respectively. In addition, laser Doppler blood flow measurements of rat skin and subcutaneous glioma revealed a dramatic reduction in blood flow in both tissues following glucose administration. These results indicate that the effects of acute hyperglycemia are site dependent and that hyperglycemia alone is not beneficial for inducing intracellular acidosis in intracerebral tumors.

The in vivo high-energy phosphorus metabolic profile and pH of an experimental intracerebral C6 glioma in rats was examined using surface coil 31P NMR spectroscopy. Initially, phosphorus-containing metabolites of the glioma were characterized by in vivo 31P surface coil spectroscopy of subcutaneously implanted tumors and by high-resolution NMR studies of perchloric acid (PCA) extracts of both freeze-clamped subcutaneous tumor tissue and cultured cells. These studies demonstrated that the C6 glioma has reduced levels of phosphocreatine (PCr) compared to the levels found in normal rat brain. Thus, reduced spectral PCr levels were useful as a metabolic indicator for monitoring the spatial selectivity of tumor metabolism distinct from that of adjacent normal brain tissue. To maximize 31P NMR signals from intracerebral tumors, tumor cells were stereotaxically placed superficially in the brain. Proton magnetic resonance imaging (1H MRI) was used to determine the size and location of the resultant brain tumors in order to preselect rats with large superficial tumors for spectroscopic study. 31P NMR spectra of the glioma tumors revealed a consistent reduction in the PCr/ATP ratio, an increase in the Pi/ATP ratio, and a slightly increased tissue pH. No correlation was found between levels of Pi/ATP and tumor pH in subcutaneous or intracerebral gliomas and the amount of necrosis as determined histologically. This study demonstrates that phosphorus metabolites of an experimental brain tumor in the rat can be monitored in vivo with minimal contributions from adjacent normal brain tissue metabolites using surface coil 31P NMR spectroscopy.