Longitudinal studies of lactate MR spectroscopic imaging (MRSI) and dynamic contrast-enhanced MR imaging (DCE-MRI) were performed at 4.7 T in two prostate tumor models grown in rats, the Dunning R3327-AT (AT) and Dunning H (H), to determine the potential of lactate and the perfusion/permeability parameter Akep as markers of tumor aggressiveness. Subcutaneous AT (n = 12) and H (n = 6) tumors were studied at different volumes between 100 and 2900 mm3 (Groups 1 to 5). Lactate concentration was determined from Selective Multiple Quantum Coherence (Sel-MQC) MRSI using phantom substitution method. Tumor enhancement after administration of Gd-DTPA was analyzed using the Brix-Hoffmann model and the Akep parameter was used as a measure of tumor perfusion/permeability. Lactate was not detected in the smallest AT tumors (Group 1; 100–270 mm3). In larger AT tumors, lactate concentration increased from 2.8 ± 1.0 mM (Group 2; 290–700 mm3) to 8.4 ± 2.9 mM (Group 3; 1000–1340 mm3), 8.2 ± 2.2 mM (Group 4; 1380–1750 mm3), and then decreased to 5.0 ± 1.7 mM (Group 5; 1900–2500 mm3) and was consistently higher in the tumor core than in the rim. Lactate was not detected in any of the Dunning H tumors. The mean tumor Akep values decreased with increasing volume in both tumor types, but were significantly higher in H tumors. In AT tumors, the Akep values were significantly higher in the rim than in the core. Histological hypoxic and necrotic fractions in AT tumors increased with volume from 0% in Group 1 to about 20% and 30%, respectively, in Group 5. Minimal amounts of hypoxia and necrosis were found in H tumors of all sizes. Thus the presence of lactate and heterogeneous perfusion/permeability are signatures of aggressive, metabolically deprived Dunning R3327-AT tumor, but not the slow-growing Dunning H tumor.

Tumor vasculature and tissue oxygen pressure can influence tumor growth, metastases, and patient survival. Elevated levels of lactate may be observed during the process of aggressive tumor development accompanied by angiogenesis (the evolution of the microenvironment). The noninvasive MR detection of lactate in tumor tissues as a potential biomarker is difficult due to the presence of co-resonating lipids that are present at high concentrations. Methods were previously reported for lactate editing using the SELective Multiple Quantum Coherence (SelMQC) method. Here we report a sequence "SS-SelMQC," Spectral-Selective SelMQC, which is a modified version of SelMQC using binomial pulses. Binomial pulses were employed in this editing sequence for frequency excitation or inversion of selective lactate resonances. Lactate detection has been demonstrated using SS-SelMQC, both in vitro ( In vivo proton MR spectroscopy (MRS) provides a noninvasive, biochemical measure of metabolism which can be used to differentiate healthy tissues from tumor tissues based on the metabolic abnormalities (1-3). Metabolites may be a priori markers of prognosis or metabolic changes can be very sensitive early indicators of treatment response. As such, metabolic approaches show promise for monitoring, and perhaps even ultimately selecting treatments. As tumors are heterogeneous, multivoxel MRS imaging (MRSI) provides a method to investigate therapy response and optimization of individual treatment regime based on various metabolite levels or concentrations within each voxel, which might signify aggressive (or indolent) disease (4 -8) in local regions of the tumor. Among the many detectable metabolites, lactate (Lac) is an important compound that reflects elevated tumor glycolysis and/or poor tissue perfusion, which may result in accelerated tumor growth, malignant transformation, and metastases (9). Lac is the endproduct of glycolysis and the methyl resonance peak is typically a doublet situated at 1.3 ppm. Different levels of tumor lactate in the MR spectrum were reported in the literature (10 -15). High Lac was observed in extracts from biopsy specimens of breast tumors (10,16) and prostate tumors (11). Low extracellular pH and high Lac levels were shown to be indicators of metastatic risk in breast cancer xenografts (12,13). Elevated Lac content in biopsy samples was shown to correlate with increased risk of metastasis and poor patient survival in head and neck cancer (14) and cervical cancer (15), while a decrease in steady-state tumor Lac levels related to tumor response to radiation (17,18) and chemotherapy (19,20). It has also been shown by Shkarin et al. (21) that Lac is likely to be found in malignant breast tumors that may be a marker for tumor diagnosis. Therefore, noninvasively measured Lac may be an additional characteristic metabolic marker for cancer studies and may improve diagnostic specificity, serve as an early marker of tumor response, and provide functional information about prognosis.Reliable measurement and interpret...