Mark G. Swanson

Combined magnetic resonance imaging and spectroscopic imaging approach to molecular imaging of prostate cancer.

Magnetic resonance spectroscopic imaging (MRSI) provides a noninvasive method of detecting small molecular markers (historically the metabolites choline and citrate) within the cytosol and extracellular spaces of the prostate, and is performed in conjunction with high‐resolution anatomic imaging. Recent studies in pre‐prostatectomy patients have indicated that the metabolic information provided by MRSI combined with the anatomical information provided by MRI can significantly improve the assessment of cancer location and extent within the prostate, extracapsular spread, and cancer aggressiveness. Additionally, pre‐ and post‐therapy studies have demonstrated the potential of MRI/MRSI to provide a direct measure of the presence and spatial extent of prostate cancer after therapy, a measure of the time course of response, and information concerning the mechanism of therapeutic response. In addition to detecting metabolic biomarkers of disease behavior and therapeutic response, MRI/MRSI guidance can improve tissue selection for ex vivo analysis. High‐resolution magic angle spinning (1H HR‐MAS) spectroscopy provides a full chemical analysis of MRI/MRSI‐targeted tissues prior to pathologic and immunohistochemical analyses of the same tissue. Preliminary 1H HR‐MAS spectroscopy studies have already identified unique spectral patterns for healthy glandular and stromal tissues and prostate cancer, determined the composition of the composite in vivo choline peak, and identified the polyamine spermine as a new metabolic marker of prostate cancer. The addition of imaging sequences that provide other functional information within the same exam (dynamic contrast uptake imaging and diffusion‐weighted imaging) have also demonstrated the potential to further increase the accuracy of prostate cancer detection and characterization. J. Magn. Reson. Imaging 2002;16:451–463.

Quantitative analysis of prostate metabolites using 1H HR-MAS spectroscopy

A method was developed to quantify prostate metabolite concentrations using 1H high‐resolution magic angle spinning (HR‐MAS) spectroscopy. T1 and T2 relaxation times (in milliseconds) were determined for the major prostate metabolites and an internal TSP standard, and used to optimize the acquisition and repetition times (TRs) at 11.7 T. At 1°C, polyamines (PAs; T1mean = 100 ± 13, T2mean = 30.8 ± 7.4) and citrate (Cit; T1mean = 237 ± 39, T2mean = 68.1 ± 8.2) demonstrated the shortest relaxation times, while taurine (Tau; T1mean = 636 ± 78, T2mean = 331 ± 71) and choline (Cho; T1mean = 608 ± 60, T2mean = 393 ± 81) demonstrated the longest relaxation times. Millimolal metabolite concentrations were calculated for 60 postsurgical tissues using metabolite and TSP peak areas, and the mass of tissue and TSP. Phosphocholine plus glycerophosphocholine (PC+GPC), total choline (tCho), lactate (Lac), and alanine (Ala) concentrations were higher in prostate cancer ([PC+GPC]mean = 9.34 ± 6.43, [tCho]mean = 13.8 ± 7.4, [Lac]mean = 69.8 ± 27.1, [Ala]mean = 12.6 ± 6.8) than in healthy glandular ([PC+GPC]mean = 3.55 ± 1.53, P < 0.01; [tCho]mean = 7.06 ± 2.36, P < 0.01; [Lac]mean = 46.5 ± 17.4, P < 0.01; [Ala]mean = 8.63 ± 4.91, P = 0.051) and healthy stromal tissues ([PC+GPC]mean = 4.34 ± 2.46, P < 0.01; [tCho]mean = 7.04 ± 3.10, P < 0.01; [Lac]mean = 45.1 ± 18.6, P < 0.01; [Ala]mean = 6.80 ± 2.95, P < 0.01), while Cit and PA concentrations were significantly higher in healthy glandular tissues ([Cit]mean = 43.1 ± 21.2, [PAs]mean = 18.5 ± 15.6) than in healthy stromal ([Cit]mean = 16.1 ± 5.6, P < 0.01; [PAs]mean = 3.15 ± 1.81, P < 0.01) and prostate cancer tissues ([Cit]mean = 19.6 ± 12.7, P < 0.01; [PAs]mean = 5.28 ± 5.44, P < 0.01). Serial spectra acquired over 12 hr indicated that the degradation of Cho‐containing metabolites was minimized by acquiring HR‐MAS data at 1°C compared to 20°C. Magn Reson Med, 2006.

Proton HR-MAS spectroscopy and quantitative pathologic analysis of MRI/3D-MRSI-targeted postsurgical prostate tissues.

Proton high‐resolution magic angle spinning (1H HR‐MAS) NMR spectroscopy and quantitative histopathology were performed on the same 54 MRI/3D‐MRSI‐targeted postsurgical prostate tissue samples. Presurgical MRI/3D‐MRSI targeted healthy and malignant prostate tissues with an accuracy of 81%. Even in the presence of substantial tissue heterogeneity, distinct 1H HR‐MAS spectral patterns were observed for different benign tissue types and prostate cancer. Specifically, healthy glandular tissue was discriminated from prostate cancer based on significantly higher levels of citrate (P = 0.04) and polyamines (P = 0.01), and lower (P = 0.02) levels of the choline‐containing compounds choline, phosphocholine (PC), and glycerophosphocholine (GPC). Predominantly stromal tissue lacked both citrate and polyamines, but demonstrated significantly (P = 0.01) lower levels of choline compounds than cancer. In addition, taurine, myo‐inositol, and scyllo‐inositol were all higher in prostate cancer vs. healthy glandular and stromal tissues. Among cancer samples, larger increases in choline, and decreases in citrate and polyamines (P = 0.05) were observed with more aggressive cancers, and a MIB‐1 labeling index correlated (r = 0.62, P = 0.01) with elevated choline. The elucidation of spectral patterns associated with mixtures of different prostate tissue types and cancer grades, and the inclusion of new metabolic markers for prostate cancer may significantly improve the clinical interpretation of in vivo prostate MRSI data. Magn Reson Med 50:944–954, 2003.

The prostate: MR imaging and spectroscopy. Present and future.

The applications of combined MR imaging and MR spectroscopic imaging of prostate cancer have expanded significantly over the past 10 years and have reached the point of clinical trial results to test robustness and clinical significance. MR spectroscopic imaging extends the diagnostic evaluation of prostate cancer beyond the morphologic information provided by MR imaging throughout the detection of cellular metabolites. The combined metabolic and anatomic information provided by MR imaging and MR spectroscopic imaging has allowed a more accurate assessment of the presence, location, extent, and aggressiveness of prostate cancer both before and after treatment. This information has already demonstrated the ability to improve therapeutic planning for individual prostate cancer patients and shows great promise in the assessment of therapeutic response and the evaluation of new treatment regimes.

Evaluation of lactate and alanine as metabolic biomarkers of prostate cancer using 1H HR-MAS spectroscopy of biopsy tissues

The goal of this study was to investigate the use of lactate and alanine as metabolic biomarkers of prostate cancer using 1H high‐resolution magic angle spinning (HR‐MAS) spectroscopy of snap‐frozen transrectal ultrasound (TRUS)‐guided prostate biopsy tissues. A long‐echo‐time rotor‐synchronized Carr‐Purcell‐Meiboom‐Gill (CPMG) sequence including an electronic reference to access in vivo concentrations (ERETIC) standard was used to determine the concentrations of lactate and alanine in 82 benign and 16 malignant biopsies (mean 26.5% ± 17.2% of core). Low concentrations of lactate (0.61 ± 0.28 mmol/kg) and alanine (0.14 ± 0.06 mmol/kg) were observed in benign prostate biopsies, and there was no significant difference between benign predominantly glandular (N = 54) and stromal (N = 28) biopsies between patients with (N = 38) and without (N = 44) a positive clinical biopsy. In biopsies containing prostate cancer there was a highly significant (P < 0.0001) increase in lactate (1.59 ± 0.61 mmol/kg) and alanine (0.26 ± 0.07 mmol/kg), and minimal overlap with lactate concentrations in benign biopsies. This study demonstrates for the first time very low concentrations of lactate and alanine in benign prostate biopsy tissues. The significant increase in the concentration of both lactate and alanine in biopsy tissue containing as little as 5% cancer could be exploited in hyperpolarized 13C spectroscopic imaging (SI) studies of prostate cancer patients. Magn Reson Med 60:510–516, 2008.

Time-dependent effects of hormone-deprivation therapy on prostate metabolism as detected by combined magnetic resonance imaging and 3D magnetic resonance spectroscopic imaging

Combined MRI and 3D spectroscopic imaging (MRI/3D‐MRSI) was used to study the metabolic effects of hormone‐deprivation therapy in 65 prostate cancer patients, who underwent either short, intermediate, or long‐term therapy, compared to 30 untreated control patients. There was a significant time‐dependent loss of the prostatic metabolites choline, creatine, citrate, and polyamines during hormone‐deprivation therapy, resulting in the complete loss of all observable metabolites (total metabolic atrophy) in 25% of patients on long‐term therapy. The amount and time‐course of metabolite loss during therapy significantly differed for healthy and malignant tissues. Citrate levels decreased faster than choline and creatine levels during therapy, resulting in an increase in the mean (choline + creatine)/citrate ratio with duration of therapy. Due to a loss of all MRSI detectable citrate, this ratio could not be used to identify cancer in 69% of patients on long‐term therapy. In the absence of citrate, however, residual prostate cancer could still be detected by elevated choline levels (choline/creatine ratio ≥1.5), or the presence of only choline in the proton spectrum. The loss of citrate and the presence of total metabolic atrophy correlated roughly with decreasing serum prostatic specific antigen levels with increasing therapy. In summary, MRI/3D‐MRSI provided both a measure of residual cancer and a time‐course of metabolic response following hormone‐deprivation therapy. Magn Reson Med 46:49–57, 2001.

Dualband spectral-spatial RF pulses for prostate MR spectroscopic imaging

Although MR spectroscopic imaging (MRSI) of the prostate has demonstrated clinical utility for the staging and monitoring of cancer extent, current acquisition methods are often inadequate in several aspects. Conventional 180° pulses can suffer from chemical shift misregistration, and have high peak‐power requirements that can exceed hardware limits in many prostate MRSI studies. Optimal water and lipid suppression are also critical to obtain interpretable spectra. While complete suppression of the periprostatic lipid resonance is desired, controlled partial suppression of water can provide a valuable phase and frequency reference for data analysis and an assessment of experimental success in cases in which all other resonances are undetectable following treatment. In this study, new spectral‐spatial RF pulses were developed to negate chemical shift misregistration errors and to provide dualband excitation with partial excitation of the water resonance and full excitation of the metabolites of interest. Optimal phase modulation was also included in the pulse design to provide 40% reduction in peak RF power. Patient studies using the new pulses demonstrated both feasibility and clear benefits in the reliability and applicability of prostate cancer MRSI. Magn Reson Med 46:1079–1087, 2001.

Quantification of choline- and ethanolamine-containing metabolites in human prostate tissues using 1H HR-MAS total correlation spectroscopy.

A fast and quantitative 2D high‐resolution magic angle spinning (HR‐MAS) total correlation spectroscopy (TOCSY) experiment was developed to resolve and quantify the choline‐ and ethanolamine‐containing metabolites in human prostate tissues in ≈1 hr prior to pathologic analysis. At a 40‐ms mixing time, magnetization transfer efficiency constants were empirically determined in solution and used to calculate metabolite concentrations in tissue. Phosphocholine (PC) was observed in 11/15 (73%) cancer tissues but only 6/32 (19%) benign tissues. PC was significantly higher (0.39 ± 0.40 mmol/kg vs. 0.02 ± 0.07 mmol/kg, z = 3.5), while ethanolamine (Eth) was significantly lower in cancer versus benign prostate tissues (1.0 ± 0.8 mmol/kg vs. 2.3 ± 1.9 mmol/kg, z = 3.3). Glycerophosphocholine (GPC) (0.57 ± 0.87 mmol/kg vs. 0.29 ± 0.26 mmol/kg, z = 1.2), phosphoethanolamine (PE) (4.4 ± 2.2 mmol/kg vs. 3.4 ± 2.6 mmol/kg, z = 1.4), and glycerophosphoethanolamine (GPE) (0.54 ± 0.82 mmol/kg vs. 0.15 ± 0.15 mmol/kg, z = 1.8) were higher in cancer versus benign prostate tissues. The ratios of PC/GPC (3.5 ± 4.5 vs. 0.32 ± 1.4, z = 2.6), PC/PE (0.08 ± 0.08 vs. 0.01 ± 0.03, z = 3.5), PE/Eth (16 ± 22 vs. 2.2 ± 2.0, z = 2.4), and GPE/Eth (0.41 ± 0.51 vs. 0.06 ± 0.06, z = 2.6) were also significantly higher in cancer versus benign tissues. All samples were pathologically interpretable following HR‐MAS analysis; however, degradation experiments showed that PC, GPC, PE, and GPE decreased 7.7 ± 2.2%, while Cho+mI and Eth increased 18% in 1 hr at 1°C and a 2250 Hz spin rate. Magn Reson Med 60:33–40, 2008.

Single‐voxel oversampled J‐resolved spectroscopy of in vivo human prostate tissue

Single‐voxel J‐resolved spectroscopy with oversampling in the F1 dimension was used to obtain water unsuppressed 1H spectra of in situ human prostate tissue in 40 previously untreated prostate cancer patients. Based on T2‐weighted MRI and previous biopsy information, voxels were placed in regions of benign or malignant peripheral zone tissue, or in regions of predominantly glandular or stromal benign prostatic hyperplasia (BPH) within the central gland. The addition of a second J‐resolved dimension allowed for the observation of the J‐modulation of citrate, as well as the resolution of polyamines from overlapping choline and creatine signals. Regions of healthy peripheral zone tissue and glandular BPH all demonstrated high levels of citrate and polyamines, with consistent coupling and J‐modulation patterns. Conversely, regions of malignant peripheral zone tissue and stromal BPH demonstrated low levels of citrate and polyamines consistent with prior in vivo and ex vivo studies. Moreover, water T2 relaxation times determined for healthy peripheral zone tissue (mean 128 ± 15.2 msec) were significantly different than for malignant peripheral zone tissue (mean 88.0 ± 14.2 msec, P = 0.005), as well as for predominantly glandular (mean 92.4 ± 12.2 msec, P = 0.009) and stromal BPH (mean 70.9 ± 12.1 msec, P = 0.003). This preliminary study demonstrates that J‐resolved spectroscopy of the in situ prostate can be acquired, and the information obtained from the second spectral dimension can provide additional physiologic information from human prostate tissue in a reasonable amount of time (< 10 min). Magn Reson Med 45:973–980, 2001.

Evaluation of the ERETIC method as an improved quantitative reference for 1H HR-MAS spectroscopy of prostate tissue.

The Electronic REference To access In vivo Concentrations (ERETIC) method was applied to 1H HR‐MAS spectroscopy. The accuracy, precision, and stability of ERETIC as a quantitative reference were evaluated in solution and human prostate tissue samples. For comparison, the reliability of 3‐(trimethylsilyl)propionic‐2,2,3,3‐d4 acid (TSP) as a quantitation reference was also evaluated. The ERETIC and TSP peak areas were found to be stable in solution over the short‐term and long‐term, with long‐term relative standard deviations (RSDs) of 4.10% and 2.60%, respectively. Quantification of TSP in solution using the ERETIC peak as a reference and a calibrated, rotor‐dependent conversion factor yielded results with a precision ≤2.9% and an accuracy error ≤4.2% when compared with the expected values. The ERETIC peak area reproducibility was superior to TSPs reproducibility, corrected for mass, in both prostate surgical and biopsy samples (4.53% vs. 21.2% and 3.34% vs. 31.8%, respectively). Furthermore, the tissue TSP peaks exhibited only 27.5% of the expected area, which would cause an overestimation of metabolite concentrations if used as a reference. The improved quantification accuracy and precision provided by ERETIC may enable the detection of smaller metabolic differences that may exist between individual tissue samples and disease states. Magn Reson Med 61:525–532, 2009.