Dicarboxylic acids as pH sensors for hyperpolarized 13C magnetic resonance spectroscopic imaging.

Imaging tumoral pH may help to characterize aggressiveness, metastasis, and therapeutic response. We report the development of hyperpolarized [2-13C,D10]diethylmalonic acid, which exhibits a large pH-dependent 13C chemical shift over the physiological range. We demonstrate that co-polarization with [1-13C,D9]tert-butanol accurately measures pH via13C NMR and magnetic resonance spectroscopic imaging in phantoms.

Dynamic nuclear polarization of biocompatible (13)C-enriched carbonates for in vivo pH imaging.

A hyperpolarization technique using carbonate precursors of biocompatible molecules was found to yield high concentrations of hyperpolarized (13)C bicarbonate in solution. This approach enabled large signal gains for low-toxicity hyperpolarized (13)C pH imaging in a phantom and in vivo in a murine model of prostate cancer.

The role of metabolic imaging in radiation therapy of prostate cancer.

The goal of this study was to correlate prostatic metabolite concentrations from snap-frozen patient biopsies of recurrent cancer after failed radiation therapy with histopathological findings, including Ki-67 immunohistochemistry and pathologic grade, in order to identify quantitative metabolic biomarkers that predict for residual aggressive versus indolent cancer. A total of 124 snap-frozen transrectal ultrasound (TRUS)-guided biopsies were acquired from 47 men with untreated prostate cancer and from 39 men with a rising prostate-specific antigen and recurrent prostate cancer following radiation therapy. Biopsy tissues with Ki-67 labeling index ≤ 5% were classified as indolent cancer, while biopsy tissues with Ki-67 labeling index > 5% were classified as aggressive cancer. The majority (15 out of 17) of cancers classified as aggressive had a primary Gleason 4 pattern (Gleason score ≥ 4 + 3). The concentrations of choline-containing phospholipid metabolites (PC, GPC, and free Cho) and lactate were significantly elevated in recurrent cancer relative to surrounding benign tissues. There was also a significant increase in [PC] and reduction in [GPC] between untreated and irradiated prostate cancer biopsies. The concentration of the choline-containing phospholipid metabolites was significantly higher in recurrent aggressive (≈ twofold) than in recurrent indolent cancer biopsies, and the receiver operating characteristic (ROC) curve analysis of total choline to creatine ratio (tCho/Cr) demonstrated an accuracy of 95% (confidence interval = 0.88-1.00) for predicting aggressive recurrent disease. The tCho/Cr was significantly higher for identifying recurrent aggressive versus indolent cancer (tCho/Cr = 2.4 ± 0.4 versus 1.5 ± 0.2), suggesting that use of a higher threshold tCho/Cr ratio in future in vivo (1)H MRSI studies could improve the selection and therapeutic planning for patients who would benefit most from salvage focal therapy after failed radiation therapy.

Multimodal wavelet embedding representation for data combination (MaWERiC): integrating magnetic resonance imaging and spectroscopy for prostate cancer detection.

Recently, both Magnetic Resonance (MR) Imaging (MRI) and Spectroscopy (MRS) have emerged as promising tools for detection of prostate cancer (CaP). However, due to the inherent dimensionality differences in MR imaging and spectral information, quantitative integration of T(2) weighted MRI (T(2)w MRI) and MRS for improved CaP detection has been a major challenge. In this paper, we present a novel computerized decision support system called multimodal wavelet embedding representation for data combination (MaWERiC) that employs, (i) wavelet theory to extract 171 Haar wavelet features from MRS and 54 Gabor features from T(2)w MRI, (ii) dimensionality reduction to individually project wavelet features from MRS and T(2)w MRI into a common reduced Eigen vector space, and (iii), a random forest classifier for automated prostate cancer detection on a per voxel basis from combined 1.5 T in vivo MRI and MRS. A total of 36 1.5 T endorectal in vivo T(2)w MRI and MRS patient studies were evaluated per voxel by MaWERiC using a three-fold cross validation approach over 25 iterations. Ground truth for evaluation of results was obtained by an expert radiologist annotations of prostate cancer on a per voxel basis who compared each MRI section with corresponding ex vivo wholemount histology sections with the disease extent mapped out on histology. Results suggest that MaWERiC based MRS T(2)w meta-classifier (mean AUC, µ = 0.89 ± 0.02) significantly outperformed (i) a T(2)w MRI (using wavelet texture features) classifier (µ = 0.55 ± 0.02), (ii) a MRS (using metabolite ratios) classifier (µ = 0.77 ± 0.03), (iii) a decision fusion classifier obtained by combining individual T(2)w MRI and MRS classifier outputs (µ = 0.85 ± 0.03), and (iv) a data combination method involving a combination of metabolic MRS and MR signal intensity features (µ = 0.66 ± 0.02).

Correlation of phospholipid metabolites with prostate cancer pathologic grade, proliferative status and surgical stage - impact of tissue environment.

This study investigates the relationship between phospholipid metabolite concentrations, Gleason score, rate of cellular proliferation and surgical stage in malignant prostatectomy samples by performing one- and two-dimensional, high-resolution magic angle spinning, total correlation spectroscopy, pathology and Ki-67 staining on the same surgical samples. At radical prostatectomy, surgical samples were obtained from 49 patients [41 with localized TNM stage T1 and T2, and eight with local cancer spread (TNM stage T3)]. Thirteen of the tissue samples were high-grade prostate cancer [Gleason score: 4 + 3 (n = 7); 4 + 4 (n = 6)], 22 low-grade prostate cancer [Gleason score: 3 + 3 (n = 17); 3 + 4 (n = 5)] and 14 benign prostate tissues. This study demonstrates that high-grade prostate cancer shows significantly higher Ki-67 staining and concentrations of phosphocholine (PC) and glycerophosphocholine (GPC) than does low-grade prostate cancer (2.4 ± 2.8% versus 7.6 ± 3.5%, p < 0.005, and 0.671 ± 0.461 versus 1.87 ± 2.15 mmolal, p < 0.005, respectively). In patients with local cancer spread, increases in [PC + GPC + PE + GPE] (PE, phosphoethanolamine; GPE, glycerophosphoethanolamine] and Ki-67 index approached significance (4.2 ± 2.5 versus 2.7 ± 2.4 mmolal, p = 0.07, and 5.3 ± 3.8% versus 2.9 ± 3.8%, p = 0.07, respectively). PC and Ki-67 were significantly lower and GPC higher in prostate tissues when compared with cell cultures, presumably because of a lack of important stromal-epithelial interactions in cell cultures. The findings of this study will need to be validated in a larger cohort of surgical patients with clinical outcome data, but support the role of in vivo (1)H MRSI in discriminating between low- and high-grade prostate cancer based on the magnitude of elevation of the in vivo total choline resonance.

Imaging considerations for in vivo 13C metabolic mapping using hyperpolarized 13C-pyruvate.

One of the challenges of optimizing signal-to-noise ratio (SNR) and image quality in (13)C metabolic imaging using hyperpolarized (13)C-pyruvate is associated with the different MR signal time-courses for pyruvate and its metabolic products, lactate and alanine. The impact of the acquisition time window, variation of flip angles, and order of phase encoding on SNR and image quality were evaluated in mathematical simulations and rat experiments, based on multishot fast chemical shift imaging (CSI) and three-dimensional echo-planar spectroscopic imaging (3DEPSI) sequences. The image timing was set to coincide with the peak production of lactate. The strategy of combining variable flip angles and centric phase encoding (cPE) improved image quality while retaining good SNR. In addition, two aspects of EPSI sampling strategies were explored: waveform design (flyback vs. symmetric EPSI) and spectral bandwidth (BW = 500 Hz vs. 267 Hz). Both symmetric EPSI and reduced BW trended toward increased SNR. The imaging strategies reported here can serve as guidance to other multishot spectroscopic imaging protocols for (13)C metabolic imaging applications.

DNP-Hyperpolarized C Magnetic Resonance Metabolic Imaging for Cancer Applications.

Critical factors in characterizing the aggressiveness and response to therapy for tumors are the availability of noninvasive biomarkers that can be combined with other clinical parameters to tailor treatment regimens to each individual patient. While conventional magnetic resonance (MR) images are widely used to estimate changes in tumor size, they do not provide the rapid readout that is required to make an early decision on whether a change in therapy is required. The use of hyperpolarized (13)C agents to obtain metabolic imaging data is of great interest for in vivo assessment of tumors. One of the first agents being considered for in vivo studies with dynamic nuclear polarization (DNP) is 1-(13)C-labeled pyruvate, which is converted to lactate or alanine, dependent upon the needs of the tissue in question. The development of this new technology and its implementation in preclinical cancer model systems has clearly demonstrated the potential for highlighting tumor aggressiveness and for monitoring changes associated with disease progression. While there is further work to do in terms of studying new agents, improving the DNP process itself and developing efficient MR methods for acquiring and analyzing the data, the preliminary results are extremely promising and provide strong motivation for considering cancer as one of the first applications of the technology.

3D MR spectroscopic imaging in the evaluation of prostate cancer.

The management of prostate cancer is a complex issue with a varying range of treatment options available. Magnetic resonance (MR) imaging of the prostate has been available for sometime but has the limitation of only anatomical evaluation. Three-dimensional MR spectroscopy is emerging as a new and sensitive tool in the metabolic evaluation of prostate cancer. This article reviews the principle, techniques, and methods of evaluation of spectroscopy and also discusses the applications of spectroscopy in the current management of prostate cancer.

In vivo 13 carbon metabolic imaging at 3T with hyperpolarized 13C-1-pyruvate.

We present for the first time dynamic spectra and spectroscopic images acquired in normal rats at 3T following the injection of (13)C-1-pyruvate that was hyperpolarized by the dynamic nuclear polarization (DNP) method. Spectroscopic sampling was optimized for signal-to-noise ratio (SNR) and for spectral resolution of (13)C-1-pyruvate and its metabolic products (13)C-1-alanine, (13)C-1-lactate, and (13)C-bicarbonate. Dynamic spectra in rats were collected with a temporal resolution of 3 s from a 90-mm axial slab using a dual (1)H-(13)C quadrature birdcage coil to observe the combined effects of metabolism, flow, and T(1) relaxation. In separate experiments, spectroscopic imaging data were obtained during a 17-s acquisition of a 20-mm axial slice centered on the rat kidney region to provide information on the spatial distribution of the metabolites. Conversion of pyruvate to lactate, alanine, and bicarbonate occurred within a minute of injection. Alanine was observed primarily in skeletal muscle and liver, while pyruvate, lactate, and bicarbonate concentrations were relatively high in the vasculature and kidneys. In contrast to earlier work at 1.5 T, bicarbonate was routinely observed in skeletal muscle as well as the kidney and vasculature.

Dynamic contrast-enhanced MRI in normal and abnormal prostate tissues as defined by biopsy, MRI, and 3D MRSI.

This study characterized dynamic contrast-enhanced (DCE) MRI of prostate tissues: cancerous peripheral zone (PZ), normal PZ, stromal benign prostatic hyperplasia (BPH), and glandular BPH. MRI, MRSI, and DCE MRI were performed on 25 patients. Tissues were identified with MRI, MRSI, and (when available) biopsy results. Motion between MRI and DCE MRI, and within DCE MRI was assessed and manually corrected. To assess tissue and patient effects, native T1's were measured in 12 of 25 patients, and DCE MRI results were normalized to muscle enhancement. Regions of cancer had a higher peak enhancement (P < 0.006), faster enhancement rate (P < 0.0008), and faster washout slope (P < 0.05) than normal PZ tissues. Stromal BPH had the fastest enhancement rate (P < 0.003) of all tissues and tended to have the greatest enhancement. Intersequence motion averaged 2.6 mm and reached 7.9 mm. Motion within DCE MRI was generally minimal (<2 pixels), but one case showed a large shift that would have confounded the results. Native T1's were similar across the prostatic tissues. Interpatient variability in DCE MRI was only partially reduced by normalization to muscle. DCE MRI of the prostate discriminated PZ cancer from normal PZ tissues and predominantly stromal and glandular BPH.

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 degrees 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.

Localized prostate cancer: effect of hormone deprivation therapy measured by using combined three-dimensional 1H MR spectroscopy and MR imaging: clinicopathologic case-controlled study.

PURPOSE: To determine the accuracy of combined magnetic resonance (MR) imaging and three-dimensional (3D) proton MR spectroscopic imaging in localizing prostate cancer to a sextant of the gland in patients receiving hormone deprivation therapy. MATERIALS AND METHODS: Combined MR imaging/3D MR spectroscopic imaging examinations were performed in 16 hormone-treated patients and 48 nontreated matched control patients before radical prostatectomy and step-section histopathologic analysis. At MR imaging, cancer presence within the peripheral zone was assessed on a per sextant basis by two readers. At 3D MR spectroscopic imaging, cancer was identified by using (choline plus creatine)-to-citrate ratios at cutoff values of 2 and 3 SDs above mean normal peripheral zone values. Data were compared by using receiver operating characteristic analysis. RESULTS: There was no significant difference in the ability of combined MR imaging/3D MR spectroscopic imaging to localize prostate cancer in treated versus control patients. For MR imaging alone, the sensitivity and specificity were 91% and 48% (reader 1) and 75% and 60% (reader 2) in treated patients versus 79% and 60% (reader 1) and 84% and 43% (reader 2) in control patients. For 3D MR spectroscopic imaging alone (>3 SDs cutoff), higher specificity (treated, 80%; controls, 73%) but lower sensitivity (treated, 56%; controls, 53%) was attained. In treated patients, high sensitivity or specificity (up to 92%) was achieved when either or both modalities indicated cancer. CONCLUSION: When performed within 4 months after initiating hormone deprivation therapy, combined MR imaging/3D MR spectroscopic imaging had the same accuracy in localizing prostate cancer as in nontreated patients.

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 > or =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.

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).

Brachytherapy for prostate cancer: endorectal MR imaging of local treatment-related changes.

PURPOSE: To determine the local treatment-related endorectal magnetic resonance (MR) imaging findings after brachytherapy for prostate cancer. MATERIALS AND METHODS: Endorectal MR imaging was performed in 35 consecutive patients at a mean interval of 12 months (range, 1-31 months) after brachytherapy for prostate cancer. Transverse T1-weighted and high-spatial-resolution transverse and coronal T2-weighted images were acquired. Two readers reviewed MR image quality and findings, with discrepancies resolved by consensus. Posttreatment urinary symptoms in patients (n = 24) were documented by using chart review. RESULTS: All studies were of diagnostic quality. On T2-weighted images, prostatic findings consisted of diffuse low signal intensity (n = 35) and indistinct zonal anatomy (n = 34). Intra- and extraprostatic seed locations could be distinguished. The most common extraprostatic site of seed implantation was the neurovascular bundles (n = 35, bilateral in 32). The most common extraprostatic tissue finding was increased signal intensity on T2-weighted images in the levator ani muscle (n = 34) and the genitourinary diaphragm (n = 28). Postbrachytherapy urinary symptoms showed no demonstrable correlation with periurethral or genitourinary diaphragm seed implantation or with signal intensity change in the genitourinary diaphragm. CONCLUSION: Endorectal MR imaging can be used to evaluate seed distribution and to demonstrate treatment-related changes after brachytherapy for prostate cancer.

Magnetic resonance imaging and spectroscopic imaging: Improved patient selection and potential for metabolic intermediate endpoints in prostate cancer chemoprevention trials.

In the design of prostate cancer chemoprevention trials there is a clear need for improved patient selection and risk stratification, as well as the use of biomarkers that could provide earlier assessment of therapeutic efficacy. Studies in preprostatectomy patients have indicated that the metabolic information provided by 3-dimensional magnetic resonance spectroscopic imaging (3D-MRSI) combined with the morphologic information provided by magnetic resonance imaging (MRI) can improve the assessment of cancer location and extent within the prostate, extracapsular spread, and cancer aggressiveness. Additionally, pre- and posttherapy studies have demonstrated the potential of MRI/3D-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. These studies suggest that the addition of MRI/3D-MRSI data to prostate-specific antigen and biopsy data may improve patient selection and risk stratification for chemoprevention trials, improve tissue sampling for ex vivo molecular marker analysis, and provide shorter-term endpoints in chemoprevention trials. However, future studies are necessary to establish the ability of MRI/3D-MRSI to accurately assess patients with premalignant or very early malignant changes, to validate metabolic markers as intermediate endpoints in chemoprevention trials, and to correlate metabolic endpoints with other promising intermediate biomarkers.

Spectroscopy in prostate cancer: hope or hype?

Clinical applications of image-based radiation therapy for the study of prostate cancer have expanded significantly over the past years. The results of recent studies of magnetic resonance imaging (MRI) combined with magnetic resonance spectroscopic imaging (MRSI) demonstrate that the MRI/MRSI exam is a unique method by which to noninvasively study the cellular metabolism and anatomy of the prostate. This technology has the potential to define the tumor volume through functional or metabolic imaging. The results of current MRI/ MRSI studies also provide evidence that the magnitude of metabolic changes in regions of cancer before therapy, as well as the extent of the time course of metabolic changes after therapy, may improve our understanding of cancer aggressiveness. Assessment of cancer spread outside the prostate can be significantly improved by combining MRI findings with estimates of metabolic abnormalities provided by MRSI. Clinically, combined MRI/MRSI has already demonstrated a potential for improved diagnosis, staging, and treatment planning for patients with prostate cancer. Additional studies will reveal both the positive aspects and clinical challenges of MRI/

Three-dimensional magnetic resonance spectroscopic imaging of brain and prostate cancer.

Clinical applications of magnetic resonance spectroscopic imaging (MRSI) for the study of brain and prostate cancer have expanded significantly over the past 10 years. Proton MRSI studies of the brain and prostate have demonstrated the feasibility of noninvasively assessing human cancers based on metabolite levels before and after therapy in a clinically reasonable amount of time. MRSI provides a unique biochemical "window" to study cellular metabolism noninvasively. MRSI studies have demonstrated dramatic spectral differences between normal brain tissue (low choline and high N-acetyl aspartate, NAA) and prostate (low choline and high citrate) compared to brain (low NAA, high choline) and prostate (low citrate, high choline) tumors. The presence of edema and necrosis in both the prostate and brain was reflected by a reduction of the intensity of all resonances due to reduced cell density. MRSI was able to discriminate necrosis (absence of all metabolites, except lipids and lactate) from viable normal tissue and cancer following therapy. The results of current MRSI studies also provide evidence that the magnitude of metabolic changes in regions of cancer before therapy as well as the magnitude and time course of metabolic changes after therapy can improve our understanding of cancer aggressiveness and mechanisms of therapeutic response. Clinically, combined MRI/MRSI has already demonstrated the potential for improved diagnosis, staging and treatment planning of brain and prostate cancer. Additionally, studies are under way to determine the accuracy of anatomic and metabolic parameters in providing an objective quantitative basis for assessing disease progression and response to therapy.

Sextant localization of prostate cancer: comparison of sextant biopsy, magnetic resonance imaging and magnetic resonance spectroscopic imaging with step section histology.

PURPOSE: We compared the accuracy of endorectal magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging with that of sextant biopsy for the sextant localization of prostate cancer. MATERIALS AND METHODS: Sextant biopsy, MRI, magnetic resonance spectroscopic imaging and radical prostatectomy with step section histology were done in 47 patients with prostate cancer. For each sextant we categorized biopsy and imaging results as positive or negative for cancer. Step section histology was used as the standard of reference. RESULTS: For sextant localization of prostate cancer MRI and magnetic resonance spectroscopic imaging were more sensitive but less specific than biopsy (67% and 76% versus 50%, and 69% and 68% versus 82%, respectively). The sensitivity of sextant biopsy was significantly less in the prostate apex than in the mid prostate or prostate base (38% versus 52% and 62%, respectively). MRI and magnetic resonance spectroscopic imaging had similar efficacy throughout the prostate compared with biopsy only as well as better sensitivity and specificity in the prostate apex (60% and 75%, and 86% and 68%, respectively). A positive biopsy or imaging result had 94% sensitivity for cancer and concordant positivity by all 3 tests was highly specific at 98%. CONCLUSIONS: Overall MRI and magnetic resonance spectroscopic imaging have accuracy similar to biopsy for intraprostatic localization of cancer and they are more accurate than biopsy in the prostate apex. These 2 imaging modalities may supplement biopsy results by increasing physician confidence when evaluating intraprostatic tumor location, which may be important for planning disease targeted therapy.