John Kurhanewicz

Metabolic imaging of patients with prostate cancer using hyperpolarized [1-¹³C]pyruvate.

Metabolic imaging with hyperpolarized pyruvate was used to safely and noninvasively visualize prostate tumors in patients. The Hyperpolarized Prostate Cancer cells have a different metabolism than healthy cells. Specifically, they consume more pyruvate—a key component in glycolysis—than their normal counterparts. Nelson and colleagues therefore used a hyperpolarized form of pyruvate ([1-13C]pyruvate) to sensitively image increased levels of its product, [1-13C]lactate, as well as the flux of pyruvate to lactate. The [1-13C]pyruvate agent was used here in a first-in-human study in men with prostate cancer. Patients received varying doses of [1-13C]pyruvate that were found to be safe. These patients were then rapidly imaged with hyperpolarized 13C magnetic resonance (MR), which was able to provide dynamic (time course) information as well as three-dimensional (3D) (spatial) data at a single time point. Tumors were detected in all patients with biopsy-proven cancer. And, importantly, with 13C MR imaging (MRI), Nelson et al. were able to see cancer in regions of the prostate that were previously considered to be tumor-free upon inspection with other conventional anatomic imaging methods. With the ability to safely image tumor location and also follow tumor metabolism over time, hyperpolarized 13C MRI may be useful both for initial diagnosis and for monitoring therapy. Although the patients in this study had early-stage disease, the authors believe that [1-13C]lactate/[1-13C]pyruvate flux will only increase with tumor grade, making this imaging technology amenable to more advanced and aggressive cancers. Future studies will focus on optimizing agent preparation and delivery to ensure that this imaging technology can benefit patients in all clinical settings. This first-in-man imaging study evaluated the safety and feasibility of hyperpolarized [1-13C]pyruvate as an agent for noninvasively characterizing alterations in tumor metabolism for patients with prostate cancer. Imaging living systems with hyperpolarized agents can result in more than 10,000-fold enhancement in signal relative to conventional magnetic resonance (MR) imaging. When combined with the rapid acquisition of in vivo 13C MR data, it is possible to evaluate the distribution of agents such as [1-13C]pyruvate and its metabolic products lactate, alanine, and bicarbonate in a matter of seconds. Preclinical studies in cancer models have detected elevated levels of hyperpolarized [1-13C]lactate in tumor, with the ratio of [1-13C]lactate/[1-13C]pyruvate being increased in high-grade tumors and decreased after successful treatment. Translation of this technology into humans was achieved by modifying the instrument that generates the hyperpolarized agent, constructing specialized radio frequency coils to detect 13C nuclei, and developing new pulse sequences to efficiently capture the signal. The study population comprised patients with biopsy-proven prostate cancer, with 31 subjects being injected with hyperpolarized [1-13C]pyruvate. The median time to deliver the agent was 66 s, and uptake was observed about 20 s after injection. No dose-limiting toxicities were observed, and the highest dose (0.43 ml/kg of 230 mM agent) gave the best signal-to-noise ratio for hyperpolarized [1-13C]pyruvate. The results were extremely promising in not only confirming the safety of the agent but also showing elevated [1-13C]lactate/[1-13C]pyruvate in regions of biopsy-proven cancer. These findings will be valuable for noninvasive cancer diagnosis and treatment monitoring in future clinical trials.

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.

Hyperpolarized 13C Lactate, Pyruvate, and Alanine: Noninvasive Biomarkers for Prostate Cancer Detection and Grading

An extraordinary new technique using hyperpolarized (13)C-labeled pyruvate and taking advantage of increased glycolysis in cancer has the potential to improve the way magnetic resonance imaging is used for detection and characterization of prostate cancer. The aim of this study was to quantify, for the first time, differences in hyperpolarized [1-(13)C] pyruvate and its metabolic products between the various histologic grades of prostate cancer using the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Fast spectroscopic imaging techniques were used to image lactate, alanine, and total hyperpolarized carbon (THC = lactate + pyruvate + alanine) from the entire abdomen of normal mice and TRAMP mice with low- and high-grade prostate tumors in 14 s. Within 1 week, the mice were dissected and the tumors were histologically analyzed. Hyperpolarized lactate SNR levels significantly increased (P < 0.05) with cancer development and progression (41 +/- 11, 74 +/- 17, and 154 +/- 24 in normal prostates, low-grade primary tumors, and high-grade primary tumors, respectively) and had a correlation coefficient of 0.95 with the histologic grade. In addition, there was minimal overlap in the lactate levels between the three groups with only one of the seven normal prostates overlapping with the low-grade primary tumors. The amount of THC, a possible measure of substrate uptake, and hyperpolarized alanine also increased with tumor grade but showed more overlap between the groups. In summary, elevated hyperpolarized lactate and potentially THC and alanine are noninvasive biomarkers of prostate cancer presence and histologic grade that could be used in future three-dimensional (13)C spectroscopic imaging studies of prostate cancer patients.

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.

Very selective suppression pulses for clinical MRSI studies of brain and prostate cancer

Focal three‐dimensional magnetic resonance spectroscopic imaging (3D MRSI) methods based on conventional point resolved spectroscopy (PRESS) localization are compromised by the geometric restrictions in volume prescription and by chemical shift registration errors. Outer volume saturation (OVS) pulses have been applied to address the geometric limits, but conventional OVS pulses do little to overcome chemical shift registration error, are not particularly selective, and often leave substantial signals that can degrade the spectra of interest. In this paper, an optimized sequence of quadratic phase pulses is introduced to provide very selective spatial suppression with improved B1 and T1 insensitivity. This method was then validated in volunteer studies and in clinical 3D MRSI exams of brain tumors and prostate cancer. Magn Reson Med 43:23–33, 2000.

Static field intensity modulation to treat a dominant intra-prostatic lesion to 90 Gy compared to seven field 3-dimensional radiotherapy

PURPOSE/OBJECTIVE Recent studies supported by histopathological correlation suggest that the combined use of endorectal magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) allows differentiation of normal and carcinomatous prostate. The goal of this study was to use static field intensity modulated three-dimensional conformal radiotherapy (SF-IMRT) to treat the entire prostate to a total dose of >70 Gy, while concurrently treating a dominant intraprostatic lesion (DIL) defined by MRI+MRS to 90 Gy while not exceeding normal tissue tolerances. MATERIALS AND METHODS For the example chosen, the DIL consisted of a large portion of the peripheral zone of the left lobe of the prostate. University of Michigan (UM-PLAN) three-dimensional treatment planning software was used to design a partially shielded 7 field conformal isodose plan that would treat the entire prostate to >70 Gy at 1.8 Gy per day (80% isodose line), while concurrently treating the DIL to 2.25 Gy per day for a total dose of 90 Gy. Dose volume histograms (DVH) were used to compare the rectal doses to rectum and other adjacent normal tissues using these two techniques. RESULTS SF-IMRT as described, allowed a total dose of 90 Gy to encompass the DIL, while the rectal dose was slightly lower than that using the standard 7 field technique to the prostate alone. For example, the dose to 30 cm3 of the rectum was 40 Gy using SF-IMRT and 48 Gy for the standard 7 field technique. Because of differences in the dose per fraction the biologic advantages of the SF-IMRT technique are likely to be even greater. CONCLUSIONS This study demonstrates the feasibility of using SF-IMRT to treat a DIL involving a single lobe of the prostate, as defined by MRI/MRS, to 90 Gy, while simultaneously treating the prostate to >70 Gy without increasing the dose to surrounding normal tissues. A similar approach could be used to treat multifocal disease. This method of treatment is an alternative to dynamic intensity modulation. It is less expensive, and can be adapted to any radiation therapy department without the use of an inverse treatment planning programs.

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.

Prostate cancer: sextant localization at MR imaging and MR spectroscopic imaging before prostatectomy--results of ACRIN prospective multi-institutional clinicopathologic study.

PURPOSE To determine the incremental benefit of combined endorectal magnetic resonance (MR) imaging and MR spectroscopic imaging, as compared with endorectal MR imaging alone, for sextant localization of peripheral zone (PZ) prostate cancer. MATERIALS AND METHODS This prospective multicenter study, conducted by the American College of Radiology Imaging Network (ACRIN) from February 2004 to June 2005, was institutional review board approved and HIPAA compliant. Research associates were required to follow consent guidelines approved by the Office for Human Research Protection and established by the institutional review boards. One hundred thirty-four patients with biopsy-proved prostate adenocarcinoma and scheduled to undergo radical prostatectomy were recruited at seven institutions. T1-weighted, T2-weighted, and spectroscopic MR sequences were performed at 1.5 T by using a pelvic phased-array coil in combination with an endorectal coil. Eight readers independently rated the likelihood of the presence of PZ cancer in each sextant by using a five-point scale-first on MR images alone and later on combined MR-MR spectroscopic images. Areas under the receiver operating characteristic curve (AUCs) were calculated with sextant as the unit of analysis. The presence or absence of cancer at centralized histopathologic evaluation of prostate specimens was the reference standard. Reader-specific receiver operating characteristic curves for values obtained with MR imaging alone and with combined MR imaging-MR spectroscopic imaging were developed. The AUCs were estimated by using Mann-Whitney statistics and appropriate 95% confidence intervals. RESULTS Complete data were available for 110 patients (mean age, 58 years; range, 45-72 years). MR imaging alone and combined MR imaging-MR spectroscopic imaging had similar accuracy in PZ cancer localization (AUC, 0.60 vs 0.58, respectively; P > .05). AUCs for individual readers were 0.57-0.63 for MR imaging alone and 0.54-0.61 for combined MR imaging-MR spectroscopic imaging. CONCLUSION In patients who undergo radical prostatectomy, the accuracy of combined 1.5-T endorectal MR imaging-MR spectroscopic imaging for sextant localization of PZ prostate cancer is equal to that of MR imaging alone.

Multiparametric magnetic resonance imaging in prostate cancer: present and future

Purpose of review The purpose of this article is to review the current status of advanced MRI techniques based on anatomic, metabolic and physiologic properties of prostate cancer with a focus on their impact in managing prostate cancer patients. Recent findings Prostate cancer can be identified based on reduced T2 signal intensity on MRI, increased choline and decreased citrate and polyamines on magnetic resonance spectroscopic imaging (MRSI), decreased diffusivity on diffusion tensor imaging (DTI), and increased uptake on dynamic contrast enhanced (DCE) imaging. All can be obtained within a 60-min 3T magnetic resonance exam. Each complementary method has inherent advantages and disadvantages: T2 MRI has high sensitivity but poor specificity; magnetic resonance spectroscopic imaging has high specificity but poor sensitivity; diffusion tensor imaging has high spatial resolution, is the fastest, but sensitivity/specificity needs to be established; dynamic contrast enhanced imaging has high spatial resolution, but requires a gadolinium based contrast agent injection, and sensitivity/specificity needs to be established. Summary The best characterization of prostate cancer in individual patients will most likely result from a multiparametric (MRI/MRSI/DTI/DCE) exam using 3T magnetic resonance scanners but questions remain as to how to analyze and display this large amount of imaging data, and how to optimally combine the data for the most accurate assessment of prostate cancer. Histological correlations or clinical outcomes are required to determine sensitivity/specificity for each method and optimal combinations of these approaches.