Combined Compressed Sensing and SENSE to Enhance Radiation Therapy Magnetic Resonance Imaging Simulation.

PURPOSE: To assess the effect of a combination of compressed sensing and SENSitivity Encoding (SENSE) acceleration techniques on radiation therapy magnetic resonance imaging (MRI) simulation workflows. METHODS AND MATERIALS: Thirty-seven acquisitions were performed with both SENSE-only (SENSE) and combined compressed sensing and SENSE (CS) techniques in 24 patients receiving radiation therapy MRI simulation for a wide range of disease sites. The anatomic field of view prescription and image resolution were identical for both SENSE and CS acquisitions to ensure fair comparison. The acquisition time of all images was recorded to assess time savings. For each image pair, image quality, and ability to contour were assessed by 2 radiation oncologists. Aside from direct image pair comparisons, the feasibility of using CS to improve MRI simulation protocols by increasing image resolution, field of view, and reducing motion artifacts was also evaluated. RESULTS: CS resulted in an average reduction of 27% in scan time with negligible changes in image quality and the ability to contour structures for RT treatment planning compared with SENSE. Physician scoring of image quality and ability to contour shows that while SENSE still has slightly better image quality compared with CS, this observed difference in image quality did not affect the ability to contour. In addition, the higher acceleration capability of CS enabled use of superior-inferior direction phase encoding in a sagittal 3-dimensional T2-weighted scan for substantially improved visibility of the prostatic urethra, which eliminated the need for a Foley catheter in most patients. CONCLUSIONS: The combination of compressed sensing and parallel imaging resulted in marked improvements in the MRI Simulation workflow. The scan time was reduced without significantly affecting image quality in the context of ability to contour. The acceleration capabilities allowed for increased image resolution under similar scanning times as well as significantly improved urethra visualization in prostate simulations.

Clinical experience and workflow challenges with magnetic resonance-only radiation therapy simulation and planning for prostate cancer.

BACKGROUND AND PURPOSE: Magnetic Resonance (MR)-only planning has been implemented clinically for radiotherapy of prostate cancer. However, fewer studies exist regarding the overall success rate of MR-only workflows. We report on successes and challenges of implementing MR-only workflows for prostate. MATERIALS AND METHODS: A total of 585 patients with prostate cancer underwent an MR-only simulation and planning between 06/2016-06/2018. MR simulation included images for contouring, synthetic-CT generation and fiducial identification. Workflow interruptions occurred that required a backup CT, a re-simulation or an update to our current quality assurance (QA) process. The challenges were prospectively evaluated and classified into syn-CT generation, motion/artifacts in the MRs, fiducial QA and bowel preparation guidelines. RESULTS: MR-only simulation was successful in 544 (93.2 %) patients. . In seventeen patients (2.9%), reconstruction of synthetic-CT failed due to patient size, femur angulation, or failure to determine the body contour. Twenty-four patients (4.1%) underwent a repeat/backup CT scan because of artifacts on the MR such as image blur due to patient motion or biopsy/surgical artifacts that hampered identification of the implanted fiducial markers. In patients requiring large coverage due to nodal involvement, inhomogeneity artifacts were resolved by using a two-stack acquisition and adaptive inhomogeneity correction. Bowel preparation guidelines were modified to address frequent rectum/gas issues due to longer MR scan time. CONCLUSIONS: MR-only simulation has been successfully implemented for a majority of patients in the clinic. However, MR-CT or CT-only pathway may still be needed for patients where MR-only solution fails or patients with MR contraindications.

Technical Note: A custom-designed flexible MR coil array for spine radiotherapy treatment planning.

PURPOSE: To assess the performance and optimize the MR image quality when using a custom-built flexible radiofrequency (RF) spine coil array fitted between the immobilization device and the patient for spine radiotherapy treatment planning. METHODS: A 32 channel flexible custom-designed receive-only coil array has been developed for spine radiotherapy simulation for a 3 T Philips MR scanner. Coil signal-to-noise performance and interactions with standard vendor hardware were assessed. In four volunteers, immobilization molds were created with a dummy version of the array within the mold, and subjects were scanned using the custom array in the mold. Phantoms and normal volunteers were scanned with both the custom spine coil array and the vendor's FDA-approved in-table posterior coil array to compare performance. RESULTS: The superior-inferior field of view for the custom spine array was ~30 cm encompassing at least 10 vertebrae. A noise correlation matrix showed at least 25 dB isolation between all coil elements. Signal-to-noise ratio (SNR) calculated on a phantom scan at the depth of the spinal cord was a factor of 3 higher with the form-fit spine array as compared to the vendor's posterior coil array. The body coil B1 transmit map was equivalent with and without the spine array in place demonstrating that the elements are decoupled from the body coil. Volunteer imaging showed improved SNR as compared to the vendor's posterior coil array. The custom array permitted a high degree of acceleration making possible the acquisition of isotropic high-resolution 1.1 × 1.1 × 1.1 mm3 three-dimensional data set over a 30-cm section of the spine in less than 5 min. CONCLUSION: The custom-designed form-fitting flexible spine coil array provided enhanced SNR and increased acceleration compared to the vendor's posterior array. Future studies will assess MR-based spinal cord imaging with the custom coil in comparison to CT myelogram.

A super-resolution framework for the reconstruction of T2-weighted (T2w) time-resolved (TR) 4DMRI using T1w TR-4DMRI as the guidance.

PURPOSE: The purpose of this study was to develop T2-weighted (T2w) time-resolved (TR) four-dimensional magnetic resonance imaging (4DMRI) reconstruction technique with higher soft-tissue contrast for multiple breathing cycle motion assessment by building a super-resolution (SR) framework using the T1w TR-4DMRI reconstruction as guidance. METHODS: The multi-breath T1w TR-4DMRI was reconstructed by deforming a high-resolution (HR: 2 × 2 × 2 mm3 ) volumetric breath-hold (BH, 20s) three-dimensional magnetic resonance imaging (3DMRI) image to a series of low-resolution (LR: 5 × 5 × 5 mm3 ) 3D cine images at a 2Hz frame rate in free-breathing (FB, 40 s) using an enhanced Demons algorithm, namely [T1BH →FB] reconstruction. Within the same imaging session, respiratory-correlated (RC) T2w 4DMRI (2 × 2 × 2 mm3 ) was acquired based on an internal navigator to gain HR T2w (T2HR ) in three states (full exhalation and mid and full inhalation) in ~5 min. Minor binning artifacts in the RC-4DMRI were automatically identified based on voxel intensity correlation (VIC) between consecutive slices as outliers (VIC < VICmean -σ) and corrected by deforming the artifact slices to interpolated slices from the adjacent slices iteratively until no outliers were identified. A T2HR image with minimal deformation (<1 cm at the diaphragm) from the T1BH image was selected for multi-modal B-Spline deformable image registration (DIR) to establish the T2HR -T1BH voxel correspondence. Two approaches to reconstruct T2w TR-4DMRI were investigated: (A) T2HR →[T1BH →FB]: to deform T2w HR to T1w BH only as T1w TR-4DMRI was reconstructed, and combine the two displacement vector fields (DVFs) to reconstruct T2w TR-4DMRI, and (B) [T2HR ←T1BH ]→FB: to deform T1w BH to T2w HR first and apply the deformed T1w BH to reconstruct T2w TR-4DMRI. The reconstruction times were similar, 8-12 min per volume. To validate the two methods, T2w- and T1w-mapped 4D XCAT digital phantoms were utilized with three synthetic spherical tumors (ϕ = 2.0, 3.0, and 4.0 cm) in the lower or mid lobes as the ground truth to evaluate the tumor location (the center of mass, COM), size (volume ratio, %V), and shape (Dice index). Six lung cancer patients were scanned under an IRB-approved protocol and the T2w TR-4DMRI images reconstructed from the two methods were compared based on the preservation of the three tumor characteristics. The local tumor-contained image quality was also characterized using the VIC and structure similarity (SSIM) indexes. RESULTS: In the 4D digital phantom, excellent tumor alignment after T2HR -T1HR DIR is achieved: ∆COM = 0.8 ± 0.5 mm, %V = 1.06 ± 0.02, and Dice = 0.91 ± 0.03, in both deformation directions using the DIR-target image as the reference. In patients, binning artifacts are corrected with improved image quality: average VIC increases from 0.92 ± 0.03 to 0.95 ± 0.01. Both T2w TR-4DMRI reconstruction methods produce similar tumor alignment errors ∆COM = 2.9 ± 0.6 mm. However, method B ([T2HR ←T1BH ]→FB) produces superior results in preserving more T2w tumor features with a higher %V = 0.99 ± 0.03, Dice = 0.81 ± 0.06, VIC = 0.85 ± 0.06, and SSIM = 0.65 ± 0.10 in the T2w TR-4DMRI images. CONCLUSIONS: This study has demonstrated the feasibility of T2w TR-4DMRI reconstruction with high soft-tissue contrast and adequately-preserved tumor position, size, and shape in multiple breathing cycles. The T2w-centric DIR (method B) produces a superior solution for the SR-based framework of T2w TR-4DMRI reconstruction with highly preserved tumor characteristics and local image features, which are useful for tumor delineation and motion management in radiation therapy.

Comparison of Motion-Insensitive T2-Weighted MRI Pulse Sequences for Visualization of the Prostatic Urethra During MR Simulation.

PURPOSE: The use of magnetic resonance imaging (MRI) for radiation therapy simulation is growing because of its ability to provide excellent delineation of target tissue and organs at risk. With the use of hypofractionated schemes in prostate cancer, urethral sparing is essential; however, visualization of the prostatic urethra can be challenging because of the presence of benign prostatic hyperplasia as well as respiratory motion artifacts. The goal of this study was to compare the utility of 2 motion-insensitive, T2-weighted MRI pulse sequences for urethra visualization in the setting of MRI-based simulation. METHODS AND MATERIALS: Twenty-two patients undergoing MRI simulation without Foley catheters were imaged on a 3 Tesla MRI scanner between October 2018 and January 2019. Sagittal multislice data were acquired using (1) MultiVane XD radial sampling with parallel imaging acceleration (MVXD) and (2) single-shot fast-spin-echo (SSFSE) sequences with acquisition times of 2 to 3 minutes per sequence. For each examination, 2 genitourinary radiologists scored prostatic urethra visibility on a 1-to-5 scale and rated the signal-to-noise ratio and the presence of artifacts in each series. RESULTS: Urethral visibility was scored higher in the MVXD series than in the SSFSE series in 18 of 22 cases (Reader 1) and 17 of 22 cases (Reader 2). The differences in scores between MVXD and SSFSE were statistically significant for both readers (P < .0001 for both, paired Student's t-test) and interobserver agreement was high (Cohen's kappa = 0.67). Both readers found the signal-to-noise ratio of the MVXD sequence to be superior in all cases. The MVXD sequence was found to generate more artifacts than the SSFSE sequence, but these tended to appear in the periphery and did not affect the ability to visualize the urethra. CONCLUSIONS: A radial T2-weighted multislice pulse sequence was superior to an SSFSE sequence for visualization of the urethra in the setting of magnetic resonance simulation for prostate cancer.

Diffusion-weighted MRI of the lung at 3T evaluated using echo-planar-based and single-shot turbo spin-echo-based acquisition techniques for radiotherapy applications.

PURPOSE: To compare single-shot echo-planar (SS-EPI)-based and turbo spin-echo (SS-TSE)-based diffusion-weighted imaging (DWI) in Non-Small Cell Lung Cancer (NSCLC) patients and to characterize the distributions of apparent diffusion coefficient (ADC) values generated by the two techniques. METHODS: Ten NSCLC patients were enrolled in a prospective IRB-approved study to compare and optimize DWI using EPI and TSE-based techniques for radiotherapy planning. The imaging protocol included axial T2w, EPI-based DWI and TSE-based DWI on a 3 T Philips scanner. Both EPI-based and TSE-based DWI sequences used three b values (0, 400, and 800 s/mm2 ). The acquisition times for EPI-based and TSE-based DWI were 5 and 8 min, respectively. DW-MR images were manually coregistered with axial T2w images, and tumor volume contoured on T2w images were mapped onto the DWI scans. A pixel-by-pixel fit of tumor ADC was calculated based on monoexponential signal behavior. Tumor ADC mean, standard deviation, kurtosis, and skewness were calculated and compared between EPI and TSE-based DWI. Image distortion and ADC values between the two techniques were also quantified using fieldmap analysis and a NIST traceable ice-water diffusion phantom, respectively. RESULTS: The mean ADC for EPI and TSE-based DWI were 1.282 ± 0.42 × 10-3 and 1.211 ± 0.31 × 10-3  mm2 /s. The average skewness and kurtosis were 0.14 ± 0.4 and 2.43 ± 0.40 for DWI-EPI and -0.06 ± 0.69 and 2.89 ± 0.62 for DWI-TSE. Fieldmap analysis showed a mean distortion of 13.72 ± 8.12 mm for GTV for DWI-EPI and 0.61 ± 0.4 mm for DWI-TSE. ADC values obtained using the diffusion phantom for the two techniques were within 0.03 × 10-3  mm2 /s with respect to each other as well as the established values. CONCLUSIONS: Diffusion-weighted turbo spin-echo shows better geometrical accuracy compared to DWI-EPI. Mean ADC values were similar with both acquisitions but the shape of the histograms was different based on the skewness and kurtosis values. The impact of differences in respiratory technique on ADC values requires further investigation.

Novel Super-Resolution Approach to Time-Resolved Volumetric 4-Dimensional Magnetic Resonance Imaging With High Spatiotemporal Resolution for Multi-Breathing Cycle Motion Assessment.

PURPOSE: To develop and evaluate a super-resolution approach to reconstruct time-resolved 4-dimensional magnetic resonance imaging (TR-4DMRI) with a high spatiotemporal resolution for multi-breathing cycle motion assessment. METHODS AND MATERIALS: A super-resolution approach was developed to combine fast 3-dimensional (3D) cine MRI with low resolution during free breathing (FB) and high-resolution 3D static MRI during breath hold (BH) using deformable image registration. A T1-weighted, turbo field echo sequence, coronal 3D cine acquisition, partial Fourier approximation, and SENSitivity Encoding parallel acceleration were used. The same MRI pulse sequence, field of view, and acceleration techniques were applied in both FB and BH acquisitions; the intensity-based Demons deformable image registration method was used. Under an institutional review board-approved protocol, 7 volunteers were studied with 3D cine FB scan (voxel size: 5 × 5 × 5 mm3) at 2 Hz for 40 seconds and a 3D static BH scan (2 × 2 × 2 mm3). To examine the image fidelity of 3D cine and super-resolution TR-4DMRI, a mobile gel phantom with multi-internal targets was scanned at 3 speeds and compared with the 3D static image. Image similarity among 3D cine, 4DMRI, and 3D static was evaluated visually using difference image and quantitatively using voxel intensity correlation and Dice index (phantom only). Multi-breathing-cycle waveforms were extracted and compared in both phantom and volunteer images using the 3D cine as the references. RESULTS: Mild imaging artifacts were found in the 3D cine and TR-4DMRI of the mobile gel phantom with a Dice index of >0.95. Among 7 volunteers, the super-resolution TR-4DMRI yielded high voxel-intensity correlation (0.92 ± 0.05) and low voxel-intensity difference (<0.05). The detected motion differences between TR-4DMRI and 3D cine were -0.2 ± 0.5 mm (phantom) and -0.2 ± 1.9 mm (diaphragms). CONCLUSION: Super-resolution TR-4DMRI has been reconstructed with adequate temporal (2 Hz) and spatial (2 × 2 × 2 mm3) resolutions. Further TR-4DMRI characterization and improvement are necessary before clinical applications. Multi-breathing cycles can be examined, providing patient-specific breathing irregularities and motion statistics for future 4D radiation therapy.

Multiatlas approach with local registration goodness weighting for MRI-based electron density mapping of head and neck anatomy.

PURPOSE: The growing use of magnetic resonance imaging (MRI) as a substitute for computed tomography-based treatment planning requires the development of effective algorithms to generate electron density maps for treatment planning and patient setup verification. The purpose of this work was to develop a method to synthesize computerized tomography (CT) for MR-only radiotherapy of head and neck cancer patients. METHODS: The algorithm is based on registration of multiple patient datasets containing both MRI and CT images (a "multiatlas" algorithm). Twelve matched pairs of good quality CT and MRI scans (those without apparent motion and blurring artifacts) were selected from a pool of head and neck cancer patients to form the atlas. All atlas MRI scans were preprocessed to reduce scanner- and patient-induced intensity inhomogeneities and to standardize their intensity histograms. Atlas CT and MRIs were coregistered using a novel bone-to-air replacement technique applied to the CT scans that improves the similarity between CTs and MRIs and facilitates the registration process. For each new patient, all atlas MRIs are deformed initially onto the new patients' MRI. We introduce a generalized registration error (GRE) metric that automatically measures the goodness of local registration between MRI pairs. The final synthetic CT value at each point is a nonlinear GRE-weighted average of the atlas CTs. For evaluation, the leave-one-out technique was used for synthetic CT generation and the mean absolute error (MAE) between the original and synthetic CT was computed over the entire CT image. The impact of our proposed CT-MR registration scheme on the accuracy of the final synthetic CT was also studied. The original treatment plans were also recomputed on the new synthetic CTs and dose-volume histogram metrics were compared. In addition, the two-dimensional (2D) gamma analysis at 1%/1 mm and 2%/2 mm dose difference/distance to agreement was also performed to study the dose distribution at the isocenter. RESULTS: MAE error (± standard deviation) between the original and the synthetic CTs was 64 ± 10, 113 ± 12, and 130 ± 28 Hounsfield Unit (HU) for the entire image, air, and bone regions respectively. Our results showed that our proposed bone-suppression based CT-MR fusion and GRE-weighted strategy could lower the overall MAE error between the original and synthetic CTs by ~69% and ~34% respectively. Dose recalculation comparison showed highly consistent results between plans based on the synthetic vs. the original CTs. The 2D gamma analysis revealed the pass rate of 95.44 ± 2.5 and 99.36 ± 0.71 for 1%/1 mm and 2%/2 mm criteria respectively. Due to local registration weighting, the method is robust with respect to MRI imaging artifacts. CONCLUSION: We developed a novel image analysis technique to synthesize CT for head and neck anatomy. Novel methods were introduced to accurately register atlas CTs and MRIs as well as to weight the final electron density maps using local registration goodness estimates. The resulting accuracy is clinically acceptable, at least for these atlas patients.

Direct Comparison of Respiration-Correlated Four-Dimensional Magnetic Resonance Imaging Reconstructed Using Concurrent Internal Navigator and External Bellows.

PURPOSE: To compare the image quality of amplitude-binned 4-dimensional magnetic resonance imaging (4DMRI) reconstructed using 2 concurrent respiratory (navigator and bellows) waveforms. METHODS AND MATERIALS: A prospective, respiratory-correlated 4DMRI scanning program was used to acquire T2-weighted single-breath 4DMRI images with internal navigator and external bellows. After a 10-second training waveform of a surrogate signal, 2-dimensional MRI acquisition was triggered at a level (bin) and anatomic location (slice) until the bin-slice table was completed for 4DMRI reconstruction. The bellows signal was always collected, even when the navigator trigger was used, to retrospectively reconstruct a bellows-rebinned 4DMRI. Ten volunteers participated in this institutional review board-approved 4DMRI study. Four scans were acquired for each subject, including coronal and sagittal scans triggered by either navigator or bellows, and 6 4DMRI images (navigator-triggered, bellows-rebinned, and bellows-triggered) were reconstructed. The simultaneously acquired waveforms and resulting 4DMRI quality were compared using signal correlation, bin/phase shift, and binning motion artifacts. The consecutive bellows-triggered 4DMRI scan was used for indirect comparison. RESULTS: Correlation coefficients between the navigator and bellows signals were found to be patient-specific and inhalation-/exhalation-dependent, ranging from 0.1 to 0.9 because of breathing irregularities (>50% scans) and commonly observed bin/phase shifts (-1.1 ± 0.6 bin) in both 1-dimensional waveforms and diaphragm motion extracted from 4D images. Navigator-triggered 4DMRI contained many fewer binning motion artifacts at the diaphragm than did the bellows-rebinned and bellows-triggered 4DMRI scans. Coronal scans were faster than sagittal scans because of the fewer slices and higher achievable acceleration factors. CONCLUSIONS: Navigator-triggered 4DMRI contains substantially fewer binning motion artifacts than bellows-rebinned and bellows-triggered 4DMRI, primarily owing to the deviation of the external from the internal surrogate. The present study compared 2 concurrent surrogates during the same 4DMRI scan and their resulting 4DMRI quality. The navigator-triggered 4DMRI scanning protocol should be preferred to the bellows-based, especially for coronal scans, for clinical respiratory motion simulation.

Limited accuracy of DCE-MRI in identification of pathological complete responders after chemoradiotherapy treatment for rectal cancer.

OBJECTIVES: To examine whether post-chemoradiotherapy (CRT) DCE-MRI can identify rectal cancer patients with pathologic complete response (pCR). METHODS: From a rectal cancer surgery database 2007-2014, 61 consecutive patients that met the following inclusion criteria were selected for analysis: (1) stage II/III primary rectal adenocarcinoma; (2) received CRT; (3) underwent surgery (4); underwent rectal DCE-MRI on a 1.5-T MRI scanner. Two experienced radiologists, in consensus, drew regions of interest (ROI) on the sagittal DCE-MRI image in the tumour bed. These were exported from ImageJ to in-house Matlab code for modelling using the Tofts model. K trans, K ep and v e values were compared to pathological response. RESULTS: Of the 61 initial patients, 37 had data considered adequate for fitting to obtain perfusion parameters. Among the 13 men and 24 women, median age 53 years, there were 8 pCR (22 %). K trans could not distinguish patients with pCR. For patients with 90 % or greater response, mean K trans and K ep values were statistically significant (p = 0.032 and 0.027, respectively). Using a cutoff value of K trans = 0.25 min-1, the AUC was 0.71. CONCLUSION: K trans could be used to identify patients with 90 % or more response to chemoradiotherapy for rectal cancer with an AUC of 0.7. KEY POINTS: • Chemoradiotherapy for rectal cancer causes decreased blood flow and permeability in the tumour bed. • Lower values of blood flow and permeability correlate with good tumour response. • K trans of 0.25min -1 best identifies patients with ≥90 % response with AUC 0.71.

Long-term outcome of magnetic resonance spectroscopic image-directed dose escalation for prostate brachytherapy.

PURPOSE: To report the long-term control and toxicity outcomes of patients with clinically localized prostate cancer, who underwent low-dose-rate prostate brachytherapy with magnetic resonance spectroscopic image (MRSI)-directed dose escalation to intraprostatic regions. METHODS AND MATERIALS: Forty-seven consecutive patients between May 2000 and December 2003 were analyzed retrospectively. Each patient underwent a preprocedural MRSI, and MRS-positive voxels suspicious for malignancy were identified. Intraoperative planning was used to determine the optimal seed distribution to deliver a standard prescription dose to the entire prostate, while escalating the dose to MRS-positive voxels to 150% of prescription. Each patient underwent transperineal implantation of radioactive seeds followed by same-day CT for postimplant dosimetry. RESULTS: The median prostate D90 (minimum dose received by 90% of the prostate) was 125.7% (interquartile range [IQR], 110.3-136.5%) of prescription. The median value for the MRS-positive mean dose was 229.9% (IQR, 200.0-251.9%). Median urethra D30 and rectal D30 values were 142.2% (137.5-168.2%) and 56.1% (40.1-63.4%), respectively. Median followup was 86.4 months (IQR, 49.8-117.6). The 10-year actuarial prostate-specific antigen relapse-free survival was 98% (95% confidence interval, 93-100%). Five patients (11%) experienced late Grade 3 urinary toxicity (e.g., urethral stricture), which improved after operative intervention. Four of these patients had dose-escalated voxels less than 1.0 cm from the urethra. CONCLUSIONS: Low-dose-rate brachytherapy with MRSI-directed dose escalation to suspicious intraprostatic regions exhibits excellent long-term biochemical control. Patients with dose-escalated voxels close to the urethra were at higher risk of late urinary stricture.

Prostate MRSI predicts outcome in radical prostatectomy patients.

BACKGROUND: New non-invasive methods are needed for sub-stratifying high-risk prostate cancer patients. Magnetic resonance spectroscopic imaging (MRSI) maps metabolites in prostate cancer, providing information on tumor aggressiveness and volume. PURPOSE: To investigate the correlation between MRSI and treatment failure (TF) after radical prostatectomy (RP). METHODS: Two-hundred sixty-two patients who underwent endorectal MRI/MRSI followed by RP at our institution from 2003 to 2007 were studied. MRI stage, number of voxels in the MRSI index lesion (NILV), number of high-grade voxels (NHGV), and number of voxels containing undetectable polyamines (NUPV) were derived. Clinical outcome was followed until August, 2014. Treatment failure was defined as 1) biochemical recurrence (BCR), 2) persistently detectable PSA after RP, or 3) adjuvant therapy initiated in the absence of BCR. MRI/MRSI features and clinical parameters were compared to TF by univariate Cox Proportional Hazards Regression. After backward selection, each MRSI parameter was included in a separate regression model adjusted for NCCN-based clinical risk score (CRS), number of biopsy cores positive (NPC), and MRI stage. RESULTS: In univariate analysis, all clinical variables were associated with TF in addition to MRI stage, NILV, NHGV, and NUPV. In multivariate analysis, NILV, NHGV, and NUPV were also significant risk factors for TF (p=0.016, p=0.002, p=0.006, respectively). The association between the number of tumor voxels with undetectable polyamines and the probability of treatment failure has not been previously reported. The number of MRSI cancer voxels correlated with extracapsular extension (ECE) (p<0.0001). CONCLUSIONS: MRSI was associated with post-radical prostatectomy treatment failure in models adjusted for the number of positive biopsy cores and clinical risk score. This is the first report that in radical prostatectomy patients MRSI has an association with treatment failure independent of the number of positive biopsy cores. MRSI may help the clinician determine whether patients with high risk disease who undergo RP are candidates for specialized additional treatment.

Anatomic segmentation improves prostate cancer detection with artificial neural networks analysis of 1H magnetic resonance spectroscopic imaging.

PURPOSE: To assess whether an artificial neural network (ANN) model is a useful tool for automatic detection of cancerous voxels in the prostate from (1)H-MRSI datasets and whether the addition of information about anatomical segmentation improves the detection of cancer. MATERIALS AND METHODS: The Institutional Review Board approved this HIPAA-compliant study and waived informed consent. Eighteen men with prostate cancer (median age, 55 years; range, 36-71 years) who underwent endorectal MRI/MRSI before radical prostatectomy were included in this study. These patients had at least one cancer area on whole-mount histopathological map and at least one matching MRSI voxel suspicious for cancer detected. Two ANN models for automatic classification of MRSI voxels in the prostate were implemented and compared: model 1, which used only spectra as input, and model 2, which used the spectra plus information from anatomical segmentation. The models were trained, tested and validated using spectra from voxels that the spectroscopist had designated as cancer and that were verified on histopathological maps. RESULTS: At ROC analysis, model 2 (AUC = 0.968) provided significantly better (P = 0.03) classification of cancerous voxels than did model 1 (AUC = 0.949). CONCLUSION: Automatic analysis of prostate MRSI to detect cancer using ANN model is feasible. Application of anatomical segmentation from MRI as an additional input to ANN improves the accuracy of detecting cancerous voxels from MRSI.

High-field small animal magnetic resonance oncology studies.

This review focuses on the applications of high magnetic field magnetic resonance imaging (MRI) and spectroscopy (MRS) to cancer studies in small animals. High-field MRI can provide information about tumor physiology, the microenvironment, metabolism, vascularity and cellularity. Such studies are invaluable for understanding tumor growth and proliferation, response to treatment and drug development. The MR techniques reviewed here include (1)H, (31)P, chemical exchange saturation transfer imaging and hyperpolarized (13)C MRS as well as diffusion-weighted, blood oxygen level dependent contrast imaging and dynamic contrast-enhanced MRI. These methods have been proven effective in animal studies and are highly relevant to human clinical studies.

Noninvasive phosphorus magnetic resonance spectroscopic imaging predicts outcome to first-line chemotherapy in newly diagnosed patients with diffuse large B-cell lymphoma.

RATIONALE AND OBJECTIVES: Based on their association with malignant proliferation, using noninvasive phosphorus MR spectroscopic imaging ((31)P MRSI), we measured the tumor content of the phospholipid-related phosphomonoesters (PME), phosphoethanolamine and phospholcholine, and its correlation with treatment outcome in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) receiving standard first-line chemotherapy. EXPERIMENTAL DESIGN: The PME value normalized to nucleoside triphosphates (PME/NTP) was measured using (31)P MRSI in tumor masses of 20 patients with DLBCL before receiving standard first-line chemotherapy. Response at 6 months was complete in 13 patients and partial in seven. Time to treatment failure (TTF) was ≤11 months in eight patients, from 18 to 30 months in three, and ≥60 months in nine. RESULTS: On a t test, the pretreatment tumor PME/NTP mean value (SD, n) of patients with a complete response at 6 months was 1.42 (0.41, 13), which was significantly different from the value of 2.46 (0.40, 7) in patients with partial response (P < .00001). A Fisher test significantly correlated the PME/NTP values with response at 6 months (sensitivity and specificity at 0.85, P < .004) while a Cox proportional hazards regression significantly correlated the PME/NTP values with TTF (hazard ratio = 5.21, P < .02). A Kaplan-Meier test set apart a group entirely composed of patients with TTF ≤ 11 months (hazard ratio = 8.66, P < .00001). CONCLUSIONS: The pretreatment tumor PME/NTP values correlated with response to treatment at 6 months and time to treatment failure in newly diagnosed patients with DLBCL treated with first-line chemotherapy, and therefore they could be used to predict treatment outcome in these patients.

Relationships between LDH-A, lactate, and metastases in 4T1 breast tumors.

PURPOSE: To investigate the relationship between lactate dehydrogenase A (LDH-A) expression, lactate concentration, cell metabolism, and metastases in murine 4T1 breast tumors. EXPERIMENTAL DESIGN: Inhibition of LDH-A expression and protein levels were achieved in a metastatic breast cancer cell line (4T1) using short hairpin RNA (shRNA) technology. The relationship between tumor LDH-A protein levels and lactate concentration (measured by magnetic resonance spectroscopic imaging, MRSI) and metastases was assessed. RESULTS: LDH-A knockdown cells (KD9) showed a significant reduction in LDH-A protein and LDH activity, less acid production, decreased transwell migration and invasion, lower proliferation, reduced glucose consumption and glycolysis, and increase in oxygen consumption, reactive oxygen species (ROS), and cellular ATP levels, compared with control (NC) cells cultured in 25 mmol/L glucose. In vivo studies showed lower lactate levels in KD9, KD5, and KD317 tumors than in NC or 4T1 wild-type tumors (P < 0.01), and a linear relationship between tumor LDH-A protein expression and lactate concentration. Metastases were delayed and primary tumor growth rate decreased. CONCLUSIONS: We show for the first time that LDH-A knockdown inhibited the formation of metastases, and was accompanied by in vivo changes in tumor cell metabolism. Lactate MRSI can be used as a surrogate to monitor targeted inhibition of LDH-A in a preclinical setting and provides a noninvasive imaging strategy to monitor LDH-A-targeted therapy. This imaging strategy can be translated to the clinic to identify and monitor patients who are at high risk of developing metastatic disease.

Serial measurement of hepatic lipids during chemotherapy in patients with colorectal cancer: a 1 H MRS study.

Hepatic steatosis is a hallmark of chemotherapy-induced liver injury. We made serial (1) H MRS measurements of hepatic lipids in patients over the time course of a 24-week chemotherapeutic regimen to determine whether (1) H MRS could be used to monitor the progression of chemotherapy-induced steatosis. Thirty-four patients with stage III or IV colorectal cancer receiving 5-fluorouracil, folinic acid and oxaliplatin (n=21) or hepatic arterial infusion of floxuridine with systemic irinotecan (n=13) were studied prospectively. (1) H MRS studies were performed at baseline and after 6 and 24 weeks of treatment. A (1) H MR spectrum was acquired from the liver during a breath hold and the ratio of fat to fat+water (FFW) was calculated to give a measure of hepatic triglycerides (HTGCs). The methodology was histologically validated in 18 patients and the reproducibility was assessed in 16 normal volunteers. Twenty-seven patients completed baseline, 6-week and 24-week (1) H MRS examinations and one was censored. Thirteen of 26 patients (50%) showed an increase in FFW after completion of treatment. Six patients (23%) developed hepatic steatosis and two patients converted from steatosis to nonsteatotic liver. Patients whose 6-week hepatic lipid levels had increased significantly relative to baseline also had a high probability of lipid elevation relative to baseline at the completion of treatment. Serial (1) H MRS is effective for the monitoring of HTGC changes during chemotherapy and for the detection of chemotherapy-associated steatosis. Six of 26 patients developed steatosis during chemotherapy. Lipid changes were observable at 6 weeks.

Performance characteristics of MR imaging in the evaluation of clinically low-risk prostate cancer: a prospective study.

PURPOSE: To prospectively evaluate diagnostic performance of T2-weighted magnetic resonance (MR) imaging and MR spectroscopic imaging in detecting lesions stratified by pathologic volume and Gleason score in men with clinically determined low-risk prostate cancer. MATERIALS AND METHODS: The institutional review board approved this prospective, HIPAA-compliant study. Written informed consent was obtained from 183 men with clinically low-risk prostate cancer (cT1-cT2a, Gleason score≤6 at biopsy, prostate-specific antigen [PSA] level<10 ng/mL [10 µg/L]) undergoing MR imaging before prostatectomy. By using a scale of 1-5 (score 1, definitely no tumor; score 5, definitely tumor), two radiologists independently scored likelihood of tumor per sextant on T2-weighted images. Two spectroscopists jointly recorded locations of lesions with metabolic features consistent with tumor on MR spectroscopic images. Whole-mount step-section histopathologic analysis constituted the reference standard. Diagnostic performance at sextant level (T2-weighted imaging) and detection sensitivities (T2-weighted imaging and MR spectroscopic imaging) for lesions of 0.5 cm3 or larger were calculated. RESULTS: For T2-weighted imaging, areas under the receiver operating characteristic curves for sextant-level detection were 0.77 (reader 1) and 0.82 (reader 2). For lesions of ≥0.5 cm3 and, 1

Preoperative nomograms incorporating magnetic resonance imaging and spectroscopy for prediction of insignificant prostate cancer.

UNLABELLED: Study Type--Prognosis (case series). Level of Evidence 4. What's known on the subject? And what does the study add? Nomograms are available that combine clinical and biopsy findings to predict the probability of pathologically insignificant prostate cancer in patients with clinically low-risk disease. Based on data from patients with Gleason score 6, clinical stage ≤ T2a and PSA <20 ng/ml, our group developed the first nomogram models for predicting insignificant prostate cancer that incorporated clinical data, detailed biopsy data and findings from MRI or MRI/MRSI (BJU Int. 2007;99(4):786-93). When tested retrospectively, these MR models performed significantly better than standard clinical models with and without detailed biopsy data. We prospectively validated the previously published MR-based nomogram models in a population of patients with Gleason score 6, clinical stage ≤ T2a and PSA <10 ng/ml. Based on data from this same population, we also developed two new models for predicting insignificant prostate cancer that combine MR findings and clinical data without detailed biopsy data. Upon initial testing, the new MR models performed significantly better than a clinical model lacking detailed biopsy data. OBJECTIVES: • To validate previously published nomograms for predicting insignificant prostate cancer (PCa) that incorporate clinical data, percentage of biopsy cores positive (%BC+) and magnetic resonance imaging (MRI) or MRI/MR spectroscopic imaging (MRSI) results. • We also designed new nomogram models incorporating magnetic resonance results and clinical data without detailed biopsy data. Nomograms for predicting insignificant PCa can help physicians counsel patients with clinically low-risk disease who are choosing between active surveillance and definitive therapy. PATIENTS AND METHODS: • In total, 181 low-risk PCa patients (clinical stage T1c-T2a, prostate-specific antigen level <10 ng/mL, biopsy Gleason score of 6) had MRI/MRSI before surgery. • For MRI and MRI/MRSI, the probability of insignificant PCa was recorded prospectively and independently by two radiologists on a scale from 0 (definitely insignificant) to 3 (definitely significant PCa). • Insignificant PCa was defined on surgical pathology. • There were four models incorporating MRI or MRI/MRSI and clinical data with and without %BC+ that were compared with a base clinical model without %BC and a more comprehensive clinical model with %BC+. Prediction accuracy was assessed using areas under receiver-operator characteristic curves. RESULTS: • At pathology, 27% of patients had insignificant PCa, and the Gleason score was upgraded in 56.4% of patients. • For both readers, all magnetic resonance models performed significantly better than the base clinical model (P ≤ 0.05 for all) and similarly to the more comprehensive clinical model. CONCLUSIONS: • Existing models incorporating magnetic resonance data, clinical data and %BC+ for predicting the probability of insignificant PCa were validated. • All MR-inclusive models performed significantly better than the base clinical model.

Preclinical study of treatment response in HCT-116 cells and xenografts with (1) H-decoupled (31) P MRS.

The topoisomerase I inhibitor, irinotecan, and its active metabolite SN-38 have been shown to induce G(2) /M cell cycle arrest without significant cell death in human colon carcinoma cells (HCT-116). Subsequent treatment of these G(2) /M-arrested cells with the cyclin-dependent kinase inhibitor, flavopiridol, induced these cells to undergo apoptosis. The goal of this study was to develop a noninvasive metabolic biomarker for early tumor response and target inhibition of irinotecan followed by flavopiridol treatment in a longitudinal study. A total of eleven mice bearing HCT-116 xenografts were separated into two cohorts where one cohort was administered saline and the other treated with a sequential course of irinotecan followed by flavopiridol. Each mouse xenograft was longitudinally monitored with proton ((1) H)-decoupled phosphorus ((31) P) magnetic resonance spectroscopy (MRS) before and after treatment. A statistically significant decrease in phosphocholine (p = 0.0004) and inorganic phosphate (p = 0.0103) levels were observed in HCT-116 xenografts following treatment, which were evidenced within twenty-four hours of treatment completion. Also, a significant growth delay was found in treated xenografts. To discern the underlying mechanism for the treatment response of the xenografts, in vitro HCT-116 cell cultures were investigated with enzymatic assays, cell cycle analysis, and apoptotic assays. Flavopiridol had a direct effect on choline kinase as measured by a 67% reduction in the phosphorylation of choline to phosphocholine. Cells treated with SN-38 alone underwent 83 ± 5% G(2) /M cell cycle arrest compared to untreated cells. In cells, flavopiridol alone induced 5 ± 1% apoptosis while the sequential treatment (SN-38 then flavopiridol) resulted in 39 ± 10% apoptosis. In vivo (1) H-decoupled (31) P MRS indirectly measures choline kinase activity. The decrease in phosphocholine may be a potential indicator of early tumor response to the sequential treatment of irinotecan followed by flavopiridol in noninvasive and/or longitudinal studies.