Quantitative assessments of image intensifier distortion induced by weak (Sub-Gauss) magnetic fields during fluoroscopically-guided procedures.

BACKGROUND: Fluoroscopically-guided procedures at our hospital have been aborted due to sigmoidal distortion (S-distortion) when an image intensifier (II) system is used in a surgical environment distant from any apparent sources of strong magnetic fields, such as a nearby magnetic resonance imaging (MRI) scanner. Clearly, current clinical practice fails to account for the impact of ambient weak magnetic fields and/or other contributing factors on S-distortion induction. PURPOSE: This study attempts to quantitatively assess the threshold level of magnetic field, along with other potential factors, that can induce intolerable S-distortion during image-intensified fluoroscopically-guided procedures. We will also discover the origins of such level of magnetic field in typical surgical facilities and provide our practical mitigation strategies accordingly. METHODS: Ten surgical facilities and their accessory equipment (e.g., surgical tables) were screened using an AC/DC gaussmeter for the distribution and magnitude of magnetic field (magnetic flux density). A 'hot spot' of magnetic field was identified to further investigate the induction of S-distortion by scanning a titanium rod phantom using a GE OEC 9900 Elite II system placed at increasing distance from the 'hot spot' corresponding to decreasing magnetic field experienced by the II. The measurements were compared to that on a 'cold spot', and a GE flat panel detector (FPD) fluoroscopy was used as the negative control. Rod phantoms made of various magnetic susceptible materials (titanium, steel, aluminium, and copper) were scanned to explore the potential effects of implant material on S-distortion. An upper extremity anthropomorphic phantom was imaged on various surgical tables to mimic clinical sceneries. The GE II model and Siemens ARCADIS Orbic II model were compared to evaluate if S-distortion induction varied among different II models. Two metrics, angle of rotation (θ) and deviation/length ratio, were used to quantify the degree of S-distortion. Three designs of external magnetic shielding were evaluated for mitigating S-distortion. RESULTS: We identified static magnetic fields up to 2500 µT and 70 µT on the floor and at 1-meter height, respectively, in random locations of surgical facilities. A large variation of magnetic field (64 ± 20 µT) was detected on the surface of surgical tables, with background magnetic fields of ∼35 µT. Quantitative assessments demonstrated that even weak magnetic fields at sub-Gauss level (<100 µT) could induce noticeable distortion artifacts, deemed unacceptable (θ > 4°). S-distortion was independent of the implant material being imaged but dependent on the II model - the threshold magnetic fields (4° distortion induction) were as low as 47 µT and 94 µT for the GE and Siemens II models. Mitigation possibilities of S-distortion include relocating the II to an area with subthreshold magnetic fields and shielding the II utilizing cylindrical mu-metal shields with an extension for alleviating the effect of openings. CONCLUSIONS: This work demonstrates that ambient sub-Gauss magnetic fields originating from any possible sources in a surgical environment have to be carefully considered when performing an image-intensified fluoroscopically-guided procedure, because such weak magnetic fields are likely able to induce unacceptable S-distortion artifacts in the acquired X-ray images leading to undesirable surgical outcomes.

Real-Time 2D MR Cine From Beam Eye's View With Tumor-Volume Projection to Ensure Beam-to-Tumor Conformality for MR-Guided Radiotherapy of Lung Cancer.

Purpose: To minimize computation latency using a predictive strategy to retrieve and project tumor volume onto 2D MR beam eye's view (BEV) cine from time-resolved four-dimensional magnetic resonance imaging (TR-4DMRI) libraries (inhalation/exhalation) for personalized MR-guided intensity-modulated radiotherapy (IMRT) or volumetric-modulated arc therapy (VMAT). Methods: Two time-series forecasting algorithms, autoregressive (AR) modeling and deep-learning-based long short-term memory (LSTM), were applied to predict the diaphragm position in the next 2D BEV cine to identify a motion-matched and hysteresis-accounted image to retrieve the tumor volume from the inhalation/exhalation TR-4DMRI libraries. Three 40-s TR-4DMRI (2 Hz, 3 × 80 images) per patient of eight lung cancer patients were used to create patient-specific inhalation/exhalation 4DMRI libraries, extract diaphragmatic waveforms, and interpolate them to f = 4 and 8 Hz to match 2D cine frame rates. Along a (40•f)-timepoint waveform, 30•f training timepoints were moved forward to produce 3×(10•f-1) predictions. The accuracy of position prediction was assessed against the waveform ground truth. The accuracy of tumor volume projections was evaluated using the center-of-mass difference (∆COM) and Dice similarity index against the TR-4DMRI ground truth for both IMRT (six beam angles, 30° interval) and VMAT (240/480 beam angles, 1.5°/0.75° interval, at 4/8 Hz, respectively). Results: The accuracy of the first-timepoint prediction is 0.36 ± 0.10 mm (AR) and 0.62 ± 0.21 mm (LSTM) at 4 Hz and 0.06 ± 0.02 mm (AR) and 0.18 ± 0.06 mm (LSTM) at 8 Hz. A 10%-20% random error in prediction-library matching increases the overall uncertainty slightly. For both IMRT and VMAT, the accuracy of projected tumor volume contours on 2D BEV cine is ∆COM = 0.39 ± 0.13 mm and DICE = 0.97 ± 0.02 at 4 Hz and ∆COM = 0.10 ± 0.04 mm and DICE = 1.00 ± 0.00 at 8Hz. Conclusion: This study demonstrates the feasibility of accurately predicting respiratory motion during 2D BEV cine imaging, identifying a motion-matched and hysteresis-accounted tumor volume, and projecting tumor volume contour on 2D BEV cine for real-time assessment of beam-to-tumor conformality, promising for optimal personalized MR-guided radiotherapy.

Feasibility of MR-guided radiotherapy using beam-eye-view 2D-cine with tumor-volume projection.

PURPOSE: Current magnetic resonance imaging (MRI) guided radiotherapy (MRgRT) applies sagittal/coronal 2D-cine to monitor major tumor motions, however, the beam eye's view (BEV) with volumetric tumor projection would be the best measure for radiation beam conformality, independent of tumor through-plane motion. The goal is to assess the feasibility, accuracy, and performance of the BEV approach. METHODS: Beam-specific BEV 2D-cine with volume-projected tumor contours were simulated to establish a 2D/3D tumor match against a tumor-motion library based on multi-breath time-resolved (TR) 4DMRI images. Two BEV-library-matching methods were developed: (1) fast screening with tumor center-of-mass (∆COM), in-plane area ratio, and DICE similarity, and finalizing with the highest DICE score and (2) DICE screening for top-3 candidates and finalizing with rigid registration. A 4D-XCAT digital phantom and 8 lung-cancer patients were used for assessment. For each patient, 3 sets of 40 s TR-4DMRI were acquired at 2 Hz and 6 representative BEV were created with the isocenter set at tumor COM in mid-respiration. One TR-4DMRI set (40 × 2 = 80-images) was used to simulate BEV 2D-cine and the other two (160-images) were used to create a library. The matching result was validated against the ground truth within the test set. Using a leave-one-out strategy, the success rate, accuracy, and speed of tumor matching were assessed for volume-projected tumors over 11520 time-points (=8patients•3sets•80images•6BEVs). RESULTS: Volume-projected tumor contour area on the 6 BEVs varies by 60% ± 8% and [Formula: see text] (in-plane/volume-projected) varies by 82% ± 9%. The [Formula: see text] changes with tumor shape, orientation, and through-plane motion. Method-1 produces 96% matching success (ΔCOM = 0.7 ± 0.2 mm, [Formula: see text]=1.01 ± 0.02, Dice=0.92 ± 0.02) with the computational time of 15 ± 1 ms/match, while method-2 produces 94% ± 1% success (ΔCOM = 0.2 ± 0.1 mm, [Formula: see text]=1.00 ± 0.01, Dice = 0.94 ± 0.02) with 223 ± 13 ms/match. CONCLUSION: This study has demonstrated the feasibility, accuracy, and benefits of BEV 2D-cine imaging with tumor-volume projection, allowing real-time tumor motion monitoring and beam conformality checking. Further clinical evaluation is necessary before MRgRT applications.

Enhanced super-resolution reconstruction of T1w time-resolved 4DMRI in low-contrast tissue using 2-step hybrid deformable image registration.

PURPOSE: Deformable image registration (DIR) in low-contrast tissues is often suboptimal because of low visibility of landmarks, low driving-force to deform, and low penalty for misalignment. We aim to overcome the shortcomings for improved reconstruction of time-resolved four-dimensional magnetic resonance imaging (TR-4DMRI). METHODS AND MATERIALS: Super-resolution TR-4DMRI reconstruction utilizes DIR to combine high-resolution (highR:2x2x2mm3 ) breath-hold (BH) and low-resolution (lowR:5x5x5mm3 ) free-breathing (FB) 3D cine (2Hz) images to achieve clinically acceptable spatiotemporal resolution. A 2-step hybrid DIR approach was developed to segment low-dynamic-range (LDR) regions: low-intensity lungs and high-intensity "bodyshell" (=body-lungs) for DIR refinement after conventional DIR. The intensity in LDR regions was renormalized to the full dynamic range (FDR) to enhance local tissue contrast. A T1-mapped 4D XCAT digital phantom was created, and seven volunteers and five lung cancer patients were scanned with two BH and one 3D cine series per subject to compare the 1-step conventional and 2-step hybrid DIR using: (a) the ground truth in the phantom, (b) highR-BH references, which were used to simulate 3D cine images by down-sampling and Rayleigh-noise-adding, and (c) cross-verification between two TR-4DMRI images reconstructed from two BHs. To assess DIR improvement, 8-17 blood vessel bifurcations were used in volunteers, and lung tumor position, size, and shape were used in phantom and patients, together with the voxel intensity correlation (VIC), structural similarity (SSIM), and cross-consistency check (CCC). RESULTS: The 2-step hybrid DIR improves contrast and DIR accuracy. In volunteers, it improves low-contrast alignment from 6.5 ± 1.8 mm to 3.3 ± 1.0 mm. In phantom, it improves tumor center of mass alignment (COM = 1.3 ± 0.2 mm) and minimizes DIR directional difference. In patients, it produces almost-identical tumor COM, size, and shape (dice> 0.85) as the reference. The VIC and SSIM are significantly increased and the number of CCC outliers are reduced by half. CONCLUSION: The 2-step hybrid DIR improves low-contrast-tissue alignment and increases lung tumor fidelity. It is recommended to adopt the 2-step hybrid DIR for TR-4DMRI reconstruction.

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.

Respiratory-Correlated (RC) vs. Time-Resolved (TR) Four-Dimensional Magnetic Resonance Imaging (4DMRI) for Radiotherapy of Thoracic and Abdominal Cancer.

Recent technological and clinical advancements of both respiratory-correlated (RC) and time-resolved (TR) four-dimensional magnetic resonance imaging (4DMRI) techniques are reviewed in light of tumor/organ motion simulation, monitoring, and assessment in radiotherapy. For radiotherapy of thoracic and abdominal cancer, respiratory-induced tumor motion, and motion variation due to breathing irregularities are the major uncertainties in treatment. RC-4DMRI is developed to assess tumor motion for treatment planning, whereas TR-4DMRI is developed to assess both motion and motion variation for treatment planning, delivery and assessment. RC-4DMRI is reconstructed to provide one-breathing-cycle motion, similar to 4D computed tomography (4DCT), the current clinical standard, but with higher soft-tissue contrast, no ionizing radiation, and less binning artifacts due to the use of an internal respiratory surrogate. Recent studies have shown that its spatial resolution has reached or exceeded that of 4DCT and scanning time becomes clinically acceptable. TR-4DMRI is recently developed with an adequate spatiotemporal resolution to assess tumor motion and motion variations for treatment simulation, delivery and assessment. The super-resolution approach is most promising since it can image any organ/body motion, whereas RC-4D MRI are limited to resolve only respiration-induced motion and some TR-4DMRI approaches may more or less depend on RC-4DMRI. TR-4DMRI provides multi-breath motion data that are useful not only in MR-guided radiotherapy but also for building a patient-specific motion model to guide radiotherapy treatment using an non-MR-equipped linear accelerator. Based on 4DMRI motion data, motion-corrected dynamic contrast imaging and diffusion-weighted imaging have also been reported, aiming to facilitate tumor delineation for more accurate radiotherapy targeting. Both RC- and TR-4DMRI have been evaluated for potential clinical applications, such as delineation of tumor volumes, where sufficiently high spatial resolution and large field-of-view are required. The 4DMRI techniques are promising to play a role in motion assessment in radiotherapy treatment planning, delivery, assessment, and adaptation.

Introduction of a pseudo demons force to enhance deformation range for robust reconstruction of super-resolution time-resolved 4DMRI.

PURPOSE: The purpose of this study was to enhance the deformation range of demons-based deformable image registration (DIR) for large respiration-induced organ motion in the reconstruction of time-resolved four-dimensional magnetic resonance imaging (TR-4DMRI) for multi-breath motion simulation. METHODS: A demons-based DIR algorithm was modified to enhance the deformation range for TR-4DMRI reconstruction using the super-resolution approach. A pseudo demons force was introduced to accelerate the coarse deformation in a multi-resolution (n = 3) DIR approach. The intensity gradient of a voxel was applied to its neighboring (5 × 5 × 5) voxels with a weight of Gaussian probability profile (σ = 1 voxel) to extend the demons force, especially on those voxels that have little intensity gradience but high-intensity difference. A digital 4DMRI phantom with 3-8 cm diaphragmatic motions was used for DIR comparison. Six volunteers were scanned with two high-resolution (highR: 2 × 2 × 2 mm3 ) breath-hold (BH) 3DMR images at full inhalation (BHI) and full exhalation (BHE) and low-resolution (lowR: 5 × 5 × 5 mm3 ) free-breathing (FB) 3DMR cine images (2 Hz) under an IRB-approved protocol. A cross-consistency check (CCC) (BHI→FB←BHE), with voxel intensity correlation (VIC) and inverse consistency error (ICE), was introduced for cross-verification of TR-4DMRI reconstruction. RESULTS: Using the digital phantom, the maximum deformable magnitude is doubled using the modified DIR from 3 to 6 cm at the diaphragm. In six human subjects, the first 15-iteration DIR using the pseudo force deforms 200 ± 150% more than the original force, and succeeds in all 12 cases, whereas the original demons-based DIR failed in 67% of tested cases. Using the pseudo force, high VIC (>0.9) and small ICE (1.6 ± 0.6 mm) values are observed for DIR of BHI&BHE, BHI→FB, and BHE→FB. The CCC identifies four questionable cases, in which two cases need further DIR refinement, without missing true negative. CONCLUSIONS: The introduction of a pseudo demons force enhances the largest deformation magnitude up to 6 cm. The cross-consistency check ensures the quality of TR-4DMRI reconstruction. Further investigation is ongoing to fully characterize TR-4DMRI for potential multi-breathing-cycle radiotherapy simulation.

Evaluation of automatic contour propagation in T2-weighted 4DMRI for normal-tissue motion assessment using internal organ-at-risk volume (IRV).

PURPOSE: The purpose of this study was to evaluate the quality of automatically propagated contours of organs at risk (OARs) based on respiratory-correlated navigator-triggered four-dimensional magnetic resonance imaging (RC-4DMRI) for calculation of internal organ-at-risk volume (IRV) to account for intra-fractional OAR motion. METHODS AND MATERIALS: T2-weighted RC-4DMRI images were of 10 volunteers acquired and reconstructed using an internal navigator-echo surrogate and concurrent external bellows under an IRB-approved protocol. Four major OARs (lungs, heart, liver, and stomach) were delineated in the 10-phase 4DMRI. Two manual-contour sets were delineated by two clinical personnel and two automatic-contour sets were propagated using free-form deformable image registration. The OAR volume variation within the 10-phase cycle was assessed and the IRV was calculated as the union of all OAR contours. The OAR contour similarity between the navigator-triggered and bellows-rebinned 4DMRI was compared. A total of 2400 contours were compared to the most probable ground truth with a 95% confidence level (S95) in similarity, sensitivity, and specificity using the simultaneous truth and performance level estimation (STAPLE) algorithm. RESULTS: Visual inspection of automatically propagated contours finds that approximately 5-10% require manual correction. The similarity, sensitivity, and specificity between manual and automatic contours are indistinguishable (P > 0.05). The Jaccard similarity indexes are 0.92 ± 0.02 (lungs), 0.89 ± 0.03 (heart), 0.92 ± 0.02 (liver), and 0.83 ± 0.04 (stomach). Volume variations within the breathing cycle are small for the heart (2.6 ± 1.5%), liver (1.2 ± 0.6%), and stomach (2.6 ± 0.8%), whereas the IRV is much larger than the OAR volume by: 20.3 ± 8.6% (heart), 24.0 ± 8.6% (liver), and 47.6 ± 20.2% (stomach). The Jaccard index is higher in navigator-triggered than bellows-rebinned 4DMRI by 4% (P < 0.05), due to the higher image quality of navigator-based 4DMRI. CONCLUSION: Automatic and manual OAR contours from Navigator-triggered 4DMRI are not statistically distinguishable. The navigator-triggered 4DMRI image provides higher contour quality than bellows-rebinned 4DMRI. The IRVs are 20-50% larger than OAR volumes and should be considered in dose estimation.

[Plasmakinetic energy transurethral resection versus transurethral bipolar plasmakinetic enucleation and resection of the prostate in the treatment of BPH with the prostate volume <100 ml].

OBJECTIVE: To investigate the influence of plasmakinetic energy transurethral resection of the prostate (PKRP) versus that of transurethral bipolar plasmakinetic enucleation and resection of the prostate (PKERP) on the bladder function, sexual function and incidence of complications in BPH patients with the prostate volume <100 ml. METHODS: We randomly assigned 140 BPH patients with the prostate volume <100 ml to receive PKRP (n = 70) or PKERP (n = 70) in our hospital from July 2013 to July 2015. We compared the maximum urinary flow rate (Qmax), residual urine volume (RUV), and the rates of ED and retrograde ejaculation before and after surgery as well as the incidence of postoperative complications between the two groups of patients. RESULTS: The Qmax and RUV of the patients were (25.11 ± 7.12) ml/s and (4.06 ± 1.74) ml in the PKERP group postoperatively, significantly improved as compared with the baseline (ï¼»8.60 ± 2.33ï¼½ ml/s and ï¼»66.85 ± 14.33ï¼½ ml, P < 0.05), and even better than (18.87 ± 4.07) ml/s and (9.45 ± 2.66) ml in the PKRP group (P < 0.05). The incidence rates of ED and retrograde ejaculation were 61.43% and 28.57% in the PKRP group, significantly higher than in the PKERP group (40.00% and 14.29%) (P < 0.05) and the baseline (35.71% and 10.00%) (P < 0.05). The postoperative incidence rate of transient urinary incontinence was remarkably higher in the PKERP than in the PKRP group (22.86% vs 8.57%, P < 0.05). There were no statistically significant differences between the two groups in the incidence rates of secondary hemorrhage, urethral injury, or genuine urinary incontinence after operation (P > 0.05). CONCLUSIONS: Compared with PKRP, PKERP can effectively improve the clinical symptoms and signs and protect the bladder function of the BPH patients with the prostate volume <100 ml, but may increase the risk of transient urinary incontinence.

Preclinical PET imaging of glycoprotein non-metastatic melanoma B in triple negative breast cancer: feasibility of an antibody-based companion diagnostic agent.

High levels of expression of glycoprotein non-metastatic B (gpNMB) in triple negative breast cancer (TNBC) and its association with metastasis and recurrence make it an attractive target for therapy with the antibody drug conjugate, glembatumumab vedotin (CDX-011). This report describes the development of a companion PET-based diagnostic imaging agent using 89Zr-labeled glembatumumab ([89Zr]DFO-CR011) to potentially aid in the selection of patients most likely to respond to targeted treatment with CDX-011. [89Zr]DFO-CR011 was characterized for its pharmacologic properties in TNBC cell lines. Preclinical studies determined that [89Zr]DFO-CR011 binds specifically to gpNMB with high affinity (Kd = 25 ± 5 nM), immunoreactivity of 2.2-fold less than the native CR011, and its cellular uptake correlates with gpNMB expression (r = 0.95). In PET studies at the optimal imaging timepoint of 7 days p.i., the [89Zr]DFO-CR011 tumor uptake in gpNMB-expressing MDA-MB-468 xenografts had a mean SUV of 2.9, while significantly lower in gpNMB-negative MDA-MB-231 tumors with a mean SUV of 1.9. [89Zr]DFO-CR011 was also evaluated in patient-derived xenograft models of TNBC, where tumor uptake in vivo had a positive correlation with total gpNMB protein expression via ELISA (r = 0.79), despite the heterogeneity of gpNMB expression within the same group of PDX mice. Lastly, the radiation dosimetry calculated from biodistribution studies in MDA-MB-468 xenografts determined the effective dose for human use would be 0.54 mSv/MBq. Overall, these studies demonstrate that [89Zr]DFO-CR011 is a potential companion diagnostic imaging agent for CDX-011 which targets gpNMB, an emerging biomarker for TNBC.

Imaging of hypoxia in mouse atherosclerotic plaques with (64)Cu-ATSM.

INTRODUCTION: Cardiovascular disease is the leading cause of death in the United States. The identification of vulnerable plaque at risk of rupture has been a major focus of research. Hypoxia has been identified as a potential factor in the formation of vulnerable plaque, and it is clear that decreased oxygen plays a role in the development of plaque angiogenesis leading to plaque destabilization. The purpose of this study is to demonstrate the feasibility of copper-64 labeled diacetyl-bis (N(4)-methylthiosemicarbazone) ((64)Cu-ATSM), a positron-emitting radiopharmaceutical taken up in low-oxygen-tension cells, for the identification of hypoxic and potentially unstable atherosclerotic plaque in a mouse model. METHODS: (64)Cu-ATSM PET was performed in 21 atherosclerotic apolipoprotein E knockout (ApoE(-/-)) mice, 6 of which were fed high-fat diet (HFD) while the others received standard-chow diet (SCD), and 13 control wild type mice fed SCD. 4 SCD ApoE(-/-) mice and 4 SCD wild type mice also underwent (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) imaging one day prior to (64)Cu-ATSM PET. RESULTS: (64)Cu-ATSM uptake was increased in the aortic arch in SCD ApoE(-/-) mice (average aortic arch/muscle (A/M) standardized uptake value ratio 7.5-30min post injection: (5.66±0.23) compared to control mice (A/M SUV ratio 7.5-30min post injection (3.87±0.22), p<0.0001). HFD ApoE(-/-) mice also showed similarly increased aortic arch uptake on PET imaging in comparison to control mice. Immunohistochemistry in both HFD and SCD ApoE(-/-) mice revealed noticeable hypoxia by pimonidazole stain in atherosclerosis which was co-localized to macrophage by CD68 staining. Autoradiography assessment demonstrated the presence of hypoxia by (64)Cu-ATSM uptake correlated with pimonidazole uptake within the ex vivo atherosclerotic aortic arch specimens. A significant increase in (18)F-FDG uptake in the SCD ApoE(-/-) mice in comparison to controls was also observed at delayed time points. CONCLUSION: This pre-clinical study suggests that (64)Cu-ATSM is a potential PET tracer for hypoxia imaging in atherosclerosis. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: While studies in humans are necessary for conclusive data, in the long term, a (64)Cu-ATSM PET imaging strategy could help facilitate the study of plaque biology in human patients.

PET/MRI of Hypoxic Atherosclerosis Using 64Cu-ATSM in a Rabbit Model.

The macrophage-rich core of advanced human atheroma has been demonstrated to be hypoxic, which may have implications in plaque stability. The goal of this study was to determine the feasibility of the hypoxia PET imaging agent 64Cu-ATSM to detect hypoxia in a rabbit model of atherosclerosis imaged on a simultaneous PET/MR scanner, using MR for both attenuation correction and depiction of lesion location. METHODS: New Zealand White rabbits fed a Western diet for 4-6 wk underwent endothelial denudation of the right femoral artery by air desiccation to induce an atherosclerotic-like lesion and underwent a sham operation on the left femoral artery. Four and 8 wk after injury, a 0- to 60-min dynamic whole-body PET/MR examination was performed after injection of approximately 111 MBq of 64Cu-ATSM. After 24 h, a 0- to 75-min dynamic PET/MR examination after injection of approximately 111 MBq of 18F-FDG was performed. The rabbits were euthanized, and the injured femoral artery (IF) and sham-operated femoral artery (SF) were collected for immunohistochemistry assessment of hypoxic macrophages (hypoxia marker pimonidazole, macrophage marker RAM-11, and hypoxia-inducible factor-1 α subunit [HIF-1α]). Regions of interest of IF, SF, and background muscle (BM) were drawn on fused PET/MR images, and IF-to-BM and SF-to-BM SUV ratios were compared using the Student t test. RESULTS: Elevated uptake of 64Cu-ATSM was found in the rabbits' IF compared with the SF. 64Cu-ATSM imaging demonstrated IF-to-SF SUVmean ratios (±SD) of 1.75 ± 0.21 and 2.30 ± 0.26 at 4 and 8 wk after injury, respectively. 18F-FDG imaging demonstrated IF-to-SF SUVmean ratios of 1.84 ± 0.12 at 8 wk after injury. IF-to-BM SUVmean ratios were significantly higher (P < 0.001) than SF-to-BM SUVmean ratios both 4 and 8 wk after injury for 64Cu-ATSM and 8 wk after injury for 18F-FDG (P < 0.05). Pimonidazole immunohistochemistry at 8 wk colocalized to RAM-11 and HIF-1α. CONCLUSION: The results show that hypoxia is present in this rabbit model of atherosclerosis and suggest that 64Cu-ATSM PET/MR is a potentially promising method for the detection of hypoxic and potentially vulnerable atherosclerotic plaque in human subjects.