Frank P. DiFilippo

Preoperative 123I/99mTc-Sestamibi Subtraction SPECT and SPECT/CT in Primary Hyperparathyroidism

The trend toward focused surgical parathyroidectomy requires precise preoperative localization of parathyroid lesions in patients with hyperparathyroidism. The purpose of this study was to directly compare the diagnostic accuracy of 99mTc-sestamibi/123I subtraction SPECT with SPECT/CT for the localization of abnormal parathyroid glands in patients with primary hyperparathyroidism. Methods: A total of 61 consecutive surgical patients with primary hyperparathyroidism underwent both 123I/99mTc-sestamibi subtraction SPECT and SPECT/CT scans preoperatively, using a hybrid SPECT/CT instrument that combined a dual-detector SPECT camera with a 6-slice multidetector spiral CT scanner. Four hours after being given 123I-sodium iodide orally, each patient received 99mTc-sestamibi intravenously, followed immediately by a simultaneous, dual-isotope SPECT scan of the neck and upper chest. Then, without moving the patient, we performed a non–contrast-enhanced CT scan of the same body region. Normalization and subtraction of the 123I SPECT images from the 99mTc SPECT images were performed. The subtraction SPECT and the coregistered fused SPECT/CT studies were interpreted separately, with images scored on a 5-point scale. Surgical and histopathologic findings were used as the standard of comparison. Results: Surgery was successful in 57 patients (solitary parathyroid adenoma in 48 patients, double parathyroid adenomas in 6 patients, and 10 hyperplastic parathyroid glands in 3 patients). The sensitivities of SPECT (50/70 = 71%) and SPECT/CT (49/70 = 70%) were similar (P = 0.779). The specificity of SPECT/CT (26/27 = 96%) was significantly greater than that of SPECT (13/27 = 48%; P = 0.006). The receiver-operating-characteristic area under the curve of SPECT/CT (0.833) was significantly greater than that of SPECT (0.632; P < 0.001). Conclusion: SPECT/CT is significantly more specific than dual-isotope subtraction SPECT for the preoperative identification of parathyroid lesions in patients with primary hyperparathyroidism.

Fasting 2-Deoxy-2-[18F]fluoro-d-glucose Positron Emission Tomography to Detect Metabolic Changes in Pulmonary Arterial Hypertension Hearts over 1 Year

BACKGROUND The development of tools to monitor the right ventricle in pulmonary arterial hypertension (PAH) is of clinical importance. PAH is associated with pathologic expression of the transcription factor hypoxia-inducible factor (HIF)-1α, which induces glycolytic metabolism and mobilization of proangiogenic progenitor (CD34(+)CD133(+)) cells. We hypothesized that PAH cardiac myocytes have a HIF-related switch to glycolytic metabolism that can be detected with fasting 2-deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography (FDG-PET) and that glucose uptake is informative for cardiac function. METHODS Six healthy control subjects and 14 patients with PAH underwent fasting FDG-PET and echocardiogram. Blood CD34(+)CD133(+) cells and erythropoietin were measured as indicators of HIF activation. Twelve subjects in the PAH cohort underwent repeat studies 1 year later to determine if changes in FDG uptake were related to changes in echocardiographic parameters or to measures of HIF activation. MEASUREMENTS AND RESULTS FDG uptake in the right ventricle was higher in patients with PAH than in healthy control subjects and correlated with echocardiographic measures of cardiac dysfunction and circulating CD34(+)CD133(+) cells but not erythropoietin. Among patients with PAH, FDG uptake was lower in those receiving β-adrenergic receptor blockers. Changes in FDG uptake over time were related to changes in echocardiographic parameters and CD34(+)CD133(+) cell numbers. Immunohistochemistry of explanted PAH hearts of patients undergoing transplantation revealed that HIF-1α was present in myocyte nuclei but was weakly detectable in control hearts. CONCLUSIONS PAH hearts have pathologic glycolytic metabolism that is quantitatively related to cardiac dysfunction over time, suggesting that metabolic imaging may be useful in therapeutic monitoring of patients.

SPECT/CT Imaging : Clinical Utility of an Emerging Technology

Single-photon emission computed tomography (SPECT) has been a mainstay of nuclear medicine practice for several decades. More recently, combining the functional imaging available with SPECT and the anatomic imaging of computed tomography (CT) has gained more acceptance and proved useful in many clinical situations. Most vendors now offer integrated SPECT/CT systems that can perform both functions on one gantry and provide fused functional and anatomic data in a single imaging session. In addition to allowing anatomic localization of nuclear imaging findings, SPECT/CT also enables accurate and rapid attenuation correction of SPECT studies. These attributes have proved useful in many cardiac, general nuclear medicine, oncologic, and neurologic applications in which the SPECT results alone were inconclusive. Optimal clinical use of this rapidly emerging imaging modality requires an understanding of the fundamental principles of SPECT/CT, including quality control issues as well as potential pitfalls and limitations. The long-term clinical and economic effects of this technology have yet to be established.

Design and performance of a multi-pinhole collimation device for small animal imaging with clinical SPECT and SPECT-CT scanners.

A multi-pinhole collimation device is developed that uses the gamma camera detectors of a clinical SPECT or SPECT-CT scanner to produce high-resolution SPECT images. The device consists of a rotating cylindrical collimator having 22 tungsten pinholes with 0.9 mm diameter apertures and an animal bed inside the collimator that moves linearly to provide helical or ordered-subsets axial sampling. CT images also may be acquired on a SPECT-CT scanner for purposes of image co-registration and SPECT attenuation correction. The device is placed on the patient table of the scanner without attaching to the detectors or scanner gantry. The system geometry is calibrated in-place from point source data and is then used during image reconstruction. The SPECT imaging performance of the device is evaluated with test phantom scans. Spatial resolution from reconstructed point source images is measured to be 0.6 mm full width at half maximum or better. Micro-Derenzo phantom images demonstrate the ability to resolve 0.7 mm diameter rod patterns. The axial slabs of a Micro-Defrise phantom are visualized well. Collimator efficiency exceeds 0.05% at the center of the field of view, and images of a uniform phantom show acceptable uniformity and minimal artifact. The overall simplicity and relatively good imaging performance of the device make it an interesting low-cost alternative to dedicated small animal scanners.

Pulmonary arterial hypertension treatment with carvedilol for heart failure: a randomized controlled trial

BACKGROUND Right-sided heart failure is the leading cause of death in pulmonary arterial hypertension (PAH). Similar to left heart failure, sympathetic overactivation and β-adrenoreceptor (βAR) abnormalities are found in PAH. Based on successful therapy of left heart failure with β-blockade, the safety and benefits of the nonselective β-blocker/vasodilator carvedilol were evaluated in PAH. METHODS PAH Treatment with Carvedilol for Heart Failure (PAHTCH) is a single-center, double-blind, randomized, controlled trial. Following 1-week run-in, 30 participants were randomized to 1 of 3 arms for 24 weeks: placebo, low-fixed-dose, or dose-escalating carvedilol. Outcomes included clinical measures and mechanistic biomarkers. RESULTS Decreases in heart rate and blood pressure with carvedilol were well tolerated; heart rate correlated with carvedilol dose. Carvedilol-treated groups had no decrease in exercise capacity measured by 6-minute walk, but had lower heart rates at peak and after exercise, and faster heart rate recovery. Dose-escalating carvedilol was associated with reduction in right ventricular (RV) glycolytic rate and increase in βAR levels. There was no evidence of RV functional deterioration; rather, cardiac output was maintained. CONCLUSIONS Carvedilol is likely safe in PAH over 6 months of therapy and has clinical and mechanistic benefits associated with improved outcomes. The data provide support for longer and larger studies to establish guidelines for use of β-blockers in PAH. TRIAL REGISTRATION ClinicalTrials.gov NCT01586156FUNDING. This project was supported by NIH R01HL115008 and R01HL60917 and in part by the National Center for Advancing Translational Sciences, UL1TR000439.

Impact of Time-of-Flight Reconstruction on Cardiac PET Images of Obese Patients

Purpose The benefit of time-of-flight (TOF) information in PET oncology studies is well established, demonstrating improved signal-to-noise ratio and enhanced lesion detection. In cardiac PET studies, tracer distribution and study interpretation differ substantially from oncology PET, and the benefit of TOF is less established. We investigate the impact of TOF on reconstructed myocardial distribution in 82Rb PET perfusion studies of obese patients, for whom TOF would have most significant impact. Methods Cardiac 82Rb PET data of 13 obese patients (8 male, 5 female patients; weight, mean, 139 kg [range, 109–191 kg]; body mass index, mean, 49 kg/m2 [range, 36–76 kg/m2]) were analyzed retrospectively. Images were reconstructed with and without TOF and with varying number of iterative updates (2–12 iterations). Convergence and clinical relevance of differences were assessed both visually and quantitatively (automated 17-segment scoring). An anthropomorphic torso phantom also was scanned in order to study how TOF affects reconstruction of a myocardial distribution. Results Time-of-flight imaging provided significant improvement in image quality and convergence rate compared with non-TOF imaging. Time-of-flight reconstruction typically required 2 to 4 iterations to converge versus 8 to 12 iterations for non-TOF reconstruction. Even at 12 iterations, non-TOF images occasionally had apparent differences in relative perfusion compared with TOF images that exceeded 10% and were considered likely to affect clinical interpretation. Conclusions Time-of-flight reconstruction has a significant clinical impact on cardiac PET in obese patients. When interpreting cardiac studies from non–TOF-capable PET scanners, one must ensure to reconstruct images with sufficient iterations and to be aware of potential artifacts.

Redox Imaging of Inflammation in Asthma

To the Editor: Glutathione (l-γ-glutamyl-l-cysteinylglycine) is found at exceptionally high levels in the human lung (1–3), where it serves as the primary redox couple in the reduced GSH and oxidized GSSG forms. We have identified that the airway epithelium of patients with asthma is shifted to greater reducing potential, recognized by a higher ratio of reduced to oxidized glutathione (4), which occurs in response to the episodic oxidative inflammation of asthma (1, 5–9). On this basis, we hypothesized that regional airway inflammation in asthma may be quantitatively evaluated by a nuclear imaging strategy based on uptake of a radiopharmaceutical (99mTc-exametazime [HMPAO]) selectively retained in tissues depending on GSH levels (10–13) (see Figure E1 in the online supplement). To test this concept, airway redox, inflammation, and 99mTc-HMPAO uptake determined by single-photon emission computed tomography (SPECT) were evaluated in individuals with asthma and in control subjects (Table E1). Some of the results of these studies have been previously reported in the form of abstracts (14–16). 99mTc-HMPAO (Ceretec; GE Healthcare, Arlington Heights, IL) readily diffuses into cells, where it is reduced to a hydrophilic form in the presence of GSH and retained in tissues (Figure E1) (10–13). 99mTc-HMPAO accumulation in the lung was confirmed to be glutathione dependent as indicated by markedly less uptake in mice depleted of glutathione with diethyl maleate (17) as compared with naive mice (Figure E1). Many studies report an increase in total glutathione in asthmatic lungs that occurs in an adaptive response to the episodic asthmatic exacerbations that are characterized by profound oxidative bursts of inflammatory cells in the airways (1, 5–9). Here, in anticipation of imaging, intracellular glutathione was determined in airway epithelial cells obtained at bronchoscopy from patients with asthma and control subjects to assess the magnitude of difference in redox potential between asthma and control lungs. Airway epithelium was obtained by gently brushing the airway, and the freshly obtained cells were immediately processed in the bronchoscopy suite for determination of reduced and oxidized glutathione and reducing potential in human airway epithelium of control subjects and patients with asthma in vivo. Similar to a prior report (4), GSH tended to be higher but GSSG lower in asthma (GSH, μM: patients with asthma, 17 ± 3 [n = 3]; control subjects, 8.9 ± 0.5 [n = 3]; P = 0.14; GSSG, μM: patients with asthma, 0.38 ± 0.04; control subjects, 0.48 ± 0.08; P = 0.2), so that the ratio of GSH to GSSG in the airway epithelium of patients with asthma was double that of control subjects (GSH/GSSG: patients with asthma, 43 ± 6; control subjects, 20 ± 4; P = 0.05) (Figure 1A). The reduction potential (Eh) of the GSH:GSSG couple calculated by Nernst equation (18, 19) revealed a significantly greater intracellular reducing state in the airway epithelium of patients with asthma as compared with control subjects (Eh, mV: patients with asthma, –323 ± 4; control subjects, –306 ± 3; P = 0.04) (Figure 1A). On this basis, we tested whether redox-based imaging might differentiate asthmatic from control lungs, and used SPECT and coregistered computed tomography (CT) imaging to quantitate 99mTc-HMPAO concentration and to determine anatomic sites of 99mTc-HMPAO retention (detailed imaging methods are presented in the online supplement). 99mTc-HMPAO SPECT/CT imaging revealed visibly greater HMPAO uptake in asthmatic lungs as compared with control lungs (Figures 1C and 1D; Movie E1). Normalized uptake values (NUVs) were significantly higher in patients with asthma than control subjects within central and middle transverse areas of lower lung regions (Figure 1E). Interestingly, there was significant variance in the 99mTc-HMPAO NUV of upper and lower lung regions of patients with asthma. Control lung uptake was similar among upper and lower lungs, and across the central, middle, and peripheral transverse regions of the lung. In contrast, patients with asthma had significantly greater 99mTc-HMPAO uptake in lower lung as compared with upper lung regions, and the greatest uptake within central lung regions as compared with middle and peripheral transverse regions (Figure 1E and Table 1). The finding of greater uptake in central lung regions is consistent with a greater distribution of conducting airways in central regions, and the notion of greater reducing potential in asthmatic airways. Overall, the 99mTc-HMPAO uptake findings indicate a greater than normal reducing potential in asthmatic airways as compared with normal airways, as well as significant heterogeneity of lung redox, with the most striking changes in the lower and central regions of the asthmatic lung. In this context, the lower and central regions tend to be the most prominent regions of air trapping (20, 21), which also supports the idea of more severe inflammation/airway disease in those regions. Figure 1. Redox imaging of asthmatic lungs. (A) Glutathione, GSH/GSSG, and glutathione (GSH:GSSG) redox potential (Eh) are greater in the airway epithelium of patients with asthma (n = 3) as compared with control subjects (n = 3). (B–D) Quantitation of ... Table 1: Regional Distribution of Inflammation and 99mTc-HMPAO Uptake in Asthmatic Lung The greater 99mTc-HMPAO uptake in lower regions of asthmatic lungs also suggested that inflammation might be greater in lower lung regions. To investigate this, bronchoalveolar lavage (BAL) was performed in the upper and lower lobes of patients with asthma to compare inflammatory cells and cytokines. BAL volume return, protein concentration, and total cell counts were similar among upper and lower lobes (Table 1). Eosinophils and cytokines that typify helper T-cell type 2 (Th2) inflammation, IL-4 and IL-13, were present in greater concentrations in lower lobes as compared with upper lobes (Table 1). In contrast, IFN-γ, a prototypic Th1-type cytokine, tended to be greater in upper lobes (Table 1). The IL-13 levels in BAL were inversely related to IFN-γ levels (R = –0.483, P = 0.02). This letter reveals that there is a greater reducing potential in the asthmatic airway as compared with control lungs but that there is also substantial heterogeneity of reducing potential across the lung in asthma. This supports the general concept that functional imaging based on redox potential may be used to identify intensity and regionality of airway inflammatory disease. It is important to note that the greater uptake of HMPAO may not necessarily be due to the airway epithelium in asthma. In fact, the endothelium is also inflamed in asthma and might also account for the uptake of the HMPAO (22–26). However, vascular endothelial growth factor was similar among upper and lower lung regions in asthma (Table 1). Further, to assess whether the variation of HMPAO uptake in asthma was related to variation in vascular perfusion, the blood flow in the pulmonary circulation was measured in the supine position, using 99mTc-macroaggregated albumin SPECT/CT (patients with asthma, n = 3; control subjects, n = 3). Pulmonary blood flows were not different in upper and lower regions of the lungs (all P > 0.5). Because all subjects underwent 99mTc-HMPAO SPECT/CT in the supine position (during injection, uptake, and scan), this validated that blood flow to upper and lower parts of the lungs was equally distributed and unlikely to be the cause of variance in upper and lower lobe HMPAO uptake in asthma. Likewise, there may be potential effects and/or dependence of 99mTc-HMPAO uptake on participant age or sex. Although numbers are small, there was no apparent association among 99mTc-HMPAO uptake by age or sex (all P > 0.3). Other studies have identified heterogeneity of remodeling and airflow obstruction in the lungs of patients with asthma as identified by anatomical and functional imaging modalities, for example, high-resolution CT imaging and hyperpolarized helium magnetic resonance imaging (21, 27). The participants in this study were patients with stable asthma, and further investigation is necessary to determine whether 99mTc-HMPAO uptake changes with asthma exacerbations and/or with greater asthma severity. Resolution limitation of SPECT imaging precludes the assignment of uptake to specific airways, limiting the generalized application of 99mTc-HMPAO SPECT/CT imaging in asthma. However, future development of redox-imaging compounds detectable by superior resolution modalities, for example, positron emission tomography, would be a valuable approach to visualize sites of remodeling by coregistered CT images and amounts of inflammation by redox imaging. Current studies rely on invasive bronchoscopic approaches to investigate regional asthma inflammation. The invasive nature and risk of these approaches can preclude enrollment of those patients with severe airflow limitation. A noninvasive functional nuclear imaging approach might offer an alternative quantitative solution to advance research in asthma and assess new biologic-based therapies.

Rubidium-82 uptake in metastases from pheochromocytoma on PET myocardial perfusion images.

Rubidium-82 (Rb-82) is commonly used for PET myocardial perfusion imaging. A 61-year-old male patient with coronary artery disease underwent cardiac Rb-82 PET myocardial perfusion and FDG PET myocardial viability scan. Besides myocardium, prominent Rb-82 uptake was identified in several pleural and osseous lesions. These were confirmed to be metastases from pheochromocytoma on the FDG PET and noncontrast CT scan. Chart review revealed that the patient had history of pheochromocytoma for more than 40 years, with widespread metastases as demonstrated by various imaging findings. The latest biopsy from an extradural spinal mass also demonstrated metastatic pheochromocytoma.

Enhanced PET resolution by combining pinhole collimation and coincidence detection

Spatial resolution of clinical PET scanners is limited by detector design and photon non-colinearity. Although dedicated small animal PET scanners using specialized high-resolution detectors have been developed, enhancing the spatial resolution of clinical PET scanners is of interest as a more available alternative. Multi-pinhole 511 keV SPECT is capable of high spatial resolution but requires heavily shielded collimators to avoid significant background counts. A practical approach with clinical PET detectors is to combine multi-pinhole collimation with coincidence detection. In this new hybrid modality, there are three locations associated with each event, namely those of the two detected photons and the pinhole aperture. These three locations over-determine the line of response and provide redundant information that is superior to coincidence detection or pinhole collimation alone. Multi-pinhole collimation provides high resolution and avoids non-colinearity error but is subject to collimator penetration and artifacts from overlapping projections. However the coincidence information, though at lower resolution, is valuable for determining whether the photon passed near a pinhole within the cone acceptance angle and for identifying through which pinhole the photon passed. This information allows most photons penetrating through the collimator to be rejected and avoids overlapping projections. With much improved event rejection, a collimator with minimal shielding may be used, and a lightweight add-on collimator for high resolution imaging is feasible for use with a clinical PET scanner. Monte Carlo simulations were performed of a (18)F hot rods phantom and a 54-pinhole unfocused whole-body mouse collimator with a clinical PET scanner. Based on coincidence information and pinhole geometry, events were accepted or rejected, and pinhole-specific crystal-map projections were generated. Tomographic images then were reconstructed using a conventional pinhole SPECT algorithm. Hot rods of 1.4 mm diameter were resolved easily in a simulated phantom. System sensitivity was 0.09% for a simulated 70-mm line source corresponding to the NEMA NU-4 mouse phantom. Higher resolution is expected with further optimization of pinhole design, and higher sensitivity is expected with a focused and denser pinhole configuration. The simulations demonstrate high spatial resolution and feasibility of small animal imaging with an add-on multi-pinhole collimator for a clinical PET scanner. Further work is needed to develop geometric calibration and quantitative data corrections and, eventually, to construct a prototype device and produce images with physical phantoms.

RIGHT VENTRICULAR FDG-PET UPTAKE SUGGESTS A SHIFT TO GLYCOLYTIC METABOLISM IN THE SETTING OF RIGHT VENTRICULAR DYSFUNCTION RELATED TO PULMONARY ARTERIAL HYPERTENSION

Pulmonary arterial hypertension (PAH) features intimal proliferation and smooth muscle hypertrophy of pulmonary vasculature. Resultant increased afterload leads to right ventricular (RV) failure. The metabolic state of cardiac myocytes is thought to determine how the RV responds to this increased