Andrew M. Hernandez

Longitudinal Evaluation of Left Ventricular Substrate Metabolism, Perfusion, and Dysfunction in the Spontaneously Hypertensive Rat Model of Hypertrophy Using Small-Animal PET/CT Imaging

Myocardial metabolic and perfusion imaging is a vital tool for understanding the physiologic consequences of heart failure. We used PET imaging to examine the longitudinal kinetics of 18F-FDG and 14(R,S)-18F-fluoro-6-thia-heptadecanoic acid (18F-FTHA) as analogs of glucose and fatty acid (FA) to quantify metabolic substrate shifts with the spontaneously hypertensive rat (SHR) as a model of left ventricular hypertrophy (LVH) and failure. Myocardial perfusion and left ventricular function were also investigated using a newly developed radiotracer 18F-fluorodihydrorotenol (18F-FDHROL). Methods: Longitudinal dynamic electrocardiogram-gated small-animal PET/CT studies were performed with 8 SHR and 8 normotensive Wistar-Kyoto (WKY) rats over their life cycle. We determined the myocardial influx rate constant for 18F-FDG and 18F-FTHA (KiFDG and KiFTHA, respectively) and the wash-in rate constant for 18F-FDHROL (K1FDHROL). 18F-FDHROL data were also used to quantify left ventricular ejection fraction (LVEF) and end-diastolic volume (EDV). Blood samples were drawn to independently measure plasma concentrations of glucose, insulin, and free fatty acids (FFAs). Results: KiFDG and KiFTHA were higher in SHRs than WKY rats (P < 3 × 10−8 and 0.005, respectively) independent of age. A decrease in KiFDG with age was evident when models were combined (P = 0.034). The SHR exhibited higher K1FDHROL (P < 5 × 10−6) than the control, with no age-dependent trends in either model (P = 0.058). Glucose plasma concentrations were lower in SHRs than controls (P < 6 × 10−12), with an age-dependent rise for WKY rats (P < 2 × 10−5). Insulin plasma concentrations were higher in SHRs than controls (P < 3 × 10−3), with an age-dependent decrease when models were combined (P = 0.046). FFA levels were similar between models (P = 0.374), but an increase with age was evident only in SHR (P < 7 × 10−6). Conclusion: The SHR exhibited alterations in myocardial substrate use at 8 mo characterized by increased glucose and FA utilizations. At 20 mo, the SHR had LVH characterized by decreased LVEF and increased EDV, while simultaneously sustaining higher glucose and similar FA utilizations (compared with WKY rats), which indicates maladaptation of energy substrates in the failing heart. Elevated K1FDHROL in the SHR may reflect elevated oxygen consumption and decreased capillary density in the hypertrophied heart. From our findings, metabolic changes appear to precede mechanical changes of LVH progression in the SHR model.

Kinetic parameter estimation using a closed-form expression via integration by parts

Dynamic emission computed tomographic imaging with compartment modeling can quantify in vivo physiologic processes, eliciting more information regarding underlying molecular disease processes than is obtained from static imaging. However, estimation of kinetic rate parameters for multi-compartment models can be computationally demanding and problematic due to local minima. A number of techniques for kinetic parameter estimation have been studied and are in use today, generally offering a tradeoff between computation time, robustness of fit and flexibility with differing sets of assumptions. This paper presents a means to eliminate all differential operations by using the integration-by-parts method to provide closed-form formulas, so that the mathematical model is less sensitive to data sampling and noise. A family of closed-form formulas are obtained. Computer simulations show that the proposed method is robust without having to specify the initial condition.

Mean glandular dose coefficients (D(g)N) for x-ray spectra used in contemporary breast imaging systems.

To develop tables of normalized glandular dose coefficients D(g)N for a range of anode-filter combinations and tube voltages used in contemporary breast imaging systems. Previously published mono-energetic D(g)N values were used with various spectra to mathematically compute D(g)N coefficients. The tungsten anode spectra from TASMICS were used; molybdenum and rhodium anode-spectra were generated using MCNPX Monte Carlo code. The spectra were filtered with various thicknesses of Al, Rh, Mo or Cu. An initial half value layer (HVL) calculation was made using the anode and filter material. A range of the HVL values was produced with the addition of small thicknesses of polymethyl methacrylate (PMMA) as a surrogate for the breast compression paddle, to produce a range of HVL values at each tube voltage. Using a spectral weighting method, D(g)N coefficients for the generated spectra were calculated for breast glandular densities of 0%, 12.5%, 25%, 37.5%, 50% and 100% for a range of compressed breast thicknesses from 3 to 8 cm. Eleven tables of normalized glandular dose (D(g)N) coefficients were produced for the following anode/filter combinations: W + 50 μm Ag, W + 500 μm Al, W + 700 μm Al, W + 200 μm Cu, W + 300 μm Cu, W + 50 μm Rh, Mo + 400 μm Cu, Mo + 30 μm Mo, Mo + 25 μm Rh, Rh + 400 μm Cu and Rh + 25 μm Rh. Where possible, these results were compared to previously published D(g)N values and were found to be on average less than 2% different than previously reported values.Over 200 pages of D(g)N coefficients were computed for modeled x-ray system spectra that are used in a number of new breast imaging applications. The reported values were found to be in excellent agreement when compared to published values.

The Effect of Iodine-based Contrast Material on Radiation Dose at CT: It’s Complicated

The studies by Sahbaee et al were well performed, and the results are provocative, but the authors of this editorial suggest that there are limitations to all modeling studies and that the results should be considered as only the first chapter in a much longer story about the role of contrast agents on radiation dose at CT.

Generation and analysis of clinically relevant breast imaging x‐ray spectra

Purpose The purpose of this work was to develop and make available x‐ray spectra for some of the most widely used digital mammography (DM), breast tomosynthesis (BT), and breast CT (bCT) systems in North America. Methods The Monte Carlo code MCNP6 was used to simulate minimally filtered (only beryllium) x‐ray spectra at 8 tube potentials from 20 to 49 kV for DM/BT, and 9 tube potentials from 35 to 70 kV for bCT. Vendor‐specific anode compositions, effective anode angles, focal spot sizes, source‐to‐detector distances, and beryllium filtration were simulated. For each 0.5 keV energy bin in all simulated spectra, the fluence was interpolated using cubic splines across the range of simulated tube potentials to produce spectra in 1 kV increments from 20 to 49 kV for DM/BT and from 35 to 70 kV for bCT. The HVL of simulated spectra with conventional filtration (at 35 kV for DM/BT and 49 kV for bCT) was used to assess spectral differences resulting from variations in: (a) focal spot size (0.1 and 0.3 mm IEC), (b) solid angle at the detector (i.e., small and large FOV size), and (c) geometrical specifications for vendors that employ the same anode composition. Results Averaged across all DM/BT vendors, variations in focal spot and FOV size resulted in HVL differences of 2.2% and 0.9%, respectively. Comparing anode compositions separately, the HVL differences for Mo (GE, Siemens) and W (Hologic, Philips, and Siemens) spectra were 0.3% and 0.6%, respectively. Both the commercial Koning and prototype “Doheny” (UC Davis) bCT systems utilize W anodes with a 0.3 mm focal spot. Averaged across both bCT systems, variations in FOV size resulted in a 2.2% difference in HVL. In addition, the Koning spectrum was slightly harder than Doheny with a 4.2% difference in HVL. Therefore to reduce redundancy, a generic DM/BT system and a generic bCT system were used to generate the new spectra reported herein. The spectral models for application to DM/BT were dubbed the Molybdenum, Rhodium, and Tungsten Anode Spectral Models using Interpolating Cubic Splines (MASMICSM‐T, RASMICSM‐T, and TASMICSM‐T; subscript “M‐T” indicating mammography and tomosynthesis). When compared against reference models (MASMIPM, RASMIPM, and TASMIPM; subscript “M” indicating mammography), the new spectral models were in close agreement with mean differences of 1.3%, −1.3%, and −3.3%, respectively, across tube potential comparisons of 20, 30, and 40 kV with conventional filtration. TASMICSbCT‐generated bCT spectra were also in close agreement with the reference TASMIP model with a mean difference of −0.8%, across tube potential comparisons of 35, 49, and 70 kV with 1.5 mm Al filtration. Conclusions The Mo, Rh, and W anode spectra for application in DM and BT (MASMICSM‐T, RASMICSM‐T, and TASMICSM‐T) and the W anode spectra for bCT (TASMICSbCT) as described in this study should be useful for individuals interested in modeling the performance of modern breast x‐ray imaging systems including dual‐energy mammography which extends to 49 kV. These new spectra are tabulated in spreadsheet form and are made available to any interested party.

kV x-ray dual digital tomosynthesis for image guided lung SBRT

Two simulated sets of digital tomosynthesis images of the lungs, each acquired at a 90 degree angle from the other, with 19 projection images used for each set and SART iterative reconstructed, gives dual tomosynthesis slice image quality approaching that of spiral CT, and with a data acquisition time that is 3% of that of cone beam CT. This fast kV acquisition, should allow near real time tracking of lung tumors in patients receiving SBRT, based on a novel TumoTrakTM multi-source X-ray tube design. Until this TumoTrakTM prototype is completed over the next year, its projected performance was simulated from the DRR images created from a spiral CT data set from a lung cancer patient. The resulting dual digital tomosynthesis reconstructed images of the lung tumor were exceptional and approached that of the gold standard Feldkamp CT reconstruction of breath hold, diagnostic, spiral, multirow, CT data. The relative dose at 46 mAs was less than 10% of what it would have been if the digital tomosynthesis had been done at the 472 mAs of the CT data set. This is for a 0.77 fps imaging rate sufficient to resolve respiratory motion in many free breathing patients during SBRT. Such image guidance could decrease the magnitudes of targeting error margins by as much as 20 mm or more in the craniocaudal direction for lower lobe lesions while markedly reducing dose to normal lung, heart and other critical structures. These initial results suggest a wide range of topics for future work.

Simulated lesion, human observer performance comparison between thin-section dedicated breast CT images versus computed thick-section simulated projection images of the breast.

The objective of this study was to compare the lesion detection performance of human observers between thin-section computed tomography images of the breast, with thick-section (>40 mm) simulated projection images of the breast. Three radiologists and six physicists each executed a two alterative force choice (2AFC) study involving simulated spherical lesions placed mathematically into breast images produced on a prototype dedicated breast CT scanner. The breast image data sets from 88 patients were used to create 352 pairs of image data. Spherical lesions with diameters of 1, 2, 3, 5, and 11 mm were simulated and adaptively positioned into 3D breast CT image data sets; the native thin section (0.33 mm) images were averaged to produce images with different slice thicknesses; average section thicknesses of 0.33, 0.71, 1.5 and 2.9 mm were representative of breast CT; the average 43 mm slice thickness served to simulate simulated projection images of the breast.The percent correct of the human observers responses were evaluated in the 2AFC experiments. Radiologists lesion detection performance was significantly (p < 0.05) better in the case of thin-section images, compared to thick section images similar to mammography, for all but the 1 mm lesion diameter lesions. For example, the average of three radiologists performance for 3 mm diameter lesions was 92% correct for thin section breast CT images while it was 67% for the simulated projection images. A gradual reduction in observer performance was observed as the section thickness increased beyond about 1 mm. While a performance difference based on breast density was seen in both breast CT and the projection image results, the average radiologist performance using breast CT images in dense breasts outperformed the performance using simulated projection images in fatty breasts for all lesion diameters except 11 mm. The average radiologist performance outperformed that of the average physicist observer, however trends in performance were similar. Human observers demonstrate significantly better mass-lesion detection performance on thin-section CT images of the breast, compared to thick-section simulated projection images of the breast.

Longitudinal Evaluation of Myocardial Fatty Acid and Glucose Metabolism in Fasted and Nonfasted Spontaneously Hypertensive Rats Using MicroPET/CT

Using longitudinal micro positron emission tomography (microPET)/computed tomography (CT) studies, we quantified changes in myocardial metabolism and perfusion in spontaneously hypertensive rats (SHRs), a model of left ventricular hypertrophy (LVH). Fatty acid and glucose metabolism were quantified in the hearts of SHRs and Wistar-Kyoto (WKY) normotensive rats using long-chain fatty acid analog 18F-fluoro-6-thia heptadecanoic acid (18F-FTHA) and glucose analog 18F-fluorodeoxyglucose (18F-FDG) under normal or fasting conditions. We also used 18F-fluorodihydrorotenol (18F-FDHROL) to investigate perfusion in their hearts without fasting. Rats were imaged at 4 or 5 times over their life cycle. Compartment modeling was used to estimate the rate constants for the radiotracers. Blood samples were obtained and analyzed for glucose and free fatty acid concentrations. SHRs demonstrated no significant difference in 18F-FDHROL wash-in rate constant (P = .1) and distribution volume (P = .1), significantly higher 18F-FDG myocardial influx rate constant (P = 4×10−8), and significantly lower 18F-FTHA myocardial influx rate constant (P = .007) than WKYs during the 2009-2010 study without fasting. SHRs demonstrated a significantly higher 18F-FDHROL wash-in rate constant (P = 5×10−6) and distribution volume (P = 3×10−8), significantly higher 18F-FDG myocardial influx rate constant (P = 3×10−8), and a higher trend of 18F-FTHA myocardial influx rate constant (not significant, P = .1) than WKYs during the 2011–2012 study with fasting. Changes in glucose plasma concentrations were generally negatively correlated with corresponding radiotracer influx rate constant changes. The study indicates a switch from preferred fatty acid metabolism to increased glucose metabolism with hypertrophy. Increased perfusion during the 2011-2012 study may be indicative of increased aerobic metabolism in the SHR model of LVH.

Average glandular dose coefficients for pendant-geometry breast CT using realistic breast phantoms

Purpose: To design volume‐specific breast phantoms from breast CT (bCT) data sets and estimate the associated normalized mean glandular dose coefficients for breast CT using Monte Carlo methods. Methods: A large cohort of bCT data sets (N = 215) was used to evaluate breast volume into quintiles (plus the top 5%). The average radius profile was then determined for each of the six volume‐specific groups and used to both fabricate physical phantoms and generate mathematical phantoms (V1‐V6; “V” denotes classification by volume). The MCNP6 Monte Carlo code was used to model a prototype bCT system fabricated at our institution; and this model was validated against physical measurements in the fabricated phantoms. The mathematical phantoms were used to simulate normalized mean glandular dose coefficients for both monoenergetic source photons “DgNCT(E)” (8–70 keV in 1 keV intervals) and polyenergetic x‐ray beams “pDgNCT” (35–70 kV in 1 kV intervals). The Monte Carlo code was used to study the influence of breast size (V1 vs. V5) and glandular fraction (6.4% vs. 45.8%) on glandular dose. The pDgNCT coefficients estimated for the V1, V3, and V5 phantoms were also compared to those generated using simple, cylindrical phantoms with equivalent volume and two geometrical constraints including; (a) cylinder radius determined at the breast phantom chest wall “Rcw”; and (b) cylinder radius determined at the breast phantom center‐of‐mass “RCOM”. Results: Satisfactory agreement was observed for dose estimations using MCNP6 compared with both physical measurements in the V1, V3, and V5 phantoms (R2 = 0.995) and reference bCT dose coefficients using simple phantoms (R2 = 0.999). For a 49 kV spectrum with 1.5 mm Al filtration, differences in glandular fraction [6.5% (5th percentile) vs. 45.8% (95th percentile)] had a 13.2% influence on pDgNCT for the V3 phantom, and differences in breast size (V1 vs. V5) had a 16.6% influence on pDgNCT for a breast composed of 17% (median) fibroglandular tissue. For cylindrical phantoms with a radius of RCOM, the differences were 1.5%, 0.1%, and 2.1% compared with the V1, V3, and V5 phantoms, respectively. Conclusion: Breast phantoms were designed using a large cohort of bCT data sets across a range of six breast sizes. These phantoms were then fabricated and used for the estimation of glandular dose in breast CT. The mathematical phantoms and associated glandular dose coefficients for a range of breast sizes (V1–V6) and glandular fractions (5th to 95th percentiles) are available for interested users.

Monte Carlo Basics for Radiation Dose Assessment in Diagnostic Radiology

Monte Carlo simulations are the basis of all modern x-ray dosimetry methods in diagnostic radiology. Monte Carlo (MC) methods are different from the larger class of computer simulation techniques in that they explicitly compute stochastic events and track the outcome. For x-ray dosimetry, MC methods track the trajectory of individual x-ray photons, one by one, as they exit an x-ray source, enter the simulated patient anatomy, and undergo scattering and absorption events. The amount of energy deposited in the “patient” is tallied at each location where a dose-deposition interaction takes place. Typically, millions to billions of photon histories are computed and the energy deposited in each volume element (voxel) in the mathematical phantom is then divided by the tissue mass of that voxel, resulting in the absorbed dose for the voxel – defined as imparted energy per unit mass. Modern computers are very fast and billions of photon histories can be realistically simulated to estimate the radiation dose deposited to anatomy from a given radiological imaging application. Despite this large number of simulated photons (e.g. 109), actual x-ray imaging involves 1014 to 1016 photons for each mammographic or CT acquisition, respectively – a factor of 10,000 or more greater than what is possible in most MC experiments. Thus, it is common to also record the air kerma at the entrance of the phantom for radiographic or mammographic applications, or the air kerma at the center of the field for computed tomography applications. In this way, a coefficient representing the absorbed dose per unit air kerma – in the interesting units of mGy/mGy, is computed. In the old days of radiology, these coefficients used different units and were sometimes called the “roentgen to rad conversion factors”. These coefficients allow dose levels in actual imaging procedures to be estimated using physically-measured air kerma levels in the radiography room or CT suite.