Daniel J. de Vries

Development and validation of a Monte Carlo simulation of photon transport in an Anger camera

The geometric component of the point spread function (PSF) of a gamma camera collimator can be determined analytically, and the penetration component can be calculated readily by numerical ray-tracing. A Monte Carlo simulation of photon transport which includes collimator scatter is developed. The simulation was implemented with an array processor which propagates up to 1024 photons in parallel, allowing accurate estimates of the total radial PSF in less than a day. The simulation was tested by imaging monoenergetic point sources of Tc-99m, Cr-51, and Sr-85 (140, 320, and 514 keV, respectively) on a General Electric Star Cam with low-energy, general-purpose, and medium-energy collimators. Comparisons of measured and simulated PSFs demonstrate the validity of the model and the significance of collimator scatter in the degradation of image quality.

Efficacy and Safety of Single-Agent Pertuzumab, a Human Epidermal Receptor Dimerization Inhibitor, in Patients with Non–Small Cell Lung Cancer

Purpose: Pertuzumab, a first-in-class human epidermal receptor 2 (HER2) dimerization inhibitor, is a humanized monoclonal anti-HER2 antibody that binds HER2s dimerization domain and inhibits HER2 signaling. Based on supporting preclinical studies, we undertook a Phase II trial of pertuzumab in patients with recurrent non–small cell lung cancer (NSCLC). Experimental Design: Patients with previously treated NSCLC accessible for core biopsy and naive to HER pathway inhibitors were treated with pertuzumab i.v. once every 3 weeks. Tumor assessments were done at 6 and 12 weeks and then every 3 months thereafter. The primary efficacy end point was overall response rate by Response Evaluation Criteria in Solid Tumors. Measurement of tumor glucose metabolism (SUVmax) by F-18-fluorodeoxyglucose positron emission tomography was used as an exploratory pharmacodynamic marker of drug activity. Results: Of 43 patients treated with pertuzumab, no responses were seen; 18 of 43 (41.9%) and 9 of 43 (20.9%) patients had stable disease at 6 and 12 weeks, respectively. The median and 3-month progression-free survival rates (PFS) were 6.1 weeks (95% confidence interval, 5.3-11.3 weeks) and 28.4% (95% confidence interval, 14.4-44.2%), respectively. Of 22 patients who underwent F-18-fluorodeoxyglucose positron emission tomography, six (27.3%) had a metabolic response to pertuzumab as evidenced by decreased SUVmax. These patients had prolonged PFS (HR = 0.11, log-rank P value = 0.018) compared with the 16 patients who had no metabolic response. Four patients (9.3%) experienced a grade 3/grade 4 adverse event judged related to pertuzumab; none exhibited grade 3/grade 4 cardiac toxicity. Conclusions: Pertuzumab is well tolerated as monotherapy. Pharmacodynamic activity correlated with prolonged PFS was detected in a moderate percentage of patients (27.3%). Further clinical development of pertuzumab should focus on rational combinations of pertuzumab with other drugs active in NSCLC.

Reducing the influence of the partial volume effect on SPECT activity quantitation with 3D modelling of spatial resolution in iterative reconstruction

Quantitative parameters such as the maximum and total counts in a volume are influenced by the partial volume effect. The magnitude of this effect varies with the non-stationary and anisotropic spatial resolution in SPECT slices. The objective of this investigation was to determine whether iterative reconstruction which includes modelling of the three-dimensional (3D) spatial resolution of SPECT imaging can reduce the impact of the partial volume effect on the quantitation of activity compared with filtered backprojection (FBP) techniques which include low-pass, and linear restoration filtering using the frequency distance relationship (FDR). The iterative reconstruction algorithms investigated were maximum-likelihood expectation-maximization (MLEM), MLEM with ordered subset acceleration (ML-OS), and MLEM with acceleration by the rescaled-block-iterative technique (ML-RBI). The SIMIND Monte Carlo code was used to simulate small hot spherical objects in an elliptical cylinder with and without uniform background activity as imaged by a low-energy ultra-high-resolution (LEUHR) collimator. Centre count ratios (CCRs) and total count ratios (TCRs) were determined as the observed counts over true counts. CCRs were unstable while TCRs had a bias of approximately 10% for all iterative techniques. The variance in the TCRs for ML-OS and ML-RBI was clearly elevated over that of MLEM, with ML-RBI having the smaller elevation. TCRs obtained with FDR-Wiener filtering had a larger bias (approximately 30%) than any of the iterative reconstruction methods but near stationarity is also reached. Butterworth filtered results varied by 9.7% from the centre to the edge. The addition of background has an influence on the convergence rate and noise properties of iterative techniques.

Segmentation of the body and lungs from Compton scatter and photopeak window data in SPECT: a Monte-Carlo investigation

In SPECT imaging of the chest, nonuniform attenuation correction requires use of a patient specific attenuation (mu) map. Such a map can be obtained by estimating the regions of (1) the lungs and (2) the soft tissues and bones, and then assigning an appropriate value of attenuation coefficient (mu) to each region. The authors proposed a method to segment such regions from the Compton scatter and photopeak window SPECT slices of Tc-99m Sestamibi studies. The Compton scatter slices are used to segment the body outline and to estimate the regions of the lungs. Locations of the back bone and sternum are estimated from the photopeak window slices to assist in the segmentation. To investigate the accuracy of using Compton scatter slices in estimating the regions of the body and the lungs, a Monte-Carlo SPECT simulation of an anthropomorphic phantom with an activity distribution and noise characteristics similar to patient data was conducted. Energy windows of various widths were simulated for use in locating a suitable Compton scatter window for imaging, The effects of attenuation correction using a mu map based on segmentation were also studied. The results demonstrated for the activity and mu maps studied herein that: (1) reasonable contrast could be obtained from Compton scatter data for the segmentation of the lung regions, (2) true positive rates of 99% and 89% for determining the body and lung regions, respectively, with total error rates of 4% and 29%, could be achieved, (3) usage of a mu map based on segmentation for attenuation correction improved relative quantification over filtered backprojection, (4) variations in the assigned mu value of 40% smaller or 40% larger in the lung regions had an insignificant impact on the results of relative quantification, (5) a wide energy window away from the photopeak window for recording scattered events could benefit both the segmentation of the lung regions and the attenuation correction of the activity in the myocardium region, and (6) usage of a smaller than true mu value in the lung regions of an assigned mu map might benefit attenuation correction for absolute quantification.

ACRIN 6665/RTOG 0132 Phase II Trial of Neoadjuvant Imatinib Mesylate for Operable Malignant Gastrointestinal Stromal Tumor: Monitoring with 18F-FDG PET and Correlation with Genotype and GLUT4 Expression

We investigated the correlation between metabolic response by 18F-FDG PET and objective response, glucose transporter type 4 (GLUT4) expression, and KIT/PDGFRA mutation status in patients with gastrointestinal stromal tumor undergoing neoadjuvant imatinib mesylate therapy. Methods: 18F-FDG PET was performed at baseline, 1–7 d, and 4 or 8 wk after imatinib mesylate initiation. Best objective response was defined by version 1.0 of the Response Evaluation Criteria in Solid Tumors (RECIST). Mutational analysis and tumor GLUT4 expression by immunohistochemistry were done on tissue obtained at baseline or surgery. Results: 18F-FDG PET showed high baseline tumor glycolytic activity (mean SUVmax, 14.2; range, 1.3–53.2), decreasing after 1 wk of imatinib mesylate (mean, 5.5; range, −0.5–47.7, P < 0.001, n = 44), and again before surgery (mean, 3.0; range, −0.5–36.1, P < 0.001, n = 40). At week 1, there were 3 patients with complete metabolic response (CMR), 33 with partial metabolic response (PMR), 6 with stable metabolic disease (SMD), and 2 with progressive metabolic disease (PMD). Before surgery, there were 3 with CMR, 33 with PMR, 4 with SMD, and none with PMD. The best response according to RECIST was 2 with partial response, 36 with stable disease, and 1 with progressive disease (n = 39). Of the patients with a posttreatment decrease in GLUT4 expression, 1 had CMR, 15 had PMR, 2 had SMD, and 1 had PMD at week 1, whereas before surgery 1 patient had CMR, 16 had PMR, 2 had SMD, and none had PMD. Among 27 patients with KIT exon 11 mutations, 1 had CMR, 22 had PMR, 3 had SMD, and 1 had PMD at week 1, whereas 1 had CMR, 22 had PMR, 2 had SMD, and 2 were unknown before surgery; among 4 patients with a wild-type genotype, 2 had PMR and 2 SMD at week 1, whereas 1 had CMR, 2 had PMR, and 1 had SMD before surgery. Conclusion: After imatinib mesylate initiation, metabolic response by 18F-FDG PET was documented earlier (1–7 d) and was of much greater magnitude (36/44) than that documented by RECIST (2/39). Immunohistochemistry data suggest that GLUT4 may play a role in 18F-FDG uptake in gastrointestinal stromal tumor, GLUT4 levels decrease after imatinib mesylate therapy in most patients with PMR, and the biologic action of imatinib mesylate interacts with glycolysis and GLUT4 expression. A greater than 85% metabolic response was observed as early as days 1–7 in patients with exon 11 mutations.

Window selection for dual photopeak window scatter correction in Tc-99m imaging

The width and placement of the windows far the dual photopeak window (DPW) scatter subtraction method for Tc-99m imaging is investigated in order to obtain a method that is stable on a multihead detector system for single photon emission computed tomography (SPECT) and is capable of providing a good scatter estimate for extended objects. For various window pairs, stability and noise were examined with experiments using a SPECT system, while Monte Carlo simulations were used to predict the accuracy of scatter estimates for a variety of objects and to guide the development of regression relations for various window pairs. The DPW method that resulted from this study was implemented with a symmetric 20% photopeak window composed of a 15% asymmetric photopeak window and a 5% lower, window abutted at 7 keV below the peak. A power function regression was used to relate the scatter-to-total ratio to the lower window-to-total ratio at each pixel, from which an estimated scatter image was calculated. DPW demonstrated good stability, achieved by abutting the two windows away from the peak. Performance was assessed and compared with Compton window subtraction (CWS). For simulated extended objects, DPW generally produced a less biased scatter estimate than the commonly used CWS method with k=0.5. In acquisitions of a clinical SPECT phantom, contrast recovery was comparable for both DPW and CWS; however, DPW showed greater visual contrast in clinical SPECT bone studies. >

Characterization of spectral and spatial distributions of penetration, scatter and lead X-rays in Ga-67 SPECT

Ga-67, a tumor-seeking imaging agent, has proven useful in the management of Hodgkins disease and non-Hodgkins lymphoma. However, Ga-67 presents challenges to accurate lesion detection and activity quantitation due to the range of energies of the gamma rays emitted. Medium- to high-energy photons produce collimator penetration, scatter and lead X-rays, which degrade contrast, resolution and quantitation in images of the more abundant, lower-energy photons. To study the effects of these interactions and to provide a tool for detection and estimation studies, the authors developed and tested a Monte Carlo (MC) simulation program. Simulated characteristic lead X-rays were compared with the difference of measurements made with and without the camera collimator, using Tc-99m (140.5 keV) in a tin source-collimator. Simulated energy spectra and images were compared with measurements of Cr-51 (320 keV) to evaluate collimator penetration and scatter, and backscatter from components behind the NaI crystal. Finally, spectra and images were compared for several emission peaks of Ga-67. The simulation provided good estimates of both spectral and spatial distributions.

Approximation of hexagonal holes by square holes in Monte Carlo simulation of gamma-camera collimation

For Monte Carlo simulations, fast calculation of the distance traveled by a photon in the septal material of parallel-hole collimators can be facilitated by using a square-hole design. Square holes can provide the same geometric efficiency, resolution and lead content (g/cm/sup 2/) as a comparable hexagonal-hole collimator by appropriate scaling of the hexagonal-hole septal width and hole size. Our objective was to study the validity of using square holes to estimate the hexagonal-hole collimator response. The geometric, penetration and collimator scatter components were compared for low-energy (LE) and medium-energy (ME) designs, using square- and hexagonal-holes and a 320 keV point source in air. The resolution (FWHM) was virtually identical for both hole shapes. The amount of penetration, and to a lesser extent collimator scatter, depended upon hole shape and pattern. However, for a 20% photopeak image, the difference in the total square-hole estimate relative to the hexagonal-hole was 10% and 3% for the LE and ME collimators, respectively. For an extended source and ME collimators, the relative difference was 3% for Cr-51 and 0.8% for Ga-67. When the two-dimensional penetration artifact is not critical and a small error in the amount of penetration is acceptable (e.g., when using energy-appropriate collimators), square-holes can be substituted for hexagonal-holes to decrease by 36% to 50% the time required for simulation.

Segmentation of the body and lungs from Compton scatter and photopeak window data in SPECT: a Monte Carlo investigation

In SPECT imaging of the chest, non-uniform attenuation correction requires use of a patient specific attenuation map. Such a map can be obtained by estimating the regions occupied by (1) the lungs and (2) the soft tissue and bones, and then assigning values of the attenuation coefficient to each region. The authors propose a method to segment such regions from the Compton scatter and photopeak window SPECT slices of Tc-99m Sestamibi studies. The Compton scatter slices are used to segment the body outline, and to estimate the region of the lungs with the anatomic information on the back bone and sternum locations from the photopeak window slices. To investigate the accuracy of using Compton scatter slices in estimating the regions of the body and the lungs, a Monte Carlo SPECT simulation of an anthropomorphic phantom with an activity distribution and noise characteristics similar to patient data was performed. Different activities were simulated in the lungs to study the influence of lung uptake. Energy windows of various widths were simulated for use in locating a suitable Compton scatter window for imaging. In a separate simulation, the map of the probability of scatter interactions (up to third order) from photons originating at a point within the heart was recorded to allow investigation of the contrast provided by the difference in density between the lungs and surrounding bones and soft tissue. The results demonstrated that (1) sufficient contrast can be derived from Compton scatter data for segmentation of the lungs; (2) accuracy of determination of body and lung regions of about 99% and 89%, respectively, can be achieved and (3) a wide energy window away from the photopeak window for recording the scattered events is preferred for the segmentation of lungs.<<ETX>>

Window selection for improved dual photopeak window scatter correction

The authors have investigated the width and placement of the windows for the dual photopeak window (DPW) scatter subtraction method, in order to obtain a method that is stable on multi-head SPECT systems and capable of providing a good scatter estimate for extended objects. Stability and noise were examined with experiments using a SPECT system, while Monte Carlo simulations were used to predict the accuracy of scatter estimates for a variety of objects and to guide the development of regression relations for various window pairs. With a 15% asymmetric photopeak window and a 5% lower window abutted at 7 keV below the peak, a method was developed to relate the scatter-to-total (STR) ratio to the lower window-to-total ratio (LTR) at each pixel. Calibration was done using images of point sources at various depths in an attenuator. Using the entire image and a small, centered region of interest (ROI) at each depth, summed counts from the scatter component, the lower window, and the total window were used as input to a regression on a power function. The total image was multiplied by the STR to form the estimated scatter image to be subtracted. The DPW method with an extended total window demonstrated improved stability, achieved by abutting the two windows away from the peak. Noise in the scatter estimate was reduced by the use of a wider region of the spectrum, as well as by filtering. By including in the regression relation the additional information provided by the ROI, the bias of the estimated scatter from extended objects was reduced. For the simulated extended objects, DPW generally produced a less biased scatter estimate than the commonly used Compton window subtraction with k=0.5.<<ETX>>