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author:("Seo, young")
1.  Design Studies of a CZT-based Detector Combined with a Pixel-Geometry-Matching Collimator for SPECT Imaging 
Single Photon Emission Computed Tomography (SPECT) suffers limited efficiency due to the need for collimators. Collimator properties largely decide the data statistics and image quality. Various materials and configurations of collimators have been investigated in many years. The main thrust of our study is to evaluate the design of pixel-geometry-matching collimators to investigate their potential performances using Geant4 Monte Carlo simulations. Here, a pixel-geometry-matching collimator is defined as a collimator which is divided into the same number of pixels as the detector’s and the center of each pixel in the collimator is a one-to-one correspondence to that in the detector. The detector is made of Cadmium Zinc Telluride (CZT), which is one of the most promising materials for applications to detect hard X-rays and γ-rays due to its ability to obtain good energy resolution and high light output at room temperature. For our current project, we have designed a large-area, CZT-based gamma camera (20.192 cm×20.192 cm) with a small pixel pitch (1.60 mm). The detector is pixelated and hence the intrinsic resolution can be as small as the size of the pixel. Materials of collimator, collimator hole geometry, detection efficiency, and spatial resolution of the CZT detector combined with the pixel-matching collimator were calculated and analyzed under different conditions. From the simulation studies, we found that such a camera using rectangular holes has promising imaging characteristics in terms of spatial resolution, detection efficiency, and energy resolution.
PMCID: PMC4219527  PMID: 25378898
CZT; pixel-geometry-matching collimator; spatial resolution; detection efficiency; deposited energy resolution; energy spectra
2.  Design of 20-aperture multipinhole collimator and performance evaluation for myocardial perfusion imaging application 
Physics in medicine and biology  2013;58(20):10.1088/0031-9155/58/20/7209.
Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) remains a critical tool in the diagnosis of coronary artery disease (CAD). However, after more than three decades of use, photon detection efficiency remains poor and unchanged. This is due to the continued reliance on parallel-hole collimators first introduced in 1964. These collimators possess poor geometric efficiency. Here we present the performance evaluation results of a newly designed multipinhole collimator with 20 pinhole apertures (PH20) for commercial SPECT systems. Computer simulations and numerical observer studies were used to assess the noise, bias and diagnostic imaging performance of a PH20 collimator in comparison with those of a low energy high resolution (LEHR) parallel-hole collimator. Ray-driven projector/backprojector pairs were used to model SPECT imaging acquisitions, including simulation of noiseless projection data and performing MLEM/OSEM image reconstructions. Poisson noise was added to noiseless projections for realistic projection data. Noise and bias performance were investigated for five mathematical cardiac and torso (MCAT) phantom anatomies imaged at two gantry orbit positions (19.5 cm and 25.0 cm). PH20 and LEHR images were reconstructed with 300 MLEM iterations and 30 OSEM iterations (10 subsets), respectively. Diagnostic imaging performance was assessed by a receiver operating characteristic (ROC) analysis performed on a single MCAT phantom; however, in this case PH20 images were reconstructed with 75 pixel-based OSEM iterations (4 subsets). Four PH20 projection views from two positions of a dual-head camera acquisition and sixty LEHR projections were simulated for all studies. At uniformly-imposed resolution of 12.5 mm, significant improvements in SNR and diagnostic sensitivity (represented by the area under the ROC curve, or AUC) were realized when PH20 collimators are substituted for LEHR parallel- hole collimators. SNR improves by factors of 1.94-2.34 for the five patient anatomies and two orbital positions studied. For the ROC analysis the PH20 AUC is larger than the LEHR AUC with a p-value of 0.0067. Bias performance, however, decreases with the use of PH20 collimators. Systematic analyses showed PH20 collimators present improved diagnostic imaging performance over LEHR collimators, requiring only collimator exchange on existing SPECT cameras for their use.
PMCID: PMC3855225  PMID: 24061162
3.  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).
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).
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).
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.
PMCID: PMC4000452  PMID: 24092939
spontaneously hypertensive rat; myocardial substrate metabolism; myocardial perfusion; 18F-fluorodihydrorotenol; 18F-fluoro-6-thia-heptadecanoic acid
4.  Temperature dependent operation of PSAPD-based compact gamma camera for SPECT imaging 
IEEE transactions on nuclear science  2011;58(5):2169-2174.
We investigated the dependence of image quality on the temperature of a position sensitive avalanche photodiode (PSAPD)-based small animal single photon emission computed tomography (SPECT) gamma camera with a CsI:Tl scintillator. Currently, nitrogen gas cooling is preferred to operate PSAPDs in order to minimize the dark current shot noise. Being able to operate a PSAPD at a relatively high temperature (e.g., 5 °C) would allow a more compact and simple cooling system for the PSAPD. In our investigation, the temperature of the PSAPD was controlled by varying the flow of cold nitrogen gas through the PSAPD module and varied from −40 °C to 20 °C. Three experiments were performed to demonstrate the performance variation over this temperature range. The point spread function (PSF) of the gamma camera was measured at various temperatures, showing variation of full-width-half-maximum (FWHM) of the PSF. In addition, a 99mTc-pertechnetate (140 keV) flood source was imaged and the visibility of the scintillator segmentation (16×16 array, 8 mm × 8 mm area, 400 μm pixel size) at different temperatures was evaluated. Comparison of image quality was made at −25 °C and 5 °C using a mouse heart phantom filled with an aqueous solution of 99mTc-pertechnetate and imaged using a 0.5 mm pinhole collimator made of tungsten. The reconstructed image quality of the mouse heart phantom at 5 °C degraded in comparision to the reconstructed image quality at −25 °C. However, the defect and structure of the mouse heart phantom were clearly observed, showing the feasibility of operating PSAPDs for SPECT imaging at 5 °C, a temperature that would not need the nitrogen cooling. All PSAPD evaluations were conducted with an applied bias voltage that allowed the highest gain at a given temperature.
PMCID: PMC3898791  PMID: 24465051
Avalanche photodiodes; Biomedical nuclear imaging; SPECT; Scintillation detectors
5.  Myocardial blood flow measurement with a conventional dual-head SPECT/CT with spatiotemporal iterative reconstructions - a clinical feasibility study 
Cardiac single photon emission computed tomography (SPECT) cameras typically rotate too slowly around a patient to capture changes in the blood pool activity distribution and provide accurate kinetic parameters. A spatiotemporal iterative reconstruction method to overcome these limitations was investigated. Dynamic rest/stress 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) SPECT/CT was performed along with reference standard rest/stress dynamic positron emission tomography (PET/CT) 13N-NH3 in five patients. The SPECT data were reconstructed using conventional and spatiotemporal iterative reconstruction methods. The spatiotemporal reconstruction yielded improved image quality, defined here as a statistically significant (p<0.01) 50% contrast enhancement. We did not observe a statistically significant difference between the correlations of the conventional and spatiotemporal SPECT myocardial uptake K 1 values with PET K 1 values (r=0.25, 0.88, respectively) (p<0.17). These results indicate the clinical feasibility of quantitative, dynamic SPECT/CT using 99mTc-MIBI and warrant further investigation. Spatiotemporal reconstruction clearly provides an advantage over a conventional reconstruction in computing K 1.
PMCID: PMC3867729  PMID: 24380045
Dynamic SPECT; myocardial perfusion imaging; 99mTc-MIBI; SPECT/CT; spatiotemporal reconstruction; uptake rate constant
6.  Tumor dosimetry using [124I]m-iodobenzylguanidine microPET/CT for [131I]m- iodobenzylguanidine treatment of neuroblastoma in a murine xenograft model 
[124I]m-iodobenzylguanidine (124I-mIBG) provides a quantitative tool for pretherapy tumor imaging and dosimetry when performed before [131I]m-iodobenzylguanidine (131I-mIBG) targeted radionuclide therapy of neuroblastoma. 124I (T1/2=4.2d) has a comparable half-life to that of 131I (T1/2=8.02d), and can be imaged by PET for accurate quantification of the radiotracer distribution. We estimated expected radiation dose in tumors from 131I-mIBG therapy using 124I-mIBG microPET/CT imaging data in a murine xenograft model of neuroblastoma transduced to express high levels of the human norepinephrine transporter (hNET).
In order to enhance mIBG uptake for in vivo imaging and therapy, NB 1691-luciferase (NB1691) human neuroblastoma cells were engineered to express high levels of hNET protein by lentiviral transduction (NB1691-hNET). Both NB1691 and NB1691-hNET cells were implanted subcutaneously and into renal capsules in athymic mice. 124I-mIBG (4.2–6.5 MBq) was administered intravenously for microPET/CT imaging at 5 time points over 95 hours (0.5, 3–5, 24, 48, and 93–95 h median time points). In vivo biodistribution data in normal organs, tumors, and whole-body were collected from reconstructed PET images corrected for photon attenuation using the CT-based attenuation map. Organ and tumor dosimetry were determined for 124I-mIBG. Dose estimates for 131I-mIBG were made, assuming the same in vivo biodistribution as 124I-mIBG.
All NB1691-hNET tumors had significant uptake and retention of 124I-mIBG, whereas unmodified NB1691 tumors did not demonstrate quantifiable mIBG uptake in vivo, despite in vitro uptake. 124I-mIBG with microPET/CT provided an accurate 3-dimensional tool for estimating the radiation dose that would be delivered with 131I-mIBG therapy. For example, in our model system, we estimated that the administration of 131I-mIBG in the range of 52.8 – 206 MBq would deliver 20 Gy to tumors.
The overexpression of hNET was found to be critical for 124I-mIBG uptake and retention in vivo. The quantitative 124I-mIBG PET/CT is a promising new tool to predict tumor radiation doses with 131I-mIBG therapy of neuroblastoma. This methodology may be applied to tumor dosimetry of 131I-mIBG therapy in human subjects using 124I-mIBG pretherapy PET/CT data.
PMCID: PMC3369020  PMID: 22382618
neuroblastoma; m-iodobenzylguanidine; iodine-124; iodine-131; PET/CT; animal model; radiation dosimetry
7.  Functional Imaging for Prostate Cancer: Therapeutic Implications 
Seminars in nuclear medicine  2012;42(5):328-342.
Functional radionuclide imaging modalities, now commonly combined with anatomical imaging modalities CT or MRI (SPECT/CT, PET/CT, and PET/MRI) are promising tools for the management of prostate cancer particularly for therapeutic implications. Sensitive detection capability of prostate cancer using these imaging modalities is one issue; however, the treatment of prostate cancer using the information that can be obtained from functional radionuclide imaging techniques is another challenging area. There are not many SPECT or PET radiotracers that can cover the full spectrum of the management of prostate cancer from initial detection, to staging, prognosis predictor, and all the way to treatment response assessment. However, when used appropriately, the information from functional radionuclide imaging improves, and sometimes significantly changes, the whole course of the cancer management. The limitations of using SPECT and PET radiotracers with regards to therapeutic implications are not so much different from their limitations solely for the task of detecting prostate cancer; however, the specific imaging target and how this target is reliably imaged by SPECT and PET can potentially make significant impact in the treatment of prostate cancer. Finally, while the localized prostate cancer is considered manageable, there is still significant need for improvement in noninvasive imaging of metastatic prostate cancer, in treatment guidance, and in response assessment from functional imaging including radionuclide-based techniques. In this review article, we present the rationale of using functional radionuclide imaging and the therapeutic implications for each of radionuclide imaging agent that have been studied in human subjects.
PMCID: PMC3408625  PMID: 22840598
8.  Multi-Material Decomposition using Low-Current X-Ray and a Photon-Counting CZT Detector 
We developed and evaluated an x-ray photon-counting imaging system using an energy-resolving cadmium zinc telluride (CZT) detector coupled with application specific integrated circuit (ASIC) readouts. This x-ray imaging system can be used to identify different materials inside the object. The CZT detector has a large active area (5×5 array of 25 CZT modules, each with 16×16 pixels, cover a total area of 200 mm × 200 mm), high stopping efficiency for x-ray photons (~ 100 % at 60 keV and 5 mm thickness). We explored the performance of this system by applying different energy windows around the absorption edges of target materials, silver and indium, in order to distinguish one material from another. The photon-counting CZT-based x-ray imaging system was able to distinguish between the materials, demonstrating its capability as a radiation-spectroscopic decomposition system.
PMCID: PMC3598635  PMID: 23503709
9.  The Metabolic Profile of Tumors Depends on both the Responsible Genetic Lesion and Tissue Type 
Cell Metabolism  2012;15(2):157-170.
The altered metabolism of tumors has been considered a target for anti-cancer therapy. However, the relationship between distinct tumor-initiating lesions and anomalies of tumor metabolism in vivo has not been addressed. We report that MYC-induced mouse liver tumors significantly increase both glucose and glutamine catabolism, whereas MET-induced liver tumors use glucose to produce glutamine. Increased glutamine catabolism in MYC-induced liver tumors is associated with decreased levels of glutamine synthetase (Glul) and the switch from Gls2 to Gls1 glutaminase. In contrast to liver tumors, MYC-induced lung tumors display increased expression of both Glul and Gls1 and accumulate glutamine. We also show that inhibition of Gls1 kills cells that over-express MYC and catabolize glutamine. Our results suggest that the metabolic profiles of tumors are likely to depend on both the genotype and tissue of origin and have implications regarding the design of therapies targeting tumor metabolism.
PMCID: PMC3282107  PMID: 22326218
10.  Combining Dynamic and Electrocardiogram-gated 82Rb-PET for Practical Implementation in the Clinic 
For many cardiac clinics, list-mode PET is impractical. Thus, separate dynamic and electrocardiogram-gated (ECG-gated) acquisitions are needed to detect harmful stenoses; indicate affected coronary arteries; and estimate stenosis severity. However, physicians usually order gated studies only due to dose, time, and cost limitations and are limited to detection. In an effort to remove these limitations, we developed a novel curve-fitting algorithm (ICD) to accurately calculate coronary flow reserve (CFR) from a combined dynamic-ECG protocol of length equal to one typical gated scan.
We shortened several retrospective dynamic studies to simulate shortened dynamic acquisitions of the combined protocol and compared: 1) the accuracy of ICD and a nominal method in extrapolating the complete functional form of arterial input functions (AIFs); and 2) the accuracy of ICD and ICD-AP (ICD with a posteriori knowledge of complete-data AIFs) in predicting CFRs.
AIFs predicted by ICD were more accurate than those predicted by the nominal method in 11/12 studies according to the Akaike Information Criterion. CFRs predicted by ICD and ICD-AP were similar to compete-data predictions (pICD = 0.94 and pICD-AP = 0.91) and had similar average errors (eICD = 2.82% and eICD-AP = 2.79%).
Both ICD and ICD-AP predicted CFR values with sufficient accuracy for the clinic according to a nuclear cardiologist and an expert analyst of PET data. Therefore, by using our method, physicians in cardiac clinics would have access to the necessary amount of information to differentiate between single-and triple- vessel disease for treatment decision-making.
PMCID: PMC3227790  PMID: 21934541
nonlinear optimization; nonlinear least squares; PET kinetics analysis; 82Rb-PET
11.  Combined SPECT and Multidetector CT for Prostate Cancer Evaluations 
111In-capromab pendetide is an imaging probe for noninvasive detection of prostate cancer dissemination, and can be difficult to interpret because of low photon statistics resulting in noisy images with limited anatomical precision. We examined if a 16-slice multidetector computed tomography (MDCT) combined with single photon emission computed tomography (SPECT) could increase the impact on the clinical management and improve confidence in SPECT image interpretations in comparison to a relatively low-mA (limited resolution) CT. 17 scans were reviewed from a SPECT combined with low-mA CT scanner; 21 scans were reviewed from a SPECT combined with 16-slice MDCT scanner. Reports of the clinical interpretations from the imaging studies, additional examinations performed by referring physicians as a follow-up to the imaging results, and long-term clinical and laboratory follow-ups were used to define confidence of the SPECT/CT readings and impact of the readings on the patient management. The impact was defined as: the occurrence of the 111In-capromab pendetide interpretation resulted in additional imaging studies or biopsies. MDCT improved the quality and confidence in the characterization of small lymph nodes with or without uptake of 111In-capromab pendetide. The increased confidence with MDCT in SPECT/CT readings was evident in all cases reviewed in this study, and the impact on the clinical management was higher (8 out of 21) using SPECT/MDCT than the impact using SPECT combined with low-mA CT (2 out of 17). The dual-modality SPECT/CT provides a quantifiable benefit when MDCT is used instead of low-mA CT, particularly for prostate cancer evaluations using 111In-capromab pendetide.
PMCID: PMC3260786  PMID: 22267999
prostate cancer; capromab pendetide; SPECT/CT; MDCT; prostate specific membrane antigen (PSMA)
12.  Lymphatic drainage mapping of prostate using filtered 99mTc-sulfur nanocolloid and SPECT/CT 
We have developed a practice procedure of prostate lymphoscintigraphy using SPECT/CT and filtered 99mTc-sulfur nanocolloid.
A total of 10 patients were enrolled for this study, and all administred with the radiotracer prepared using a 100-nm membrane filter at a commercial radiopharmacy. Whole-body scans and SPECT/CT studies were performed within 1.5–3 hours after the radiotracer administration directly into six locations of the prostate gland under a transrectal ultrasound guide. Radiation dose was estimated from the first 3 patients. The lymphatic drainage mapping and identification of lymph nodes were performed.
Radiation dose estimates of filtered 99mTc-sulfur nanocollid from the first three patients were in the range of 3.9–5.2 mSv/MBq. Our results showed the locations of lymph nodes drainged from the prostate gland are similar to those found using 99mTc-Nanocoll.
Without the proprietary radiolabeled nanocolloid indicated for lymphoscintigraphy, prostate lymph node mapping and identification were feasible using filtered 99mTc-sulfur nanocolloid.
PMCID: PMC3129454  PMID: 21680690
prostate cancer; sulfur colloid; SPECT/CT; lymphatic mapping; sentinel node
13.  Depth-of-Interaction Compensation Using a Focused-Cut Scintillator for a Pinhole Gamma Camera 
Preclinical SPECT offers a powerful means to understand the molecular pathways of drug interactions in animal models by discovering and testing new pharmaceuticals and therapies for potential clinical applications. A combination of high spatial resolution and sensitivity are required in order to map radiotracer uptake within small animals. Pinhole collimators have been investigated, as they offer high resolution by means of image magnification. One of the limitations of pinhole geometries is that increased magnification causes some rays to travel through the detection scintillator at steep angles, introducing parallax errors due to variable depth-of-interaction in scintillator material, especially towards the edges of the detector field of view. These parallax errors ultimately limit the resolution of pinhole preclinical SPECT systems, especially for higher energy isotopes that can easily penetrate through millimeters of scintillator material. A pixellated, focused-cut (FC) scintillator, with its pixels laser-cut so that they are collinear with incoming rays, can potentially compensate for these parallax errors and thus improve the system resolution. We performed the first experimental evaluation of a newly developed focused-cut scintillator. We scanned a Tc-99m source across the field of view of pinhole gamma camera with a continuous scintillator, a conventional “straight-cut” (SC) pixellated scintillator, and a focused-cut scintillator, each coupled to an electron-multiplying charge coupled device (EMCCD) detector by a fiber-optic taper, and compared the measured full-width half-maximum (FWHM) values. We show that the FWHMs of the focused-cut scintillator projections are comparable to the FWHMs of the thinner SC scintillator, indicating the effectiveness of the focused-cut scintillator in compensating parallax errors.
PMCID: PMC3126617  PMID: 21731108
Single photon emission computed tomography; scintillation detectors; biomedical applications of nuclear radiation; biomedical nuclear imaging
14.  Vorinostat increases expression of functional norepinephrine transporter in neuroblastoma in vitro and in vivo model systems 
Histone deacetylase (HDAC) inhibition causes transcriptional activation or repression of several genes that in turn can influence the biodistribution of other chemotherapeutic agents. Here, we hypothesize that the combination of vorinostat, a HDAC inhibitor, with 131I-metaiodobenzylguanidine (MIBG) would lead to preferential accumulation of the latter in neuroblastoma (NB) tumors via increased expression of the human norepinephrine transporter (NET).
Experimental Design
In vitro and in vivo experiments examined the effect of vorinostat on the expression of NET, an uptake transporter for 131I-MIBG. Human NB cell lines (Kelly and SH-SY-5Y) and NB1691luc mouse xenografts were employed. The upregulated NET protein was characterized for its effect on 123I-MIBG biodistribution.
Preincubation of NB cell lines, Kelly and SH-SY-5Y, with vorinostat caused dose-dependent increases in NET mRNA and protein levels. Accompanying this was a corresponding dose-dependent increase in MIBG uptake in NB cell lines. Four-fold and 2.5 fold increases were observed in Kelly and SH-SY-5Y cells, respectively, pre-treated with vorinostat in comparison to untreated cells. Similarly, NB xenografts, created by intravenous tail vein injection of NB1691-luc, and harvested from nude mice livers treated with vorinostat (150 mg/kg i.p.) showed substantial increases in NET protein expression. Maximal effect of vorinostat pretreatment in NB xenografts on 123I-MIBG biodistribution was observed in tumors that exhibited enhanced uptake in vorinostat treated (0.062 ± 0.011 μCi/(mg tissue-dose injected)) versus untreated mice (0.022 ± 0.003 μCi/(mg tissue-dose injected); p < 0.05).
The results of our study provide preclinical evidence that vorinostat treatment can enhance NB therapy with 131I-MIBG.
PMCID: PMC3247296  PMID: 21421857
norepinephrine transporter; MIBG; Vorinostat; histone deacetylase inhibitor; neuroblastoma xenograft; biodistribution
15.  The effect of internalizing human single chain antibody fragment on liposome targeting to epithelioid and sarcomatoid mesothelioma 
Biomaterials  2011;32(10):2605-2613.
Immunoliposomes (ILs) anchored with internalizing human antibodies capable of targeting all subtypes of mesothelioma can be useful for targeted imaging and therapy of this malignant disease. The objectives of this study were to evaluate both the in vitro and in vivo tumor targeted internalization of novel internalizing human single chain antibody (scFv) anchored ILs on both epithelioid (M28) and sarcomatoid (VAMT-1) subtypes of human mesothelioma. ILs were prepared by post-insertion of mesothelioma-targeting human scFv (M1) onto preformed liposomes and radiolabeled with 111In (111In-IL-M1), along with control non-targeted liposomes (111In-CL). Incubation of 111In-IL-M1 with M28, VAMT-1, and a control non-tumorigenic cell-line (BPH-1) at 37°C for 24 h revealed efficient binding and rapid internalization of ILs into both subtypes of tumor cells but not into the BPH-1 cells; internalization accounted for approximately 81-94% of total cell accumulation in mesothelioma cells compared to 37-55% in control cells. In tumor bearing mice intravenous (i.v.) injection of 111In-IL-M1 led to remarkable tumor accumulation: 4 % and 4.7% injected dose per gram (% ID/g) for M28 and VAMT-1 tumors, respectively, 48 h after injection. Furthermore, tumor uptake of 111In-IL-M1 in live xenograft animal models was verified by single photon emission computed tomography (SPECT/CT). In contrast, i.v. injection of 111In-CL in tumor-bearing mice revealed very low uptake in both subtypes of mesothelioma, 48 h after injection. In conclusion, M1 scFv-anchored ILs showed selective tumor targeting and rapid internalization into both epithelioid and sarcomatoid subtypes of human mesothelioma, demonstrating its potential as a promising vector for enhanced tumor drug targeting.
PMCID: PMC3040448  PMID: 21255833
Immunoliposomes; scFv antibody; mesothelioma; SPECT/CT imaging; tumor targeting
16.  Novel human single chain antibody fragments that are rapidly interalizing effectively target epithelioid and sarcomatoid mesotheliomas 
Cancer research  2011;71(7):2428-2432.
Human antibodies targeting all subtypes of mesothelioma could be useful to image and treat this deadly disease. Here we report tumor targeting of a novel internalizing human single chain antibody fragment (scFv) labeled with 99mTc (99mTc-M40) in murine models of mesothelioma of both epithelioid (M28) and sarcomatoid (VAMT-1) origins. 99mTc-M40 was taken up rapidly and specifically by both subtype tumor cells in vitro, with 68–92% internalized within 1h. The specificity of binding was evidenced by blocking (up to 95%) with 10-fold excess of unlabeled M40. In animal studies, tumors of both subtypes were clearly visualized by SPECT/CT as early as 1h post-injection of 99mTc-M40. Tumor uptake measured as percent of injected dose per gram tissue (%ID/g) at 3h was 4.38 and 5.84 for M28 and VAMT-1 tumors respectively, significantly greater than all organs or tissues studied (liver, 2.62%ID/g; other organs or tissues <1.7%ID/g), except the kidneys (130.7%ID/g), giving tumor-to-blood ratios of 5:1 and 7:1 and tumor-to-muscle ratios of 45:1 and 60:1, for M28 and VAMT-1 respectively. The target-mediated uptake was confirmed by a nearly 70% reduction in tumor activity following administration of 10-fold excess of unlabeled scFv. Taken together, these results indicate that M40 can rapidly and specifically target epithelioid and sarcomatoid tumor cells, demonstrating the potential of this agent as a versatile targeting ligand for imaging and therapy of all subtypes of mesothelioma.
PMCID: PMC3071798  PMID: 21447742
17.  Combined SPECT and multidetector CT for prostate cancer evaluations 
111In-capromab pendetide is an imaging probe for noninvasive detection of prostate cancer dissemination, and can be difficult to interpret because of low photon statistics resulting in noisy images with limited anatomical precision. We examined if a 16-slice multidetector computed tomography (MDCT) combined with single photon emission computed tomography (SPECT) could increase the impact on the clinical management and improve confidence in SPECT image interpretations in comparison to a relatively low-mA (limited resolution) CT. 17 scans were reviewed from a SPECT combined with low-mA CT scanner; 21 scans were reviewed from a SPECT combined with 16-slice MDCT scanner. Reports of the clinical interpretations from the imaging studies, additional examinations performed by referring physicians as a follow-up to the imaging results, and long-term clinical and laboratory follow-ups were used to define confidence of the SPECT/CT readings and impact of the readings on the patient management. The impact was defined as: the occurrence of the 111In-capromab pendetide interpretation resulted in additional imaging studies or biopsies. MDCT improved the quality and confidence in the characterization of small lymph nodes with or without uptake of 111In-capromab pendetide. The increased confidence with MDCT in SPECT/CT readings was evident in all cases reviewed in this study, and the impact on the clinical management was higher (8 out of 21) using SPECT/MDCT than the impact using SPECT combined with low-mA CT (2 out of 17). The dual-modality SPECT/CT provides a quantifiable benefit when MDCT is used instead of low-mA CT, particularly for prostate cancer evaluations using 111In-capromab pendetide.
PMCID: PMC3260786  PMID: 22267999
Prostate cancer; capromab pendetide; SPECT/CT; MDCT; prostate specific membrane antigen (PSMA)
18.  Phantom experiments on a PSAPD-based compact gamma camera with submillimeter spatial resolution for small animal SPECT 
IEEE transactions on nuclear science  2010;57(5):2518-2523.
We demonstrate a position sensitive avalanche photodiode (PSAPD) based compact gamma camera for the application of small animal single photon emission computed tomography (SPECT). The silicon PSAPD with a two-dimensional resistive layer and four readout channels is implemented as a gamma ray detector to record the energy and position of radiation events from a radionuclide source. A 2 mm thick monolithic CsI:Tl scintillator is optically coupled to a PSAPD with a 8mm×8mm active area, providing submillimeter intrinsic spatial resolution, high energy resolution (16% full-width half maximum at 140 keV) and high gain. A mouse heart phantom filled with an aqueous solution of 370 MBq 99mTc-pertechnetate (140 keV) was imaged using the PSAPD detector module and a tungsten knife-edge pinhole collimator with a 0.5 mm diameter aperture. The PSAPD detector module was cooled with cold nitrogen gas to suppress dark current shot noise. For each projection image of the mouse heart phantom, a rotated diagonal readout algorithm was used to calculate the position of radiation events and correct for pincushion distortion. The reconstructed image of the mouse heart phantom demonstrated reproducible image quality with submillimeter spatial resolution (0.7 mm), showing the feasibility of using the compact PSAPD-based gamma camera for a small animal SPECT system.
PMCID: PMC3026481  PMID: 21278833
Avalanche photodiodes; Biomedical nuclear imaging; Single photon emission computed tomography; Scintillation detectors
19.  Patient-Specific Method of Generating Parametric Maps of Patlak Ki without Blood Sampling or Metabolite Correction: A Feasibility Study 
Currently, kinetic analyses using dynamic positron emission tomography (PET) experience very limited use despite their potential for improving quantitative accuracy in several clinical and research applications. For targeted volume applications, such as radiation treatment planning, treatment monitoring, and cerebral metabolic studies, the key to implementation of these methods is the determination of an arterial input function, which can include time-consuming analysis of blood samples for metabolite correction. Targeted kinetic applications would become practical for the clinic if blood sampling and metabolite correction could be avoided. To this end, we developed a novel method (Patlak-P) of generating parametric maps that is identical to Patlak Ki (within a global scalar multiple) but does not require the determination of the arterial input function or metabolite correction. In this initial study, we show that Patlak-P (a) mimics Patlak Ki images in terms of visual assessment and target-to-background (TB) ratios of regions of elevated uptake, (b) has higher visual contrast and (generally) better image quality than SUV, and (c) may have an important role in improving radiotherapy planning, therapy monitoring, and neurometabolism studies.
PMCID: PMC3168784  PMID: 21912742
20.  Selective activation of p53-mediated tumour suppression in high-grade tumours 
Nature  2010;468(7323):567-571.
Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related death worldwide, with an overall 5-year survival rate of only 10–15% 1. Deregulation of the Ras pathway is a frequent hallmark of NSCLC, often through mutations that directly activate Kras 2. p53 is also frequently inactivated in NSCLC and, since oncogenic Ras can be a potent trigger of p53 3, it seems likely that oncogenic Ras signalling plays a major and persistent part in driving the selection against p53. Hence, pharmacological restoration of p53 is an appealing therapeutic strategy for treating this disease 4. Here, we model the likely therapeutic impact of p53 restoration in a spontaneously evolving mouse model of NSCLC initiated by sporadic oncogenic activation of endogenous Kras 5. Surprisingly, p53 restoration failed to induce significant regression of established tumours although it did result in a significant decrease in the relative proportion of tumours classed as high grade. This is due to selective activation of p53 only in the more aggressive tumour cells within each tumour. Such selective activation of p53 correlates with marked up regulation in Ras signal intensity and induction of the oncogenic signalling sensor p19ARF 6. Our data indicate that p53-mediated tumour suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumour evolution and to the efficacy of therapeutic p53 restoration to eradicate cancers.
PMCID: PMC3011233  PMID: 21107427
21.  Technological Development and Advances in SPECT/CT 
Seminars in nuclear medicine  2008;38(3):177-198.
SPECT/CT has emerged over the past decade as a means of correlating anatomical information from CT with functional information from SPECT. The integration of SPECT and CT in a single imaging device facilitates anatomical localization of the radiopharmaceutical to differentiate physiological uptake from that associated with disease and patient-specific attenuation correction to improve the visual quality and quantitative accuracy of the SPECT image. The first clinically available SPECT/CT systems performed emission-transmission imaging using a dual-headed SPECT camera and a low-power x-ray CT sub-system. Newer SPECT/CT systems are available with high-power CT sub-systems suitable for detailed anatomical diagnosis, including CT coronary angiography and coronary calcification that can be correlated with myocardial perfusion measurements. The high-performance CT capabilities also offer the potential to improve compensation of partial volume errors for more accurate quantitation of radionuclide measurement of myocardial blood flow and other physiological processes and for radiation dosimetry for radionuclide therapy. In addition, new SPECT technologies are being developed that significantly improve the detection efficiency and spatial resolution for radionuclide imaging of small organs including the heart, brain, and breast, and therefore may provide new capabilities for SPECT/CT imaging in these important clinical applications.
PMCID: PMC3049175  PMID: 18396178
22.  Targeting Prostate Cancer Cells In Vivo Using a Rapidly Internalizing Novel Human Single-Chain Antibody Fragment 
Human antibodies targeting prostate cancer cell surface epitopes may be useful for imaging and therapy. The objective of this study was to evaluate the tumor targeting of an internalizing human antibody fragment, a small-size platform, to provide high contrast in a mouse model of human prostate carcinoma.
A prostate tumor-targeting single-chain antibody fragment (scFv), UA20, along with a nonbinding control scFv, N3M2, were labeled with 99mTc and evaluated for binding and rapid internalization into human prostate tumor cells in vitro and tumor homing in vivo using xenograft models. For the in vitro studies, the labeled UA20 scFv was incubated at 37°C for 1 h with metastatic prostate cancer cells (DU145) to assess the total cellular uptake versus intracellular uptake. For the animal studies, labeled UA20 and N3M2 scFvs were administered to athymic mice implanted subcutaneously with DU145 cells. Mice were imaged with small-animal SPECT/CT with concomitant biodistribution at 1 and 3 h after injection.
The UA20 scFv was labeled in 55%–65% yield and remained stable in phosphate buffer within 24 h. The labeled UA20 scFv was taken up specifically by prostate tumor cells. Internalization was rapid, because incubation at 37°C for less than 1 h resulted in 93% internalization of total cell-associated scFvs. In animal studies, SPECT/CT showed significant tumor uptake as early as 1 h after injection. At 3 h after injection, tumor uptake was 4.4 percentage injected dose per gram (%ID/g), significantly greater than all organs or tissues studied (liver, 2.7 %ID/g; other organs or tissues, <1 %ID/g), except the kidneys (81.4 %ID/g), giving tumor-to-blood and tumor-to-muscle ratios of 12:1 and 70:1, respectively. In contrast, the control antibody exhibited a tumor uptake of only 0.26 %ID/g, similar to that of muscle and fat. Tumor-specific targeting was evidenced by reduced tumor uptake of nearly 70% on administration of a 10-fold excess of unlabeled UA20 scFv. Kidney uptake was nonspecific, consistent with the route of excretion by scFvs.
The UA20 scFv showed rapid and specific internalization in prostate tumor cells in vitro and accumulation in prostate tumor xenografts in vivo, demonstrating the potential for future development for prostate cancer imaging and targeted therapy.
PMCID: PMC2832590  PMID: 20150269
molecular imaging; prostate cancer; antibody fragment
23.  In vivo Tumor Grading of Prostate Cancer using Quantitative 111In-Capromab Pendetide SPECT/CT 
We have developed an in vivo antibody uptake quantification method using 111In-capromab pendetide single photon emission computed tomography combined with computed tomography (SPECT/CT) technology. Our goal is to evaluate this noninvasive antibody quantification method for potential prostate tumor grading.
Our phantom experiments focused on the robustness of an advanced iterative reconstruction algorithm that involves corrections for photon attenuation, scatter, and geometric blurring caused by radionuclide collimators. The conversion factors between image values and tracer concentrations (in Bq/ml) were calculated from uniform phantom filled with aqueous solution of 111InCl3 using the same acquisition protocol and reconstruction parameters as for patient studies. In addition, the spatial resolution of the reconstructed images was measured from a point source phantom. The measured spatial resolution was modeled into a point spread function (PSF), and the PSF was implemented in a deconvolution-based partial volume error (PVE) correction algorithm. The recovery capability to correctly estimate true tracer concentration values was tested using prostate-like and bladder-like lesion phantoms fitted in the modified NEMA/IEC body phantom. Patients with biopsy-proven prostate cancer (n=10) who underwent prostatectomy were prospectively enrolled in the preoperative SPECT/CT studies at the San Francisco VA Medical Center. The CT portion of SPECT/CT was used for CT-based attenuation map generation as well as an anatomical localization tool for clinical interpretation. Pathologic Gleason grades were compared with in vivo “antibody uptake value” (AUV) normalized by injected dose, effective half-life, and injection-scan time difference. AUVs were calculated in each lobe of prostate gland with cylindrical volumes of interest (VOIs) having dimensions of 1.5 cm both in diameter and height.
Reconstructed SPECT images further corrected by the deconvolution-based PVE correction could recover true tracer concentrations in volumes as small as 7.77 ml up to 90% in phantom measurements. From patient studies, there was a statistically significant correlation (ρ = 0.71, P = 0.033) between higher AUVs (from either left or right lobe) and higher components of pathologic Gleason scores.
Our results strongly indicate noninvasive prostate tumor grading potential using quantitative 111In-capromab pendetide SPECT/CT for prostate cancer evaluation.
PMCID: PMC2821016  PMID: 20008977
prostate cancer; capromab pendetide; SPECT; SPECT/CT; quantification; tracer quantification; quantitative SPECT; prostate specific membrane antigen (PSMA)
24.  Biodistributions of 177Lu- and 111In- labeled 7E11 Antibodies to Prostate-Specific Membrane Antigen in Xenograft Model of Prostate Cancer and Potential Use of 111In-7E11 as a Pretherapeutic Agent for 177Lu-7E11 Radioimmunotherapy 
Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein highly expressed in many prostate cancers, and can be targeted with radiolabeled antibodies for diagnosis and treatment of this disease. To serve as a radioimmunotherapeutic agent, a kinetically inert conjugate is desired to maximize tumor uptake and tumor radiation dose with minimal nonspecific exposure to bone marrow and other major organs. In this study, we assessed the pharmacokinetics and biodistribution of the 7E11 monoclonal antibody (MAb) radiolabeled with the lutetium-177 (177Lu) - tetraazacyclododecanetetraacetic acid (DOTA) conjugate system (177Lu-7E11) versus those of the 7E11 MAb radiolabeled with the indium-111 (111In) – glycyl-tyrosyl-(N,-diethylenetriaminepentaacetic acid)-lysine hydrochloride (DTPA) conjugate system (111In-7E11, also known as ProstaScint®), to determine the feasibility of using 111In-7E11 as a pretherapeutic agent for 177Lu-7E11 radioimmunotherapy. Pharmacokinetic and biodistribution studies of 177Lu-7E11 in LNCaP xenograft mice were performed at 2, 8, 12, 24, 72, and 168 hours after radiopharmaceutical administration. For 111In-7E11, pharmacokinetic and biodistribution studies were performed at 8, 24, and 72 hours. Parallel studies of 177Lu-7E11 in nontumor bearing mice at 8, 24, and 72 hours postinjection served as controls. Gamma scintigraphy was performed, followed by autoradiography and tissue counting to demonstrate and quantify the distributions of radioconjugated MAb in the tumor and normal tissues. Both 177Lu- and 111In- 7E11 conjugates demonstrated an early blood pool phase in which uptake was dominated by the blood, lung, spleen and liver, followed by uptake and retention of the radiolabeled antibody in the tumor which was most prominent at 24 h. Total accumulation of radioconjugated MAb in tumor at 24 h was greater in the case of 177Lu-7E11 in comparison to that of 111In-7E11. Continued accumulation in tumor was observed for the entire time course studied for both 177Lu-7E11 and 111In-7E11. The liver was the only major organ demonstrating a significant difference in accumulation between the two conjugates. In conclusion, pharmacokinetic and biodistribution studies of 177Lu-7E11 in LNCaP xenograft mouse models support its potential application as a radioimmunotherapeutic agent targeting prostate cancer, and the distribution and tumor uptake of 111In-7E11 appear to be similar to those of 177Lu-7E11, supporting its use as a pretherapeutic tool to assess the potential accumulation of 177Lu-7E11 radioimmunotherapeutic at sites of prostate cancer. However, the different accumulation patterns of the 111In and 177 Lu immunoconjugates in liver will likely prevent the use of 111In-7E11 as a true dosimetry tool for 177Lu-7E11 radioimmunotherapy.
PMCID: PMC2841328  PMID: 19034582
prostate cancer; immunoscintigraphy; lutetium-177; indium-111; radioimmunotherapy; prostate-specific membrane antigen; bioluminescence imaging
25.  In vivo microCT imaging of rodent cerebral vasculature 
Physics in medicine and biology  2008;53(7):N99-107.
Computed tomography (CT) remains a critical diagnostic tool for evaluating patients with cerebrovascular disease, and the advent of specialized systems for imaging rodents has extended these techniques to small animal models of these diseases. We therefore have evaluated in vivo methods of imaging rat models of hemorrhagic stroke using a high resolution compact computed tomography (‘microCT’) system (FLEX(tm) X-O(tm), Gamma Medica-Ideas, Northridge, CA). For all in vivo studies, the head of the anesthetized rat was secured in a custom immobilization device for microCT imaging with 512 projections over 2 min at 60 kVp and 0.530 mA (Itube × t/rotation = 63.6 mAs). First, imaging without iodinated contrast was performed (a) to differentiate the effect of contrast agent in contrast-enhanced CT and (b) to examine the effectiveness of the immobilization device between two time points of CT acquisitions. Then, contrast-enhanced CT was performed with continuous administration of iopromide (300 mgI ml−1 at 1.2 ml min−1) to visualize aneurysms and other vascular formations in the carotid and cerebral arteries that may precede subarachnoid hemorrhage. The accuracy of registration between the noncontrast and contrast-enhanced CT images with the immobilization device was compared against the images aligned with normalized mutual information using FMRIB's linear image registration tool (FLIRT). Translations and rotations were examined between the FLIRT-aligned noncontrast CT image and the nonaligned noncontrast CT image. These two data sets demonstrated translational and rotational differences of less than 0.5 voxel (∼85 μm) and 0.5°, respectively. Noncontrast CT demonstrated a very small volume (0.1 ml) of femoral arterial blood introduced surgically into the rodent brain. Continuous administration of iopromide during the CT acquisition produced consistent vascular contrast in the reconstructed CT images. As a result, carotid arteries and major cerebral blood vessels were visible with contrast-enhanced CT, but not with noncontrast CT. In conclusion, the CT-compatible immobilization device was useful for in vivo microCT imaging of intracranial blood and of vascular structures within and immediately adjacent to the rodent brain. The microCT imaging technique is also compatible with continuous administration of a conventional iodinated contrast agent (e.g. iopromide) and therefore does not require specialized small animal specific contrast agent that has comparatively long in vivo residence time.
PMCID: PMC2593105  PMID: 18364539

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