[show abstract][hide abstract] ABSTRACT: Among U.S. men, prostate cancer (PC) accounts for 29% of all newly diagnosed cancers. A reliable scintigraphic agent to image PC and its metastatic or recurrent lesions and to determine the effectiveness of its treatment will contribute to the management of this disease. All PC overexpresses VPAC1 receptors. This investigation evaluated a probe specific for a (64)Cu-labeled receptor for PET imaging of experimental human PC in athymic nude mice and spontaneously grown PC in transgenic mice.
The probe, TP3939, was synthesized, purified, and labeled with (64)Cu and (99m)Tc. Using a muscle relaxivity assay, biologic activity was assessed and inhibitory concentrations of 50% calculated. Receptor affinity (Kd) for human PC3 cells was determined using (99m)Tc-TP3939 and (64)CuCl(2.) Blood clearance and in vivo stability were studied. After intravenous administration of either (64)Cu-TP3939 or (64)CuCl(2) in PC3 xenografts and in transgenic mice, PET/CT images were acquired. Prostate histology served as the gold standard. Organ distribution studies (percentage injected dose per gram [%ID/g]) in normal prostate were performed. The ratios of tumor to muscle, tumor to blood, normal prostate to muscle, and tumor to normal prostate were determined.
Chemical and radiochemical purities of TP3939 were 96.8% and 98% +/- 2%, respectively. Inhibitory concentrations of 50% and affinity constants were 4.4 x 10(-8) M and 0.77 x 10(-9) M, respectively, for TP3939 and 9.1 x 10(-8) M and 15 x 10(-9) M, respectively, for vasoactive intestinal peptide 28. Binding of (64)CuCl(2) to PC3 was nonspecific. Blood clearance was rapid. In vivo transchelation of (64)Cu-TP3939 to plasma proteins was less than 15%. (64)Cu-TP3939 uptake in PC was 7.48 +/- 3.63 %ID/g at 4 h and 5.78 +/- 0.66 %ID/g at 24 h after injection and was significantly (P < 0.05) greater than with (64)CuCl(2) (4.79 +/- 0.34 %ID/g and 4.03 +/- 0.83 %ID/g at 4 and 24 h, respectively). The ratios of PC to normal prostate at 4 and 24 h were 4 and 2.7, respectively. (64)Cu-TP3939 distinctly imaged histologic grade IV prostate intraepithelial neoplasia in transgenic mice, but (18)F-FDG and CT did not.
Data indicate that TP3939, with its uncompromised biologic activity, delineated xenografts and cases of occult PC that were not detectable with (18)F-FDG. (64)Cu-TP3939 is a promising probe for PET imaging of PC. It may also be useful for localizing recurrent lesions and for determining the effectiveness of its treatment.
Journal of Nuclear Medicine 02/2008; 49(1):112-21. · 5.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: Vasoactive intestinal peptide and pituitary adenylate cyclase activating peptide have high affinity for VPAC1, VPAC2 and PAC1 receptors overexpressed on human cancer cells. Four potent analogues of these peptides, TP3939, TP3982, TP4200 and TP3805 were labeled with (64)Cu and evaluated ex vivo and in vivo to asses their biological activity and receptor specificity. The ultimate goal is to utilize (64)Cu analogues for positron emission tomography (PET) imaging of breast cancers in humans. Radiochemical purity of each analogue was >92%. The muscle relaxivity assay revealed IC(50) to be 5.3x10(-8) M, 4.4x10(-8) M, 8.1x10(-8) M, 8.1x10(-9) M and Kd values determined by receptor specific cell binding assays were 3.3 nM, 0.33 nM, 0.2 nM and 0.72 nM for TP3805, TP3939, TP3982, and TP4200 respectively. The receptor affinity, using human breast cancer tissues, was 10.93 times greater than normal breast tissues. RT-PCR confirmed increased VPAC1 receptor expression on human breast tumor cells over normal cells and corroborated with autoradiography data. The blood clearance was rapid and in vivo translocation of (64)Cu to plasma protein was <15%. Data demonstrate that these analogues are potent, have uncompromised biological activity and are worthy of further evaluation for accurate PET imaging of human breast cancers and in determining malignant and benign lesions.
[show abstract][hide abstract] ABSTRACT: Treatment of breast cancer is hampered by a large unmet need for rapid, sensitive, specific staging and stratification of palpable and nonpalpable abnormalities. Mammography and physical examination miss many early breast cancers, yet detect many benign lesions. Cyclin D1, encoded by CCND1 messenger RNA (mRNA), and insulin-like growth factor 1 receptor (IGF1R) are key regulators of cell proliferation that are overexpressed in most breast cancers. Therefore, we hypothesized that malignant breast masses could be imaged and quantitated externally by PET with a dual-specificity probe that targets both CCND1 mRNA and IGF1R.
We designed a CCND1-specific peptide nucleic acid (PNA) hybridization sequence (CTGGTGTTCCAT), separated by a C-terminal spacer to a cyclized IGF1 peptide analog (d-Cys-Ser-Lys-Cys), for IGF1R-mediated endocytosis. On the N-terminus we attached a chelator (1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetyl [DO3A]) for the positron-emitting nuclide (64)Cu. We administered the [(64)Cu]CCND1-IGF1 analog radiohybridization probes, as well as sequence controls, by tail vein to immunocompromised female NCr mice bearing human MCF7 estrogen-dependent, receptor-positive xenografts. We imaged the mice by PET and CT 4 and 24 h later, and measured tissue distribution of the radiohybridization probes.
We observed 8 +/- 2-fold higher PET intensity in the center of the breast cancer xenografts than in the contralateral tissues at 24 h after injection of the [(64)Cu]CCND1-IGF1 analog radiohybridization probe. IGF1 blocking yielded significantly weaker images (P < 0.05) relative to the tumor-free side at 24 h after injection, as did a PNA mismatch probe, a peptide mismatch probe, and free (64)CuCl(2).
These results are consistent with our hypothesis for radiohybridization PET of overexpressed CCND1 mRNA, dependent on IGF1R-mediated endocytosis, in suspect masses. Early noninvasive detection of initial cancerous transformation, as well as invasive or recurrent breast cancer, with dual-specificity radiohybridization probes, might enable molecularly targeted staging, stratification, and choice of therapy.
Journal of Nuclear Medicine 11/2007; 48(10):1699-707. · 5.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is a compelling need to image pancreas cancer at an early stage. Human pancreas cancer cells display elevated levels of KRAS protein due to high copy numbers of KRAS mRNA, and elevated levels of insulin-like growth factor 1 receptor (IGF1R) due to overexpression of IGF1R mRNA. Therefore we hypothesized that pancreas cancer could be detected in vivo with a single probe that targets both KRAS mRNA and IGF1R. Because positron emission tomography (PET) is a sensitive imaging technique, we designed a probe incorporating the positron-emitting nuclide (64)Cu. The KRAS-specific hybridization probe consisted of 1,4,7-tris(carboxymethylaza)cyclododecane-10-aza-acetyl (DO3A) on the N-terminus of a peptide nucleic acid (PNA) hybridization sequence (GCCATCAGCTCC) linked to a cyclized IGF1 peptide analog (d-Cys-Ser-Lys-Cys) on the C-terminus, for IGF1R-mediated endocytosis. A series of such KRAS radiohybridization probes with 0, 1, 2 or 3 mismatches to KRAS G12D mRNA, including exact matches to wild type KRAS mRNA and KRAS G12V mRNA, along with a double d(Ala) replacement IGF1 peptide control, were assembled by continuous solid phase synthesis. To test the hypothesis that KRAS-IGF1 dual probes could specifically image KRAS mRNA expression noninvasively in human IGF1R-overexpressing AsPC1 pancreas cancer xenografts in immunocompromised mice, [(64)Cu]PNA radiohybridization probes and controls were administered by tail vein. The [(64)Cu]KRAS-IGF1 radiohybridization probe yielded strong tumor contrast in PET images, 8.6 +/- 1.4-fold more intense in the center of human pancreas cancer xenografts than in the contralateral muscle at 4 h post-injection. Control experiments with single base KRASmismatches, an IGF1 peptide mismatch, and a breast cancer xenograft lacking KRAS activation yielded weak tumor contrast images. These experiments are consistent with our hypothesis for noninvasive PET imaging of KRAS oncogene expression in pancreas cancer xenografts. Imaging oncogene mRNAs with radiolabel-PNA-peptide nanoparticles might provide specific genetic characterization of preinvasive and invasive pancreas cancers for staging and choice of therapy.
Cancer biology & therapy 07/2007; 6(6):948-56. · 3.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: Early external detection of cancer gene activity might enable early treatment of cancer and might reduce cancer mortality. We hypothesized that oncogene mRNA overexpressed at thousands of copies per malignant cell in a zone of transformed cells could be imaged externally by scintigraphic imaging, PET (positron emission tomography) or MRI (magnetic resonance imaging) with PNA (peptide nucleic acid) hybridization probes that include chelators for metal cations and a cyclized peptide analogue of IGF-1 (insulin-like growth factor 1), D(Cys-Ser-Lys-Cys), to mediate internalization by IGF1R (IGF-1 receptor) overexpressed on cancer cells. We observed that human MCF7 breast cancer cells that overexpress IGF1R efficiently internalized fluorescein-chelator-PNA-D(Cys-Ser-Lys-Cys) to the cytoplasm, but not with D(Cys-Ala-Ala-Cys). Scintigraphic imaging of MCF7 xenografts in immunocompromised mice revealed that CCND1 and MYC [(99m)Tc]chelator-PNA-D(Cys-Ser-Lys-Cys) probes yielded xenograft. PET imaging with [(64)Cu]chelator-PNA-D(Cys-Ser-Lys-Cys) yielded stronger signals. Scintigraphic imaging of human AsPC1 pancreas cancer xenografts with [(99m)Tc]chelator-KRAS PNA-D(Cys-Ser-Lys-Cys) yielded strong xenograft signals. Stronger xenograft image intensities were obtained by PET imaging of [(64)Cu]chelator-KRAS PNA-D(Cys-Ser-Lys-Cys). MRI required extension of chelator-polydiamidopropanoate dendrimers from the N-termini of the PNA probes to increase the number of contrast paramagnetic gadolinium (III) cations per probe. These results provide a basis for detection of oncogene activity in tissues from outside the body by hybridization with metal-chelator-PNA-peptides that are selectively internalized by cancer cells.
Biochemical Society Transactions 03/2007; 35(Pt 1):72-6. · 2.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: The antiangiogenic approach to controlling cancer requires a better understanding of angiogenesis and the discovery of new compounds that modulate this key biological process. Here we investigated the role of endorepellin, an angiostatic protein fragment that is derived from the C-terminus of perlecan, a heparan sulfate proteoglycan, in controlling tumor angiogenesis in vivo.
We administered human recombinant endorepellin systemically to mice bearing orthotopic squamous carcinoma xenografts or syngeneic Lewis lung carcinoma tumors. We monitored tumor growth, angiogenesis, metabolism, hypoxia, and mitotic index by using quantitative immunohistochemistry and positron emission tomography scan imaging. In addition, we determined the localization of injected endorepellin using near-infrared labeling and immunohistochemistry of frozen tumor sections. Finally, we isolated tumor-derived endothelial cells and tested whether endorepellin could interact with these cells and disrupt in vitro capillary morphogenesis. All statistical tests were two-sided.
Endorepellin specifically targeted the tumor vasculature as determined by immunohistochemical analysis and accumulated in the tumor perivascular zones where it persisted for several days as discrete deposits. This led to inhibition of tumor angiogenesis (as measured by decreased CD31-positive cells, mean control = 1902 CD31-positive pixels, mean endorepellin treated = 343.9, difference between means = 1558, 95% confidence interval [CI] = 1296 to 1820, P<.001), enhanced tumor hypoxia, and a statistically significant decrease in tumor metabolism and mitotic index (as measured by decreased Ki67-positive cells, mean control Ki67 pixels = 5970, mean endorepellin-treated Ki67 pixels = 3644, difference between means = 2326, 95% CI = 1904 to 2749, P<.001) compared to untreated controls. Endorepellin was actively internalized by tumor-derived endothelial cells causing a redistribution of alpha2beta1 integrin such that both proteins colocalized to punctate deposits in the perivascular region. Endorepellin treatment inhibited in vitro capillary morphogenesis of both normal and tumor-derived endothelia.
Our results provide support for the hypothesis that endorepellin is an effective antitumor vasculature agent that could be used as a therapeutic modality to combat cancer.
[show abstract][hide abstract] ABSTRACT: Decorin is not only a regulator of matrix assembly but also a key signaling molecule that modulates the activity of tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR). Decorin evokes protracted internalization of the EGFR via a caveolar-mediated endocytosis, which leads to EGFR degradation and attenuation of its signaling pathway. In this study, we tested if systemic delivery of decorin protein core would affect the biology of an orthotopic squamous carcinoma xenograft. After tumor engraftment, the animals were given intraperitoneal injections of either vehicle or decorin protein core (2.5-10 mg kg(-1)) every 2 days for 18-38 days. This regimen caused a significant and dose-dependent inhibition of the tumor xenograft growth, with a concurrent decrease in mitotic index and a significant increase in apoptosis. Positron emission tomography showed that the metabolic activity of the tumor xenografts was significantly reduced by decorin treatment. Decorin protein core specifically targeted the tumor cells enriched in EGFR and caused a significant down-regulation of EGFR and attenuation of its activity. In vitro studies showed that the uptake of decorin by the A431 cells was rapid and caused a protracted down-regulation of the EGFR to levels similar to those observed in the tumor xenografts. Furthermore, decorin induced apoptosis via activation of caspase-3. This could represent an additional mechanism whereby decorin might influence cell growth and survival.
Journal of Biological Chemistry 10/2006; 281(36):26408-18. · 4.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: Arterial input function (AIF) measurement for quantification of small animal PET studies is technically challenging and limited by the small blood volume of small laboratory animals. The present study investigated the use of a standard arterial input function (SAIF) to simplify the experimental procedure.
Twelve [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET studies accompanied by serial arterial blood sampling were acquired in seven male Sprague-Dawley rats under isoflurane anaesthesia without (every rat) and with additional (five rats) vibrissae stimulation. A leave-one-out procedure was employed to validate the use of a SAIF with individual scaling by one (1S) or two (2S) arterial blood samples.
Automatic slow bolus infusion of [(18)F]FDG resulted in highly similar AIF in all rats. The average differences of the area under the curve of the measured AIF and the individually scaled SAIF were 0.11+/-4.26% and 0.04+/-2.61% for the 1S (6-min sample) and the 2S (4-min/43-min samples) approach, respectively. The average differences between the cerebral metabolic rates of glucose (CMR(glc)) calculated using the measured AIF and the scaled SAIF were 1.31+/-5.45% and 1.30+/-3.84% for the 1S and the 2S approach, respectively.
The use of a SAIF scaled by one or (preferably) two arterial blood samples can serve as a valid substitute for individual AIF measurements to quantify [(18)F]FDG PET studies in rats. The SAIF approach minimises the loss of blood and should be ideally suited for longitudinal quantitative small animal [(18)F]FDG PET studies.
European journal of nuclear medicine and molecular imaging 09/2006; 33(8):948-54. · 5.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: In 2005, breast cancer will kill approximately 40,410 women in the U.S., and pancreatic cancer will kill approximately 31,800 men and women in the U.S. Clinical examination and mammography, the currently accepted breast cancer screening methods, miss almost half of breast cancers in women younger than 40 years, approximately one-quarter of cancers in women aged 40-49 years, and one-fifth of cancers in women over 50 years old. Pancreatic cancer progresses rapidly, with only 1% of patients surviving more than 5 years after diagnosis. However, if the disease is diagnosed when it is localized, the 5-year survival is approximately 20%. It would be beneficial to detect breast cancer and pancreatic cancer at the earliest possible stage, when multimodal therapy with surgery, radiotherapy, and chemotherapy have the greatest chance of prolonging survival. Human estrogen receptor-positive breast cancer cells typically display elevated levels of Myc protein due to overexpression of MYC mRNA, elevated cyclin D1 protein due to overexpression of CCND1 mRNA, and elevated insulin-like growth factor 1 receptor (IGF1R) due to overexpression of IGF1R mRNA. We hypothesized that scintigraphic detection of MYC or CCND1 peptide nucleic acid (PNA) probes with an IGF1 peptide loop on the C-terminus, and a Tc-99m-chelator peptide on the N-terminus, could measure levels of MYC or CCND1 mRNA noninvasively in human IGF1R-overexpressing MCF7 breast cancer xenografts in immunocompromised mice. Similarly, human pancreatic cancer cells typically display elevated levels of KRAS mRNA and elevated IGF1R. Hence, we also hypothesized that a KRAS Tc-99m-chelator PNA-peptide probe could detect overexpression of KRAS mRNA in pancreatic cancer xenografts by scintigraphic imaging, or by positron emission tomography (PET) with a KRAS Cu-64-chelator PNA-peptide. Human MCF7 breast cancer xenografts in immunocompromised mice were imaged scintigraphically 4-24 h after tail-vein administration of MYC or CCND1 Tc-99m-chelator PNA-peptides, but not after administration of mismatch controls. Similarly, human Panc-1 pancreatic cancer cells xenografts were imaged scintigraphically 4 and 24 h after tail-vein administration of a KRAS Tc-99m-chelator PNA-peptide, and AsPC1 xenografts were imaged by PET 4 and 24 h after tail-vein adminstration of a KRAS Cu-64-chelator PNA-peptide. The radioprobes distributed normally to the kidneys, livers, tumors, and other tissues. External molecular imaging of oncogene mRNAs in solid tumors with radiolabel-PNA-peptide chimeras might in the future provide additional genetic characterization of pre-invasive and invasive breast cancers.
Annals of the New York Academy of Sciences 01/2006; 1059(1):106 - 144. · 4.38 Impact Factor
[show abstract][hide abstract] ABSTRACT: To effectively study small animal models of disease in vivo a wide range of PET and SPECT imaging agents need to be employed. In an effort to achieve high resolution and high sensitivity small animal SPECT imaging we propose the notion of using a multiple pinhole insert in a PET scanner (pPET). Adapting PET scanners to enable pinhole SPECT imaging is an attractive solution for many reasons. Most PET systems are full ring detectors which offer the potential for pinhole configurations that fully sample an object without the need for complex detector rotation. Dual modality studies can be performed without moving the subject providing perfect spatial alignment. Furthermore, enabling SPECT imaging in a PET scanner makes financial sense by reducing the initial investment and maintenance costs. In this study we prove the feasibility of using a pinhole insert to enable SPECT imaging in PET scanners. Simulations performed using the geometry of the Mosaic (Philips), a dedicated small animal PET scanner (Rdet=98.5 mm), show a variety of attractive pinhole configurations offering a blend of resolution (to under 1.0 mm), sensitivity (up to 0.5%), field of view (up to 40 mm) and good image quality. Measurements with the Mosaic demonstrate that by raising the high voltage, to account for the lower light output, 140 keV gammas can be efficiently detected and adequately positioned for both GSO (gadolinium oxyorthosilicate) and LYSO (lutetium yttrium orthosilicate) scintillators. Initial imaging studies with a 12×1 (holes × rows) collimator with 1.0 mm pinholes at a 30 mm radius demonstrate the feasibility and show promising resolution (1.5 mm FWHM), good image quality, and a relatively large field of view.
[show abstract][hide abstract] ABSTRACT: The evolution of positron emission tomography (PET) imaging for small animals has led to the development of dedicated PET scanner designs with high resolution and sensitivity. The animal PET scanner achieves these goals for imaging small animals such as mice and rats. The scanner uses a pixelated Anger-logic detector for discriminating 2 × 2 × 10 mm<sup>3</sup> crystals with 19-mm-diameter photomultiplier tubes. With a 19.7-cm ring diameter, the scanner has an axial length of 11.9 cm and operates exclusively in three-dimensional imaging mode, leading to very high sensitivity. Measurements show that the scanner design achieves a spatial resolution of 1.9 mm at the center of the field-of-view. Initially designed with gadolinium orthosilicate but changed to lutetium-yttrium orthosilicate, the scanner now achieves a sensitivity of 3.6% for a point source at the center of the field-of-view with an energy window of 250-665 keV. Iterative image reconstruction, together with accurate data corrections for scatter, random, and attenuation, are incorporated to achieve high-quality images and quantitative data. These results are demonstrated through our contrast recovery measurements as well as sample animal studies.
IEEE Transactions on Medical Imaging 08/2005; · 4.03 Impact Factor
[show abstract][hide abstract] ABSTRACT: Transmission scans using a single-photon point source on a positron emission tomography (PET) scanner are inherently acquired in a cone-beam geometry. Traditionally, these data are binned into radially parallel oblique projections and then rebinned using single-slice rebinning (SSRB) into a set of two-dimensional parallel sinograms. For axially oblique lines of response (LORs), the SSRB approximation results in axial and tangential blurring of the transmission image, especially at large radial distances. For the animal PET scanner recently completed at the University of Pennsylvania, there is interest in placing the transmission source outside the scanner in order to maximize the transverse field of view (FOV). For this extremely asymmetric configuration, however, the LORs are very oblique (axial angle=19-42 deg). We compared three methods of processing transmission data, SSRB or FORE followed by two-dimensional (2D) reconstruction and an iterative algorithm for transmission data that uses the cone-beam LORs directly (TR-OSEM-CB). All three algorithms produce acceptable transmission images when the source is inside the scanner. For the case when the transmission source is outside the scanner, TR-OSEM-CB produces images with only minor artifacts near the ends of the axial FOV. SSRB and FORE images have significant axial blurring, although the central region of the FORE image is artifact-free and potentially useful for generating attenuation correction factors. Moving the source closer to the detector ring reduces the residual artifacts seen with TR-OSEM-CB.
[show abstract][hide abstract] ABSTRACT: A high-sensitivity, high-resolution brain PET scanner ("G-PET") has been developed. This scanner is similar in geometry to a previous brain scanner developed at the University of Pennsylvania, the HEAD Penn-PET, but the detector technology and electronics have been improved to achieve enhanced performance.
This scanner has a detector ring diameter of 42.0 cm with a patient aperture of 30.0 cm and an axial field of view of 25.6 cm. It comprises a continuous light-guide that couples 18,560 (320 x 58 array) 4 x 4 x 10 mm(3) gadolinium oxyorthosilicate (GSO) crystals to 288 (36 x 8 array) 39-mm photomultiplier tubes in a hexagonal arrangement. The scanner operates only in 3-dimensional (3D) mode because there are no interplane septa. Performance measurements on the G-PET scanner were made following National Electrical Manufacturers Association NU 2-2001 procedures for most measurements, although NU 2-1994 procedures were used when these were considered more appropriate for a brain scanner (e.g., scatter fraction and counting-rate performance measurements).
The transverse and axial resolutions near the center are 4.0 and 5.0 mm, respectively. At a radial offset of 10 cm, these numbers deteriorate by approximately 0.5 mm. The absolute sensitivity of this scanner measured with a 70-cm long line source is 4.79 counts per second (cps)/kBq. The scatter fraction measured with a line source in a 20-cm-diameter x 19-cm-long cylinder is 39% (for a lower energy threshold of 410 keV). For the same cylinder, the peak noise equivalent counting rate is 60 kcps at an activity concentration of 7.4 kBq/mL (0.20 micro Ci/mL), whereas the peak true coincidence rate is 132 kcps at an activity concentration of 14 kBq/mL (0.38 micro Ci/mL). Images from the Hoffman brain phantom as well as (18)F-FDG patient scans illustrate the high quality of images acquired on the G-PET scanner.
The G-PET scanner attains the goal of high performance for brain imaging through the use of an Anger-logic GSO detector design with continuous optical coupling. This detector design leads to good energy resolution, which is needed in 3D imaging to minimize scatter and random coincidences.
Journal of Nuclear Medicine 09/2003; 44(8):1340-9. · 5.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tumor hypoxia is an important prognostic indicator for cancer therapy outcome. EF5 [2-(2-nitro-1[ H]-imidazol-1-yl)- N-(2,2,3,3,3-pentafluoropropyl)-acetamide] has been employed to measure tumor hypoxia in animals and humans using immunohistochemical methods. EF5 is a lipophilic molecule designed to have a very uniform biodistribution, a feature of obvious benefit for use in PET imaging. The present study represents the first demonstration of noninvasive PET imaging of rat tumors using fluorine-18 labeled EF5. Because of the small tumor size, partial volume effects may result in underestimation of concentration of the compound. Therefore, validation of the PET data was performed by gamma counting of the imaged tissue. The tumor models studied were the Morris 7777 (Q7) hepatoma (n=5) and the 9L glioma (n=2) grown subcutaneously in rats. Our previous studies have demonstrated that early passage 9L tumors are not severely hypoxic and that Q7 tumors are characterized by heterogeneous regions of tumor hypoxia (i.e., Q7 tumors are usually more hypoxic than early passage 9L tumors). The seven rats were imaged in the HEAD Penn-PET scanner at various time points after administration of 50-100 micro Ci (18)F-EF5 in 30 mg/kg carrier nonradioactive EF5. The carrier was used to ensure drug biodistribution comparable to prior studies using immunohistochemical methods. (18)F-EF5 was excreted primarily via the urinary system. Images obtained 10 min following drug administration demonstrated that the EF5 distributed evenly to all organ systems, including brain. Later images showed increased uptake in most Q7 tumors compared with muscle. Liver uptake remained relatively constant over the same time periods. Tumor to muscle ratios ranged from 0.82 to 1.73 (based on PET images at 120 min post injection) and 1.47 to 2.95 (based on gamma counts at approximately 180 min post injection). Tumors were easily visible by 60 min post injection when the final tumor to muscle ratios (based on gamma counts) were greater than 2. Neither of the 9L tumors nor the smallest Q7 tumor met this criterion, and these tumors were not seen on the PET images. These preliminary results suggest that (18)F-EF5 is a promising agent for noninvasive assessment of tumor hypoxia. Plans are underway to initiate a research project to determine the safety and preliminary evidence for the efficacy of this preparation in patients with brain tumors.
European journal of nuclear medicine and molecular imaging 03/2003; 30(2):259-66. · 5.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: We present the first imaging results from phantom measurements of a dedicated, breast-only positron emission imager, BPET, using NaI(Tl) Curve Plate detectors. The scanner uses 19 mm thick NaI(Tl) detectors in a split-ring design which surrounds the breast as the woman lies prone and the breast hangs down from the body. Because the detectors are close to the breast and the scanner detects photons that do not pass through the body, system sensitivity and spatial resolution are both optimized. The split ring design provides for flexibility for needle aspirations of masses or alternate viewing orientations. We have measured energy resolution, spatial resolution, scatter fraction, and system sensitivity. We have compared the BPET scanner's performance to our clinical whole-body scanner using a breast phantom with hot spheres simulating lesions. The results show that for activity concentrations that correspond to clinical FDG doses, the dedicated scanner has better lesion detectability than the whole-body scanner for the 20 cm detector separation used.
[show abstract][hide abstract] ABSTRACT: A high sensitivity, high resolution brain PET scanner has been
developed. The scanner comprises 58 rows of 320 4×4×10 mm
<sup>3</sup> gadolinium orthosilicate (GSO) crystals, coupled to a
continuous light guide that is sampled by 288 39-mm photomultiplier
tubes in a hexagonal grid. A distortion removal algorithm has been
developed to remove position non-linearities and to identify individual
crystal regions in a flood image with physical crystal locations on the
scanner. A central profile through a sinogram of a point source in the
center of the scanner shows that the spatial resolution (fwhm) is 3.5 mm
(fwtm=8.4 mm). The Hoffman brain phantom has been successfully imaged to
demonstrate the capability of the scanner
[show abstract][hide abstract] ABSTRACT: Anesthetics used to keep small animals motionless during PET studies are a major confounding factor in the uptake and retention of radiotracers, particularly in the brain. This study proposes the use of radioactive fiducial markers to track and recover motion using only data from the PET scanner allowing anaesthetized imaging. Three small Na-22 fiducials (1mm, 10uCi) were attached to the outside of a micro hot-rod cylinder. To measure the accuracy with which fiducial markers can be tracked in the presence of a radioactive background the cylinder was filled with 1mCi F-18 and translated through the field of view at a known speed. For further validation the cylinder was filled with 0.3mCi F-18 and waved in a random motion path for 10 min. To process the listmode data is first gated into short time frame (100ms) images using simple ray casting. Each time frame image was registered (Mutual Information) to a reference frame to recover motion transforms. The listmode data is reprocessed transforming each event and binning into a single motion corrected sinogram which is reconstructed using standard programs. In the controlled motion study the fiducial markers were tracked with high precision (mean abs. error = 0.34mm). The motion recovered images were artifact free, showed good image quality, and a minimal loss of resolution. These studies suggest that motion tracking with radioactive fiducials is possible, and is suitable to enable anaesthetized brain imaging in a rat.
[show abstract][hide abstract] ABSTRACT: Methods: PET images are acquired with the patient in the supine position by a GSO-based Philips Allegro system (Philips Medical Systems, Andover, MA) and are reconstructed using 3D RAMLA with voxel sizes of 4x4x4 mm. Images sizes are typically 144x144x(45 to 170) slices (for breast or whole body scans, respectively). A 10 µCi/gram dose of FDG adjusted for patient weight is injected. Both transmission and emission images are acquired. Prone breast MRI images are acquired by a GE Signa 1.5T scanner (General Electric Medical Systems, Milwaukee, WI). T1 3D SPGR images are acquired using the standard GE software. Pre- and post-contrast (Gadolinium) images are reconstructed using a custom technique (1,2). Voxel sizes for T1 images are 0.9x0.9x(2 to 4) mm with 256x256 images. The pre- and post- contrast images are 0.5x0.5x(2 to 4) mm and 512x384 pixels. Ten patients have been scanned from a population with suspicious lesions (ranging from 3x3x4 mm to 24x43x100 mm). Results: Given these data sets (T1, pre- and post-contrast MRI, and transmission and emission PET) many comparisons can be made. For example, T1 MRI to transmission PET, pre-contrast MRI to emission PET, etc. Figure 1 illustrates the sequence of registration techniques as applied to the various modalities that we found to be most effective. Image registration techniques may be broadly classified into either rigid body (single, global transformation) or elastic/deformable (many local transformations) (3). Two methods of rigid body registration (mutual information (4) and principle components analysis) are compared. A new semi-deformable registration technique (consisting of separate affine transformations for each breast) and the deformable method described in (5) are presented as well. Conclusions: With varying degrees of accuracy, one may accomplish the difficult task of registering PET and MRI breast images. Our experiments indicate that Thirion's demons method performed best at registering MRI images acquired with various MRI protocols. For PET transmission and emission registration, Thirion's algorithm performed poorly and rigid body registration using correlation performed best. None of these methods performed well for MRI to PET transmission registration. Therefore, we developed a new method that we call pushpins that estimates two affine transformations (one for each breast) from only 6 points specified by the user in a T1 MRI and the corresponding PET transmission data set.