Evaluation of attenuation correction in cardiac PET using PET/MR.

BACKGROUND: Simultaneous acquisition Positron emission tomography/magnetic resonance (PET/MR) is a new technology that has potential as a tool both in research and clinical diagnosis. However, cardiac PET acquisition has not yet been validated using MR imaging for attenuation correction (AC). The goal of this study is to evaluate the feasibility of PET imaging using a standard 2-point Dixon volume interpolated breathhold examination (VIBE) MR sequence for AC. METHODS AND RESULTS: Evaluation was performed in both phantom and patient data. A chest phantom containing heart, lungs, and a lesion insert was scanned by both PET/MR and PET/CT. In addition, 30 patients underwent whole-body 18F-fluorodeoxyglucose PET/CT followed by simultaneous cardiac PET/MR. Phantom study showed 3% reduction of activity values in the myocardium due to the non-inclusion of the phased array coil in the AC. In patient scans, average standardized uptake values (SUVs) obtained by PET/CT and PET/MR showed no significant difference (n = 30, 4.6 ± 3.5 vs 4.7 ± 2.8, P = 0.47). There was excellent per patient correlation between the values acquired by PET/CT and PET/MR (R 2 = 0.97). CONCLUSIONS: Myocardial SUVs PET imaging using MR for AC shows excellent correlation with myocardial SUVs obtained by standard PET/CT imaging. The 2-point Dixon VIBE MR technique can be used for AC in simultaneous PET/MR data acquisition.

Generating lung tumor internal target volumes from 4D-PET maximum intensity projections.

PURPOSE: Positron emission tomography (PET) of lung tumors suffers from breathing-motion induced blurring. Respiratory-correlated PET ameliorates motion blurring and enables visualization of lung tumor functional uptake throughout the breathing cycle but has achieved limited clinical use in radiotherapy planning. In this work, the authors propose a process for generating a gated PET maximum intensity projection (MIP), a breathing-phase projection of the 4D image set comprising gated PET images, as a technique to quantitatively and efficiently incorporate respiratory-correlated PET information into radiotherapy treatment planning. METHODS: 4D-CT and respiratory-gated PET using [(18)F]fluorodeoxyglucose (FDG) were acquired of three patients with a total of four small (4-18 cc), clearly defined lower-lobe lung tumors. Internal target volumes (ITVs) for the lung tumors were generated by threshold-based segmentation of PET-MIP images and ungated PET images (ITV(PET-MIP) and ITV(3D-PET), respectively), and by manual contouring of CT-MIP and end-exhale and end-inhale phases of 4D-CT (ITV(CT-MIP)) by a radiation oncologist. Because of the sensitivity of tumor segmentation to threshold value, several different thresholds were tested for ITV generation, including 40%, 30%, and 20% of maximum standardized uptake value (SUV(max)) for FDG as well as absolute SUV thresholds of 2.5 and 3.0. The normalized overlap and relative volumes of ITV(PET-MIP) and ITV(3D-PET) with respect to ITV(CT-MIP) were compared. The images were also visually compared. ITV(CT-MIP) was considered a gold standard for these tumors with CT-visible morphology. RESULTS: The mean and standard deviation normalized overlap and relative volumes between ITV(PET-MIP) and ITV(CT-MIP) were 0.68 ± 0.07 and 1.07 ± 0.42, respectively, averaged over all four tumors and all five threshold values. The mean and standard deviation normalized overlap and relative volumes of ITV(3D-PET) and ITV(CT-MIP) were 0.47 ± 0.12 and 0.69 ± 0.56, respectively. CONCLUSIONS: PET-MIP images better match CT-MIP images for this sample of four small CT-visible tumors as compared to ungated PET images, based on the metrics of volumetric overlap and relative volumes as well as visual interpretation. The PET-MIP is a way to incorporate 4D-PET imaging into the process of lung tumor contouring that is time-efficient for the radiation oncologist and involves minimal effort to implement in treatment planning software, because it requires only a single PET image beyond contouring on CT alone.

Image quality with non-standard nuclides in PET.

Non-standard positron emission tomography (PET) nuclides bring with them the prospect of new chemistry leading the way to novel approaches for targeted imaging and therapy. In particular, the kinetic energy of the positron of some of these nuclides is high (as much as 4 MeV) and, thus, a highly specific PET probe can be very lethal to cancerous cells. However, the high positron energy will degrade the spatial resolution, and this degradation will be more important in high-resolution, small animal PET imaging, where most of the novel tracers are developed. This paper discusses the image quality in small animal PET imaging obtained with such nuclides. The nuclides of (60)Cu, (61)Cu and (64)Cu, (76)Br, (94)mTc, and (89)Zr will be particularly analyzed. The spatial resolution will be seen to degrade with nuclides with higher positron end-point energy, going from 1.7 mm for (18)F to 2.2 mm for (76)Br, for example. Many of these novel PET nuclides decay by the emission of cascades gamma rays that are detected in coincidence with the positron annihilation photons which create additional noise on the images. However, the use of an image reconstruction algorithm, which includes a model of the statistical nature of nuclear decay and the modeling of the tomograph response, contributes to both improve the spatial resolution and at the same time reduce the image noise.

Production of non-standard PET radionuclides and the application of radiopharmaceuticals labeled with these nuclides.

The field of positron emission tomography (PET) has expanded dramatically over recent years. In spite of this expansion the large majority of clinical studies are carried out utilizing one radiopharmaceutical-2-fluoro-2-deoxyglucose. Many research groups are developing novel radiopharmaceuticals. A major emphasis is on other agents labeled with 18F. Several other positron emitting radionuclides can be prepared in high yields in small biomedical cyclotrons. Some of these have half-lives that make delivery significantly easier than the delivery of 18F compounds. These radionuclides include: 64Cu (half life 12.7 h), 76Br (half life 16.2 h), 86Y (half life 14.74 h) and 124I (half life 4.2 days). The method of production of these and other 'non-standard' PET radionuclides will be discussed and the method of labeling radiopharmaceuticals with these radionuclides described. Several of these radiopharmaceuticals have been studied in animal models as well and a limited number translated to the human situation.

The three-photon yield from e+ annihilation in various fluids.

Positronium in the triplet state decays by the emission of three photons and it has been proposed that their simultaneous detection can be used for medical imaging. The three-photon yield has been observed to be enhanced in low O(2) levels in some fluids but has never been measured in biologically relevant liquids. In this study, the delayed three-photon decay yield, at both high and low O(2) levels, has been extracted by fitting the time dependence of the two-photon yield to a set of coupled differential equations. The differential equations, in a simple yet seemingly satisfactory fashion, account for the e(+) capture to form positronium, its decay and the interconversion of the two spin configurations. Our results indicate that the delayed three-photon fraction is 0.25% in water (or blood-like) samples and exhibits no (or exceedingly small) dependence on the dissolved oxygen content. If one assumes that the direct component contributes a fraction expected by annihilation on free electrons (1/372), then the total three-photon fraction is 0.52% in the samples of biological relevance.

Small animal imaging. current technology and perspectives for oncological imaging.

Advances in the biomedical sciences have been accelerated by the introduction of many new imaging technologies in recent years. With animal models widely used in the basic and pre-clinical sciences, finding ways to conduct animal experiments more accurately and efficiently becomes a key factor in the success and timeliness of research. Non-invasive imaging technologies prove to be extremely valuable tools in performing such studies and have created the recent surge in small animal imaging. This review is focused on three modalities, PET, MR and optical imaging which are available to the scientist for oncological investigations in animals.

Positron emission tomography shows that intrathecal leptin reaches the hypothalamus in baboons.

Human obesity may be caused by a resistance to circulating leptin. Evidence from rodents and humans suggests that a major component of this resistance is an impairment in the ability of the blood-brain barrier (BBB) to transport leptin from the blood to the brain. One potential way to bypass the BBB is by administering leptin into the intrathecal (i.t.) space. To be effective, i.t. leptin would have to move caudally from the site of injection, enter the cranium, and reach the hypothalamic arcuate nucleus at the base of the pituitary fossa. However, many substances, especially small, lipid-soluble molecules, do not diffuse far from the site of i.t. injection but are resorbed back into blood. To determine whether i.t. leptin can move caudally, we injected leptin conjugated to diethylenetriaminepentaacetic acid (DTPA) and labeled with (68)Ga (G-Ob) into the lumbar space of three baboons. We also studied unconjugated DTPA labeled with (68)Ga, which did not move up the spinal cord but rapidly appeared in blood after i.t. injection. In contrast, G-Ob steadily moved toward the cranium and had reached the hypothalamus 91 and 139 min after i.t. injection in two baboons. We estimated the concentration of leptin in the hypothalamic region to be at least 8 ng/ml, which is about 40 times higher than cerebrospinal fluid levels in normal weight humans and about 4 times higher than the highest level ever recorded after the peripheral administration of leptin. In a third baboon, the leptin neither moved caudally nor appeared in the blood. We conclude that leptin administered i.t. can reach the hypothalamus in therapeutic concentrations, although there is considerable individual variation.

Toxicity and dosimetry of (177)Lu-DOTA-Y3-octreotate in a rat model.

Radiolabeled somatostatin analogs have demonstrated effectiveness for targeted radiotherapy of somatostatin receptor-positive tumors in both tumor-bearing rodent models and humans. A radionuclide of interest for cancer therapy is reactor-produced (177)Lu (t(1/2) = 6.64 d; beta(-) [100%]). The high therapeutic efficacy of the somatostatin analog (177)Lu-DOTA-Tyr(3)-octreotate (DOTA-Y3-TATE, where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) was previously demonstrated in a tumor-bearing rat model (Erion et al., J. Nucl. Med. 1999;40:223P; de Jong et al., Int. J. Cancer, 2001; 92:628-633). In the current study, the toxicity and dosimetry of (177)Lu-DOTA-Y3-TATE were determined in both normal and tumor-bearing rats. Doses of (177)Lu-DOTA-Y3-TATE ranging from 0 to 123 mCi/kg were administered to rats and complete blood counts (CBCs) and blood chemistries were analyzed out to 6 weeks. No overt signs of toxicity were observed with (177)Lu-DOTA-Y3-TATE (i.e., lethargy, weight loss, scruffy coat or diarrhea) at any of the dose levels. Blood chemistries and CBCs were normal except for the white blood cell counts, which showed a dose-dependent decrease. The maximum tolerated dose was not reached at 123 mCi/kg. The biodistribution of (177)Lu-DOTA-Y3-TATE was determined in CA20948 rat pancreatic tumor-bearing rats, and the data were used to estimate human absorbed doses to normal tissues. The dose-limiting organ was determined to be the pancreas, followed by the adrenal glands. The absorbed dose to the rat CA20948 tumor was estimated to be 336 rad/mCi (91 mGy/MBq). These data demonstrate that (177)Lu-DOTA-Y3-TATE is an effective targeted radiotherapy agent at levels that show minimal toxicity in this rat model.

Tumor uptake of copper-diacetyl-bis(N(4)-methylthiosemicarbazone): effect of changes in tissue oxygenation.

UNLABELLED: We showed previously that, in vitro, copper-diacetyl-bis(N(4)-methylthiosemicarbazone) (Cu-ATSM) uptake is dependent on the oxygen concentration (pO2). We also showed that, in vivo, Cu-ATSM uptake is heterogeneous in animal tumors known to contain hypoxic fractions. This study was undertaken to confirm the pO2 dependence of this selective uptake in vivo by correlating Cu-ATSM uptake with measured tumor pO2. METHODS: Experiments were performed with the 9L gliosarcoma rat model using a needle oxygen electrode to measure tissue pO2. Using PET and electronic autoradiography, Cu-ATSM uptake was measured in tumor tissue under various pO2 levels. The oxygen concentration within implanted tumors was manipulated by chemical means or by altering the inhaled oxygen content. RESULTS: A good correlation between low pO2 and high Cu-ATSM accumulation was observed. Hydralazine administration in animals caused a decrease in the average tumor pO2 from 28.61 +/- 8.74 mm Hg to 20.81 +/- 7.54 mm Hg in untreated control animals breathing atmospheric oxygen. It also caused the tumor uptake of Cu-ATSM to increase by 35%. Conversely, in animals breathing 100% oxygen, the average tumor pO2 increased to 45.88 +/-15.9 mm Hg, and the tumor uptake of Cu-ATSM decreased to 48% of that of the control animals. PET of animals treated in a similar fashion yielded time-activity curves showing significantly higher retention of the tracer in hypoxic tissues than in oxygenated tissues. CONCLUSION: These data confirm that Cu-ATSM uptake in tissues in vivo is dependent on the tissue pO2, and that significantly greater uptake and retention occur in hypoxic tumor tissue. Therefore, the possible use of Cu-ATSM PET as a prognostic indicator in the management of cancer is further validated.

64Cu-TETA-octreotide as a PET imaging agent for patients with neuroendocrine tumors.

UNLABELLED: 64Cu (half-life, 12.7 h; beta+, 0.653 MeV [17.4%]; beta-, 0.579 MeV [39%]) has shown potential as a radioisotope for PET imaging and radiotherapy. (111)In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe1-octreotide (OC) was developed for imaging somatostatin-receptor-positive tumors using conventional scintigraphy. With the advantages of PET over conventional scintigraphy, an agent for PET imaging of these tumors is desirable. Here, we show that 64Cu-TETA-OC (where TETA is 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid) and PET can be used to detect somatostatin-receptor-positive tumors in humans. METHODS: Eight patients with a history of neuroendocrine tumors (five patients with carcinoid tumors and three patients with islet cell tumors) were imaged by conventional scintigraphy with (111)In-DTPA-OC (204-233 MBq [5.5-6.3 mCi]) and by PET imaging with 64Cu-TETA-OC (111 MBq [3 mCi]). Blood and urine samples were collected for pharmacokinetic analysis. PET images were collected at times ranging from 0 to 36 h after injection, and the absorbed doses to normal organs were determined. RESULTS: In six of the eight patients, cancerous lesions were visible by both (111)In-DTPA-OC SPECT and 64Cu-TETA-OC PET. In one patient, (111)In-DTPA-OC showed mild uptake in a lung lesion that was not detected by 64Cu-TETA-OC PET. In one patient, no tumors were detected by either agent; however, pathologic follow-up indicated that the patient had no tumors. In two patients whose tumors were visualized with (111)In-DTPA-OC and 64Cu-TETA-OC, 64Cu-TETA-OC and PET showed more lesions than (111)In-DTPA-OC. Pharmacokinetic studies showed that 64Cu-TETA-OC was rapidly cleared from the blood and that 59.2% +/- 17.6% of the injected dose was excreted in the urine. Absorbed dose measurements indicated that the bladder wall was the dose-limiting organ. CONCLUSION: The high rate of lesion detection, sensitivity, and favorable dosimetry and pharmacokinetics of 64Cu-TETA-OC indicate that it is a promising radiopharmaceutical for PET imaging of patients with neuroendocrine tumors.

Copper-64-diacetyl-bis(N4-methylthiosemicarbazone): An agent for radiotherapy.

Systemic administration of hypoxia-selective (64)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) has increased significantly the survival time of hamsters bearing human GW39 colon cancer tumors. Radiotherapy experiments were performed in animals bearing either 7-day-old (0.5-1.0 g) or 15-day-old (1.5-2.0 g) tumors. Studies compared animals treated with a single dose of 0, 4, 6, 7, 8, or 10 mCi of (64)Cu-ATSM (1 Ci = 37 GBq) with or without the vasodilator hydralazine. A multiple dose regimen of 3 x 4 mCi at 72-h intervals was studied also. Single doses of >6 mCi of (64)Cu-ATSM and the dose-fractionation protocol significantly increased the survival time of the hamsters compared with controls. The highest dose, 10 mCi of (64)Cu-ATSM, increased survival to 135 days in 50% of animals bearing 7-day-old tumors, 6-fold longer than control animals' survival (20 days), with only transient leucopenia and thrombocytopenia but no overt toxicity. Human absorbed doses were calculated from hamster biodistribution; the dose-critical organs were the lower large intestine (1.43 +/- 0.19 rad/mCi) and upper large intestine (1.20 +/- 0.38 rad/mCi). High-resolution MRI and positron-emission tomography using a therapeutic administration of 10 mCi were used to monitor tumor volume and morphology and to assess tumor dosimetry accurately, giving a tumor dose of 81 +/- 7.5 rad/mCi. (64)Cu-ATSM has increased the survival time of tumor-bearing animals significantly with no acute toxicity and thus is a promising agent for radiotherapy.

Conjugation of monoclonal antibodies with TETA using activated esters: biological comparison of 64Cu-TETA-1A3 with 64Cu-BAT-2IT-1A3.

A simple method for conjugation of monoclonal antibodies (mAbs) with the chelating agent 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), has been developed using commercially available reagents. This method involved activation of a single carboxyl group of TETA with N-hydroxysulfosuccinimide and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide. The resulting activated ester of TETA was reacted with the anti-colorectal carcinoma mAb 1A3 at molar ratios ranging from 10:1 to 100:1 to give immunoconjugates modified with an average of 0.4 to 2.0 functional chelators per antibody molecule. The TETA-1A3 conjugate was labeled with 64Cu at specific activities as high as 15.4 microCi/microgram, and the radiolabeled mAb exhibited high in vitro serum stability and minimal loss of immunoreactivity. The biodistribution of 64Cu-labeled TETA-1A3 in hamsters bearing GW39 human colon carcinoma xenografts was compared to that of 64Cu-BAT-2IT-1A3 (BAT = 6-(p-bromoacetamidobenzyl)-1,4,8,11-tetraazacyclotetradecane-1,4,8,11- tetraacetic acid; 2IT = 2-iminothiolane). Both conjugates showed high tumor uptake (6.60-9.05% injected dose/gram) from 24 to 48 h post-injection and generally similar blood clearance and non-target organ uptakes. Human absorbed dose estimates derived from the hamster biodistribution data showed the critical organs for both conjugates to be the large intestine and the red marrow. Our results suggest that the in vitro and in vivo performance characteristics of 64Cu-TETA-1A3 compare favorably with those of 64Cu-BAT-2IT-1A3 and that further evaluation of the diagnostic and therapeutic efficacy of 64Cu-TETA-1A3 is warranted.

Signals for a transition from surface to bulk emission in thermal multifragmentation.

Excitation-energy-gated two-fragment correlation functions have been studied between E(*)/A = (2-9)A MeV for equilibriumlike sources formed in 8-10 GeV/c pi(-) and p+197Au reactions. Comparison with an N-body Coulomb-trajectory code shows an order of magnitude decrease in the fragment emission time in the interval E(*)/A = (2-5)A MeV, followed by a nearly constant breakup time at higher excitation energy. The decrease in emission time is strongly correlated with the onset of multifragmentation and thermally induced radial expansion, consistent with a transition from surface-dominated to bulk emission expected for spinodal decomposition.

Comparative dosimetry of copper-64 and yttrium-90-labeled somatostatin analogs in a tumor-bearing rat model.

90Y-DOTA-tyrosine3-octreotide (90Y-DOTA-Y3-OC) is currently being evaluated as a radiotherapy agent for trials in patients with somatostatin-receptor positive cancer. In this study, we compared the estimated absorbed doses to human organs, as well as to a CA20948 rat tumor, of 90Y- and 64Cu-labeled DOTA-Y3-OC and DOTA-Y3-octreotate (DOTA-Y3-TATE). Assuming that the radiopharmaceutical biodistributions are the same in rodents and humans, human absorbed dose estimates were obtained from rat biodistribution data. The absorbed doses of 90Y-DOTA-Y3-TATE were determined from the biodistribution of the 88Y-labeled peptide, with and without co-injection of a therapeutic amount of the 90Y-labeled peptide. Additionally, the absorbed doses of 90Y-DOTA-Y3-TATE were determined from data using two different biodistribution endpoints, 48 h and 168 h. Human absorbed dose estimates were calculated using MIRD methodology assuming that rats and humans have the same biodistribution. The biodistribution of the radiolabeled somatostatin analogs was dependent on the peptide and the radiometal. For 90Y-DOTA-Y3-TATE, the tumor dose was dependent on both the administration of therapeutic 90Y-peptide and the biodistribution endpoint. Our data suggested that, for both radionuclides, the TATE derivatives imparted a higher absorbed dose to the tumor than the OC analogs. 90Y-DOTA-Y3-OC and 64Cu-DOTA-Y3-OC were comparable with respect to their tumor-to-normal tissue dose ratios, while 90Y-DOTA-Y3-TATE appeared to have distinct advantages over 64Cu-DOTA-Y3-TATE.