Manufacture of strontium-82/rubidium-82 generators and quality control of rubidium-82 chloride for myocardial perfusion imaging in patients using positron emission tomography

We describe a protocol to manufacture ⁸²Sr/⁸²Rb generators and ⁸²RbCl for myocardial imaging with PET. The generators are manufactured in 3 stages: (1) preparation of a tin oxide column, (2) leak test of the generator column and (3) loading of the generator with ⁸²Sr. The generators produced sterile and non-pyrogenic ⁸²RbCl for i.v. injection. No significant ⁸²Sr/⁸⁵Sr breakthroughs were observed after elution with 20 l of saline. The automated system delivered human doses of ⁸²RbCl accurately.     

Prognostic value of vasodilator response using rubidium-82 positron emission tomography myocardial perfusion imaging in patients with coronary artery disease

Background

Prognostic value of positron emission tomography (PET) myocardial perfusion imaging (MPI) is well established. There is paucity of data on how the prognostic value of PET relates to the hemodynamic response to vasodilator stress. We hypothesize that inadequate hemodynamic response will affect the prognostic value of PET MPI.

Methods and results

Using a multicenter rubidium (Rb)-82 PET registry, 3406 patients who underwent a clinically indicated rest/stress PET MPI with a vasodilator agent were analyzed. Patients were categorized as, “responders” [increase in heart rate?≥?10 beats per minute (bpm) and decrease in systolic blood pressure (SBP) ≥10 mmHg], “partial responders” (either a change in HR or SBP), and “non-responders” (no change in HR or SBP). Primary outcome was all-cause death (ACD), and secondary outcome was cardiac death (CD). Ischemic burden was measured using summed stress score (SSS) and % left ventricular (LV) ischemia. After a median follow-up of 1.68 years (interquartile range?=?1.17- 2.55), there were 7.9% (n?=?270) ACD and 2.6% (n?=?54) CD. Responders with a normal PET MPI had an annualized event rate (AER) of 1.22% (SSS of 0–3) and 1.58% (% LV ischemia?=?0). Partial and non-responders had higher AER with worsening levels of ischemic burden. In the presence of severe SSS ≥12 and LV ischemia of ≥10%, partial responders had an AER of 10.79% and 10.36%, compared to non-responders with an AER of 19.4% and 12.43%, respectively. Patient classification was improved when SSS was added to a model containing clinical variables (NRI: 42%, p?<?0.001) and responder category was added (NRI: 61%,

Conclusion

Hemodynamic response during a vasodilator Rb-82 PET MPI is predictive of ACD. Partial and non-responders may require additional risk stratification leading to altered patient management.

     

Quantitative in vivo measurements of tumor perfusion using rubidium-81 and positron emission tomography

Rubidium-81 (t1/2 = 4.58 hr) was investigated as a tumor perfusion tracer in the VX2 carcinoma implanted into rabbit thigh muscle using a large-area, multiwire proportional chamber positron emission tomography (PET) system. Perfusion was determined using the arterial reference sample method, and the results from PET imaging were compared with postmortem tissue sampling. Absolute quantitation of tumor perfusion was achieved using external probes to estimate local extraction fraction. Redistribution of rubidium-81 (81Rb) was investigated using a dual-tracer technique. Average perfusion was found to be 13.5 and 3.7 ml/min/100 g in tumor and normal muscle, respectively. The extraction fraction as estimated from a two-compartment model ranged from 0.94 to 1.00. No significant redistribution of 81Rb was observed in these tissues. Nine patients with malignancies were studied using 81Rb and PET. Tumor perfusion in four patients with carcinoma of the breast was elevated by a factor of 1.8 (range 1.2-2.3) compared to contralateral normal breast.     

Three-dimensional display of positron emission tomography of the heart

A method for producing images of 82Rb myocardial perfusion and 11C carbon monoxide gated blood pool images is described. In the case of 82Rb images, cylindrical projection displaying myocardial activity as viewed from the side is presented to complement the polar projection. Cubic display of the conventional short- and long-axis slices is described that permits interactive selection of any desired slices. A three-dimensional cine display of the left ventricle rotating about its long axis is produced that gives a very realistic presentation of myocardial activity. Very similar processing techniques are applied to gated carbon-11 blood-pool studies to yield beating images of the surface of the blood pool in multiple projections.     

Occupational radiation dose associated with Rb-82 myocardial perfusion positron emission tomography imaging

BACKGROUND: We determined staff radiation dose during rest and stress rubidium 82 myocardial perfusion positron emission tomography (PET) imaging. METHODS AND RESULTS: Patients received 1,587 +/- 163 MBq (42.9 +/- 4.4 mCi) Rb-82 during rest or pharmacologic stress. A pressurized ion chamber was used to monitor radiation exposure in 50 examinations. For comparison, staff exposure during pharmacologic stress in 20 other patients receiving 1,204 +/- 55.5 MBq (32.54 +/- 1.5 mCi) technetium 99m 2-methoxy isobutyl isonitrile (MIBI) was measured. For Rb-82 infusion and PET acquisition, the mean dose was 0.45 +/- 0.25 microSv (0.045 +/- 0.025 mrem). Exposure for routine stress testing at variable distances from the patient was equivalent to background. Similar exposure for pharmacologic stress testing through 7 minutes after injection of Tc-99m MIBI at variable distances was 1.075 +/- 0.32 microSv (0.108 +/- 0.03 mrem). However, exposure for stress tests starting 7 minutes after Rb-82 infusion at 0.5 m was estimated at 0.4 microSv (0.04 mrem). To determine the potential radiation dose for those responding to a medical emergency or otherwise in close proximity to a patient, we measured the mean cumulative dose at 0.5 m from 0 to 7 minutes of Rb-82 infusion, which resulted in 19.1 +/- 5.8 microSv (1.9 +/- 0.58 mrem). CONCLUSIONS: Radiation doses for all tasks during routine Rb-82 stress-rest PET are lower than measured Tc-99m MIBI values. However, the radiation dose in close proximity to the patient during or immediately after Rb-82 infusion can be considerably higher, underscoring the need for strict attention to source distance and contact times.     

Quantification in clinical fluorodeoxyglucose positron emission tomography

Positron emission tomography (PET) is increasingly used clinically to provide functional information on disease processes, especially in oncology using the glucose analogue 2-[18F]fluoro-2-deoxy-D-glucose (F-FDG). In the clinical setting it has become standard practice to use simplified imaging protocols compared to the often complex methods developed for research using PET. This is partly due to scarcity of resources but also for reasons of patient comfort and compliance, and not least expense and patient throughput. Fortunately the resulting loss in information can be justified to some extent on the grounds that in clinical PET it is usually relative rather than absolute metabolic rates that are of interest. Nonetheless, there remain unresolved questions of how best to perform quantification in clinical PET.     

18F-Fluoride positron emission tomography and positron emission tomography/computed tomography

(18)F-Fluoride is a positron-emitting bone-seeking agent, the uptake of which reflects blood flow and remodeling of bone. Assessment of (18)F-fluoride kinetics using quantitative positron emission tomography (PET) methods allows the regional characterization of lesions of metabolic bone diseases and the monitoring of their response to therapy. It also enables the assessment of bone viability and discrimination of uneventful and impaired healing processes of fractures, bone grafts and osteonecrosis. Taking advantage of the favorable pharmacokinetic properties of the tracer combined with the high performance of PET technology, static (18)F-fluoride PET is a highly sensitive imaging modality for detection of benign and malignant osseous abnormalities. Although (18)F-fluoride uptake mechanism corresponds to osteoblastic activity, it is also sensitive for detection of lytic and early marrow-based metastases, by identifying their accompanying reactive osteoblastic changes, even when minimal. The instant fusion of increased (18)F-fluoride uptake with morphological data of computed tomography (CT) using hybrid PET/CT systems improves the specificity of (18)F-fluoride PET in cancer patients by accurately differentiating between benign and malignant sites of uptake. The results of a few recent publications suggest that (18)F-fluoride PET/CT is a valuable modality in the diagnosis of pathological osseous conditions in patients also referred for nononcologic indications. (18)F-fluoride PET and PET/CT are, however, not widely used in clinical practice. The limited availability of (18)F-fluoride and of PET and PET/CT systems is a major factor. At present, there are not enough data on the cost-effectiveness of (18)F-fluoride PET/CT. However, it has been stated by some experts that (18)F-fluoride PET/CT is expected to replace (99m)Tc-MDP bone scintigraphy in the future.     

Quantification of myocardial perfusion using cardiac magnetic resonance imaging correlates significantly to rubidium-82 positron emission tomography in patients with severe coronary artery disease: A preliminary study

Introduction

Aim was to compare absolute myocardial perfusion using cardiac magnetic resonance imaging (CMRI) based on Tikhonov's procedure of deconvolution and rubidium-82 positron emission tomography (Rb-82 PET).

Materials and methods

Fourteen patients with coronary artery stenosis underwent rest and adenosine stress imaging by 1.5-Tesla MR Scanner and a mCT/PET 64-slice Scanner. CMRI were analyzed based on Tikhonov's procedure of deconvolution without specifying an explicit compartment model using our own software. PET images were analyzed using standard clinical software. CMRI and PET data was compared with Spearman's rho and Bland–Altman analysis.

Results

CMRI results were strongly and significantly correlated with PET results for the absolute global myocardial perfusion differences (r = 0.805, p = 0.001) and for global myocardial perfusion reserve (MPR) (r = 0.886, p < 0.001). At vessel territorial level, CMRI results were also significantly correlated with absolute PET myocardial perfusion differences (r = 0.737, p < 0.001) and MPR (r = 0.818, p < 0.001). Each vessel territory had similar strong correlation for absolute myocardial perfusion differences (right coronary artery (RCA): r = 0.787, p = 0.001; left anterior descending artery (LAD): r = 0.796, p = 0.001; left circumflex artery (LCX): r = 0.880, p < 0.001) and for MPR (RCA: r = 0.895, p < 0.001; LAD: r = 0.886, p < 0.001; LCX: r = 0.886, p < 0.001).

Conclusion

On a global and vessel territorial basis, CMRI-measured absolute myocardial perfusion differences and MPR were strongly and significantly correlated with the Rb-82 PET findings.     

A cost analysis of positron emission tomography.

OBJECTIVE: Changes in regulations and improvements in reimbursement have propelled positron emission tomography (PET) into clinical use, making it increasingly important to understand the costs of this emerging service. Cost analyses are important tools to do this. Data published previously on these topics reflect assumptions that are no longer valid. The aim of this study was to determine the cost of developing and operating a PET facility and to evaluate whether a regional cyclotron serving several scanners reduces costs. MATERIALS AND METHODS: Financial data were collected on capital expense and global operating costs through interviews with industry experts, evaluation of prior studies, and review of expenses incurred at the University of Southern California PET center. A data model and cost templates were developed. Expenses were allocated either to the production or purchase of radiopharmaceuticals or to the provision of the PET scan, and the cost per procedure was determined. A sensitivity analysis was performed on the net present value for key parameters. RESULTS: A cyclotron serving a single scanner is not financially viable. The radiopharmaceutical distribution configurations were financially sound. In these cases, the cost of the radiopharmaceutical was approximately $700 per dose with modest levels of production (12 doses per day). In addition, the average cost of PET scans (technical scan and professional charges) ranged from approximately $900 to $1400. The critical factor for profitability was shown to be throughput. CONCLUSION: This analysis provides significant insight into the cost of PET and the comparative costs of offering PET through four operating configurations. Reductions in equipment prices, increased availability of radiopharmaceuticals, growth in demand, and improvements in reimbursement have all contributed to the financial viability of this imaging technique.     

Cost analyses of positron emission tomography for clinical use

Costs associated with the clinical use of positron emission tomography (PET) at the Mallinckrodt Institute of Radiology are analyzed according to the two major components: radiopharmaceutical production and imaging. Estimated annual costs are +584,500 for PET radiopharmaceutical production and +644,250 for PET imaging (1982 U.S. dollars). The economic break-even point charge to cover expenses is +615-+2,780 per clinical procedure, depending on several variables, especially procedure volume. Charges for PET clinical procedures will be among the highest of all charges for diagnostic imaging procedures, perhaps even higher than these estimates at some institutions. Several technologic and procedural approaches to reducing costs are suggested, the most promising being the anticipated availability of positron-emitting radionuclides from commercial suppliers.     

Imaging gliomas with positron emission tomography and single-photon emission computed tomography

Over the last two decades the large volume of research involving various brain tracers has shed invaluable light on the pathophysiology of cerebral neoplasms. Yet the question remains as to how best to incorporate this newly acquired insight into the clinical context. Thallium is the most studied radiotracer with the longest track record. Many, but not all studies, show a relationship between (201)Tl uptake and tumor grade. Due to the overlap between tumor uptake and histologic grades, (201)Tl cannot be used as the sole noninvasive diagnostic or prognostic tool in brain tumor patients. However, it may help differentiating a high-grade tumor recurrence from radiation necrosis. MIBI is theoretically a better imaging agent than (201)Tl but it has not convincingly been shown to differentiate tumors according to grade. MDR-1 gene expression as demonstrated by MIBI does not correlate with chemoresistance in high grade gliomas. Currently, MIBI's clinical role in brain tumor imaging has yet to be defined. IMT, a radio-labeled amino acid analog, may be useful for identifying postoperative tumor recurrence and, in this application, appears to be a cheaper, more widely available tool than positron emission tomography (PET). However, its ability to accurately identify tumor grade is limited. 18 F-2-Fluoro-2-deoxy-d-glucose (FDG) PET predicts tumor grade, and the metabolic activity of brain tumors has a prognostic significance. Whether FDG uptake has an independent prognostic value above that of histology remains debated. FDG-PET is effective in differentiating recurrent tumor from radiation necrosis for high-grade tumors, but has limited value in defining the extent of tumor involvement and recurrence of low-grade lesions. Amino-acid tracers, such as MET, perform better for this purpose and thus play a complementary role to FDG. Given the poor prognosis of patients with gliomas, particularly with high-grade lesions, the overall clinical utility of single photon emission computed tomography (SPECT) and PET in characterizing recurrent lesions remains dependent on the availability of effective treatments. These tools are thus mostly suited to the evaluation of treatment response in experimental protocols designed to improve the patients' outcome.     

Cyclotrons and positron emission tomography radiopharmaceuticals for clinical imaging

Positron emission tomography (PET) requires positron-emitting radionuclides that emit 511-keV photons detectable by PET imagers. Positron-emitting radionuclides are commonly produced in charged particle accelerators, eg, linear accelerators or cyclotrons. The most widely available radiopharmaceuticals for PET imaging are carbon-11-, nitrogen-13-, and oxygen-15-labeled compounds, many of which, either in their normal state or incorporated in other compounds, serve as physiological tracers. Other useful PET radiopharmaceuticals include fluorine-18-, bromine-75-, gallium-68 (68Ga)-, rubidium-82 (82Rb)-, and copper-62 (62Cu)-labeled compounds. Many positron emitters have short half-lives and thus require on-site cyclotrons for application, and others (68Ga, 82Rb, and 62Cu) are available from radionuclides generators using relatively long-lived parent radionuclides. This review is divided into two sections: cyclotrons and PET radiopharmaceuticals for clinical imaging. In the cyclotron section, the principle of operation of the cyclotron, types of cyclotrons, medical cyclotrons, and production of radionuclides are discussed. In the section on PET radiopharmaceuticals, the synthesis and clinical use of PET radiopharmaceuticals are described.     

Fundamentals of positron emission tomography

Positron emission tomography is a modern radionuclide method of measuring physiological quantities or metabolic parameters in vivo. The method is based on: (1) radioactive labelling with positron emitters; (2) the coincidence technique for the measurement of the annihilation radiation following positron decay; (3) analysis of the data measured using biological models. The basic aspects and problems of the method are discussed. The main fields of future research are the synthesis of new labelled compounds and the development of mathematical models of the biological processes to be investigated.     

Principal component analysis of dynamic positron emission tomography images

Multivariate image analysis can be used to analyse multivariate medical images. The purpose could be to visualize or classify structures in the image. One common multivariate image analysis technique which can be used for visualization purposes is principal component analysis (PCA). The present work concerns visualization of organs and structures with different kinetics in a dynamic sequence utilizing PCA. When applying PCA on positron emission tomography (PET) images, the result is initially not satisfactory. It is illustrated that one major explanation for the behaviour of PCA when applied to PET images is that it is a data-driven technique which cannot separate signals from high noise levels. With a better understanding of the PCA, gained with a strategy of examining the image data set, the transformations, and the results using visualization tools, a surprisingly easily understood methodology can be derived. The proposed methodology can enhance clinically interesting information in a dynamic PET imaging sequence in the first few principal component images and thus should be able to aid in the identification of structures for further analysis.