Quantification of regional extravascular lung water in dogs with positron emission tomography, using constant infusion of 15O-labeled water

Continuous infusion of 15O-labeled water allows a quantitative measurement of the total water pool in the chest region by positron emission tomography (PET). By subsequent inhalation of 11CO the intravascular space (blood pool) can be quantitated as well. After a suitable normalization of the intravascular activities the extravascular water can be determined by subtraction of the blood pool from the water pool. The regional extravascular lung water distribution can be visualized in tomographic slices. The method was validated in an animal experiment using five dogs. They were measured before and after induction of a lung edema by IV injection of oleic acid. The increase of extravascular lung water was monitored by the thermo-dye-dilution method (TDD). The correlation of extravascular lung water as measured by TDD with PET measurements is good (r = 0.94). The PET values agree also with gravimetric lung water determinations. An absolute quantitation of regional extravascular lung water is possible after absorption correction of the PET data via transmission measurements and calibration of the camera system. The uncertainty in the absolute quantification is +/- 20%. In the experiments described here the mean extravascular lung water was 0.13 g/cm3 before and 0.25 g/cm3 after induction of lung edema.     

Quantification of regional myocardial oxygen metabolism in normal pigs using positron emission tomography with injectable 15O-O2

Purpose

Although ¹⁵O-O₂ gas inhalation can provide a reliable and accurate myocardial metabolic rate for oxygen by PET, the spillover from gas volume in the lung distorts the images. Recently, we developed an injectable method in which blood takes up ¹⁵O-O₂ from an artificial lung, and this made it possible to estimate oxygen metabolism without the inhalation protocol. In the present study, we evaluated the effectiveness of the injectable ¹⁵O-O₂ system in porcine hearts.

Methods

PET scans were performed after bolus injection and continuous infusion of injectable ¹⁵O-O₂ via a shunt between the femoral artery and the vein in normal pigs. The injection method was compared to the inhalation method. The oxygen extraction fraction (OEF) in the lateral walls of the heart was calculated by a compartmental model in view of the spillover and partial volume effect.

Results

A significant decrease of lung radioactivity in PET images was observed compared to the continuous inhalation of ¹⁵O-O₂ gas. Furthermore, the injectable ¹⁵O-O₂ system provides a measurement of OEF in lateral walls of the heart that is similar to the continuous-inhalation method (0.71?±?0.036 and 0.72?±?0.020 for the bolus-injection and continuous-infusion methods, respectively).

Conclusion

These results indicate that injectable ¹⁵O-O₂ has the potential to evaluate myocardial oxygen metabolism.     

Clinical impact of hemodynamic parameter measurement for cerebrovascular disease using positron emission tomography and 15O-labeled tracers

Positron emission tomography (PET) measurement of cerebral blood flow and metabolism has been a basic and standard method for evaluation of hemodynamics in patients with cerebral vascular disease (CVD). Despite the recent rapid spread of PET and PET/CT facilities, the number of patient examinations with ¹⁵O-gas PET scans is declining because most facilities are used for cancer studies. They avoid ¹⁵O-gas PET study because it is time consuming and the technique and calculation methods appear to be complicated. However, reconsidering the benefits and usefulness of conventional ¹⁵O-gas PET study is a good opportunity to understand its potential possibility. Physiological evaluation of cerebral perfusion and metabolism provided the basic concept of hemodynamics in impaired circulation and the development of evidence-based medicine in neurosurgical treatment for CVD. This method can be used for two major objectives, clinical examination with a less-invasive simplified method, and quantitative precise measurements with model analysis for research purposes. Both are important for developing further practical and investigational approaches using ¹⁵O-gas PET.     

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.     

Reproducibility of repeated human regional splenic blood flow measurements using [15O] water and positron emission tomography.

The reproducibility of measurement of regional splenic blood flow by dynamic positron emission tomography (PET) using [15O]water was evaluated. In 19 patients, the correlation between the first and second of two serial dynamic measurements was significant (P=1.78 x 10(-6); r=0.858). The regression equation was y = 1.06x, and the slope of the line described had a 95% confidence interval of 0.09. The error apparent between the two measurements was 0.129 (95% confidence interval 0.059). The results demonstrated sufficiently good reproducibility for measurements of regional splenic blood flow with PET and [15O]water to suggest use of this method for serial measurements intended to detect change, including drug effects.     

Assessment of pancreatic blood flow with positron emission tomography and oxygen-15 water

Dynamic positron emission tomography (PET) was performed following an intravenous bolus injection of 15O-water for the assessment of regional pancreatic blood flow in 4 normal volunteers and 11 patients with pancreatic cancer. The regional pancreatic blood flow index (PFI) was calculated by the autoradiographic method assuming the time-activity curves of the aorta as an input function. The mean PFI value was 0.514 +/- 0.098 in the normal pancreas but it was decreased in pancreatic cancer (0.249 +/- 0.076) (p less than 0.01), with a concomitant decrease in the pancreatic region distal to the tumor. On the other hand, in cases with body or tail cancer, the part proximal to the tumor (nontumorous head region) had a similar PFI value (0.554 +/- 0.211) to that of normal cases. Thus, a PET study with 15O-water permits quantitative assessment of pancreatic blood flow which decreased in both pancreatic cancer and concomitant obstructive pancreatitis distal to the tumor.     

Quantification aspects of patient studies with Fe in positron emission tomography

Quantification accuracy in positron emission tomography (PET) using non-pure positron emitters, such as ⁵²Fe, may be influenced by gamma radiation emitted in the decay of these isotopes. High-energy positrons, emitted in the decay of the ⁵²Fe-daughter ^52mMn, also affect the quantification accuracy. A specific problem of the ⁵²Fe/^52mMn decay chain in vivo is that the kinetics of iron and manganese are different, and that PET cannot discriminate between the two nuclides. The effect of the decay properties of ⁵²Fe/^52mMn on the performance of PET was investigated using phantoms. Minor degradation in PET performance was found for ⁵²Fe/^52mMn compared to the pure low-energy positron emitter ¹⁸F. A method is presented to obtain a correction factor for the ^52mMn radioactivity in blood. A model for correction of ^52mMn-radioactivity in organs, based on existing data on manganese kinetics, is given. The presented corrections are discussed and illustrated in a patient study.     

Noninvasive assessment of regional cardiac adenosine using positron emission tomography.

One of the early metabolic changes associated with myocardial ischemia is the breakdown of adenine nucleotides resulting in the enhanced production of adenosine. In order to image regional cardiac adenosine by positron emission tomography (PET) the enzymatic conversion of adenosine into [11C]-S-adenosylhomocysteine ([11C]SAH) was used in the presence of 11C-labeled homocysteine thiolactone (adenosine + [11C] - homocysteine-->[11C] - SAH + H2O). Following production of an experimental coronary constriction in anesthetized dogs carrier added 1-[11C]-D,L-homocysteine thiolactone (5-27 mCi, 30 mg/kg) was infused over 1 min. This intervention, while hemodynamically ineffective, increased the plasma homocysteine concentration from 2.5 to 306 microM, which thereafter declined with a T1/2 of 28 min to 97 microM after 60 min. During the first minutes following infusion of [11C] homocysteine, the radioactivity concentration in the blood pool, the nonischemic and the ischemic myocardium were similar. Between 20 and 60 min, however, the regional radioactivity concentration was highest in the perfusion area of the stenosed vessel: 6.6% compared to 5.2 and 5.2% of the injected dose per 1 I tissue. The elevated radioactivity concentration was strictly confined to the perfusion area of the occluded artery. Using [35S]-L-homocysteine (20 microCi; 30 mg/kg) chromatographic separation of SAH in tissue extracts confirmed that the radioactivity accumulation was due to trapping of adenosine in the cellular SAH-pool. These experiments provide first evidence that 1-[11C]homocysteine thiolactone can be successfully used to assess regional adenosine formation in the heart with PET via measurement of [11C] SAH accumulation.     

Quantitative assessment of regional myocardial blood flow using oxygen-15-labelled water and positron emission tomography: a multicentre evaluation in Japan

Recently, a method has been proposed for the quantitative measurement of regional myocardial blood flow (MBF) using oxygen-15-labelled water and positron emission tomography (PET). A multicentre project was organized with the intention of evaluating the accuracy of this method, particularly as a multicentre clinical investigative tool. Each of seven institutions performed PET studies on more than five normal volunteers following a specified protocol. The PET study included a transmission scan, a 15O-carbon monoxide static scan and a 15O-water dynamic scan, thereby yielding MBF values which should have been independent of the spatial resolution of the PET scanner employed. Fifty-three subjects (aged 20-63 years, mean+/-SD 36+/-12 years) were studied at rest, and 31 of these subjects were also studied after dipyridamole in five institutions. Inter-institution consistency and intra-subject variation in MBF values were then evaluated. MBF averaged for all subjects was 0.93+/-0.34 ml min(-1) g(-1) at rest and 3.40+/-1.73 ml min(-1) g(-1) after the administration of dipyridamole, and the flow reserve (defined as the ratio of the two MBF values) was 3.82+/-2.12; these values are consistent with previous reports. Resting MBF values were significantly correlated with the heart rate-blood pressure product (RPP) (y=0.31+6.56E-5x, P<0.010), and RPP was in resting MBF observed in all institutions was well explained by the age-dependent RPP. No significant difference was observed in resting MBF among the institutions. Except in one institution, no significant difference was seen in dipyridamole MBF or myocardial flow reserve. No significant difference was found among the myocardial segments. Regional variation was reasonably small in five institutions, but was not acceptable in two institutions, which was attributed to the scanner performance. These observations suggest that the 15O-water PET technique is useful for a multicentre clinical study if the PET scanner can provide time-activity data with good count statistics.     

Quantitative assessment of regional myocardial blood flow using oxygen-15-labelled water and positron emission tomography: a multicentre evaluation in Japan

Recently, a method has been proposed for the quantitative measurement of regional myocardial blood flow (MBF) using oxygen-15-labelled water and positron emission tomography (PET). A multicentre project was organized with the intention of evaluating the accuracy of this method, particularly as a multicentre clinical investigative tool. Each of seven institutions performed PET studies on more than five normal volunteers following a specified protocol. The PET study included a transmission scan, a ¹⁵O-carbon monoxide static scan and a ¹⁵O-water dynamic scan, thereby yielding MBF values which should have been independent of the spatial resolution of the PET scanner employed. Fifty-three subjects (aged 20–63 years, mean±SD 36±12 years) were studied at rest, and 31 of these subjects were also studied after dipyridamole in five institutions. Inter-institution consistency and intra-subject variation in MBF values were then evaluated. MBF averaged for all subjects was 0.93±0.34 ml min^–1 g^–1 at rest and 3.40±1.73 ml min^–1 g^–1 after the administration of dipyridamole, and the flow reserve (defined as the ratio of the two MBF values) was 3.82±2.12; these values are consistent with previous reports. Resting MBF values were significantly correlated with the heart rate–blood pressure product (RPP) (y=0.31+6.56E^-5 x, P<0.010), and RPP was in resting MBF observed in all institutions was well explained by the age-dependent RPP. No significant difference was observed in resting MBF among the institutions. Except in one institution, no significant difference was seen in dipyridamole MBF or myocardial flow reserve. No significant difference was found among the myocardial segments. Regional variation was reasonably small in five institutions, but was not acceptable in two institutions, which was attributed to the scanner performance. These observations suggest that the ¹⁵O-water PET technique is useful for a multicentre clinical study if the PET scanner can provide time-activity data with good count statistics. Received 25 April and in revised form 30 August 1999     

The reproducibility of independently measuring human regional hepatic arterial,portal and total hepatic blood flow using [15O]water and positron emission tomography

The reproducibility of repeated human regional hepatic blood flow quantification using [15O]water and positron emission tomography (PET) was evaluated as a method of monitoring the effect of drug administration on hepatic blood flow. Nineteen patients underwent two measurements of hepatic blood flow by PET. Fifteen minutes after the first dynamic study using [15O]water, a second dynamic study was performed, and hepatic blood flow was calculated. The correlation between the first and second dynamic study of arterial blood flow was highly significant (P=6.31 x 10(-10), r=0.946). The regression line was y=1.08x. The mean error between studies was 0.158. The correlation between the first and second dynamic study of portal blood flow also was significant (P=1.29 x 10(-7), r=0.897). The regression line was y=1.03x. The mean error between the studies was 0.164. The correlation between total hepatic blood flow in the first and second dynamic study, too, was significant (P=2.68 x 10(-7), r=0.888). The regression line was defined by y=1.06x. The mean error between studies was 0.140. Hepatic blood flow has increased if the second measurement of hepatic arterial, portal, and total blood flow is more than 115%, 111% and 114% of baseline, and has decreased if the second measurement is less than 101%, 95% and 98% of the first measurement.     

Quantification of subendocardial and subepicardial blood flow using 15O-labeled water and PET: experimental validation.

The purpose of this study was to assess the feasibility and accuracy of quantifying subendocardial and subepicardial myocardial blood flow (MBF) and the relative coronary flow reserves (CFR) using (15)O-labeled water (H(2)(15)O) and 3-dimensional-only PET. METHODS: Eight pigs were scanned with H(2)(15)O and (15)O-labeled carbon monoxide (C(15)O) after partially occluding the circumflex (n = 3) or the left anterior descending (n = 5) coronary artery, both at rest and during hyperemia induced by intravenous dipyridamole. Radioactive microspheres were injected during each of the H(2)(15)O scans. RESULTS: In a total of 256 paired measurements of MBF, ranging from 0.30 to 4.46 mL.g(-1).min(-1), microsphere and PET MBF were fairly well correlated. The mean difference between the 2 methods was -0.01 +/- 0.52 mL.g(-1).min(-1) with 95% of the differences lying between the limits of agreement of -1.02 and 1.01 mL.g(-1).min(-1). CFR was significantly reduced (P < 0.05) in the ischemic subendocardium (PET = 1.12 +/- 0.45; microspheres = 1.09 +/- 0.50; P = 0.86) and subepicardium (PET = 1.2 +/- 0.35; microspheres = 1.32 +/- 0.5; P = 0.39) in comparison with remote subendocardium (PET = 1.7 +/- 0.62; microspheres = 1.64 +/- 0.61; P = 0.68) and subepicardium (PET = 1.79 +/- 0.73; microspheres = 2.19 +/- 0.86; P = 0.06). CONCLUSION: Dynamic measurements using H(2)(15)O and a 3-dimensional-only PET tomograph allow regional estimates of the transmural distribution of MBF over a wide flow range, although transmural flow differences were underestimated because of the partial-volume effect. PET subendocardial and subepicardial CFR were in good agreement with the microsphere values.     

Threshold modification for tumour imaging in non-small-cell lung cancer using positron emission tomography

AIM: Positron emission tomography (PET) has been used increasingly in the staging and radiotherapy treatment planning of non-small-cell lung cancer (NSCLC). This study investigates the factors that affect the resultant size of a given image on PET. METHODS: PET was used to assess the geometric characteristics of a series of radioisotope-filled, stationary spheres of known volume, surrounded by positron-emitting radioactive tracer of variable activity. The resultant PET-derived spherical volumes were then referenced to the known spherical volumes in order to illustrate quantitatively the potential influence of image threshold, tumour size and background concentration. This influence was further illustrated by clinical examples. RESULTS: Considering the diameter of the spheres used in this study (10-48 mm), higher image thresholds were required for accurate rendering of the smallest spherical volumes. This inverse relationship was most consistently illustrated at the lowest background intensity ratios. CONCLUSION: PET-derived volumes of NSCLC must be interpreted with caution. The data presented in this study may be used to guide the selection of appropriate image thresholds for potential clinical application.     

18F-fluorodeoxyglucose positron emission tomography in small-cell lung cancer

Positron emission tomography (PET) imaging is not used routinely in small-cell lung cancer (SCLC) but has been proven useful in non-small-cell lung cancer. The performance of (18)F-fluorodeoxyglucose (FDG)-PET in patients with SCLC was evaluated in this study. Fifteen patients with proven SCLC were evaluated (8 men and 7 women; mean age, 68 years; range, 50-81 years). Among the 15 patients with SCLC, 3 were newly diagnosed and 12 had received chemotherapy or radiation therapy before PET. Five patients underwent surgery (3 newly diagnosed and 2 after therapy) after PET scan, and 14 received chemotherapy, radiation therapy, or both. The patient who was not treated with chemotherapy or radiation therapy underwent surgery only. All patients had computed tomographic (CT) scans before PET and had clinical follow-up for at least 2 months after PET. The patients received 3.4 to 4.15 mCi of (18)F-FDG intravenously after fasting for at least 4 hours. Whole-body PET scans were acquired approximately 50 min after injection by using an ADAC Laboratories C-PET plus scanner. Among the 12 patients treated before PET, 2 were found with solitary pulmonary nodules positive on PET. Subsequent surgical resection and pathology showed 1 true positive and 1 false positive (postradiation pneumonitis). Six of these 12 patients had extrapulmonary metastases or large intense hilar or pulmonary uptake on PET, or both. Four of these 12 had no evidence of abnormal FDG uptake and were considered true negatives. The 3 patients with newly diagnosed SCLC were all true positives on PET, confirmed by surgery. One false negative on CT scan was attributed to postradiation fibrosis. These preliminary data suggest that whole-body FDG-PET can provide the basis for determining which treatment modality would be the most appropriate during the early stages of SCLC, when surgery is still an option, and it is a useful tool to assess the effect of treatment in patients with this disease. A more accurate assessment of SCLC will be possible if FDG-PET scan is combined with CT during the early evaluation of these patients.     

Quantification in positron emission tomography for research in pharmacology and drug development

Positron emission tomography (PET) is a quantitative in vivo tracer technique, enabling images of the distribution of biochemical, physiological and pharmacological functions in living tissue, at a resolution of a few millimetres. Applications include the imaging of blood flow rate, metabolic rate and neuroreceptor distribution and function. These applications are playing an increasing role in drug development. This brief article seeks to emphasize how these applications of PET need to rest on a solid quantitative foundation.     

Quantification method in [18F]fluorodeoxyglucose brain positron emission tomography using independent component analysis

OBJECTIVE: To extract accurate image-derived input functions from dynamic brain positron emission tomography images (DBPIs) using independent component analysis (ICA). METHODS: A modified linear model with haematocrit correction was used to improve the accuracy of input functions estimated by independent component analysis and to reduce the error of quantitative analysis. Two types of material were examined: (1) a simulated dynamic phantom with a three-compartment, four-parameter model; (2) clinical 2-h DBPIs with a standard plasma sampling procedure. The input function was extracted from DBPIs using independent component analysis. The modified linear model with haematocrit correction was used to obtain the independent component analysis-estimated input function (Iica). For comparison, the input function derived from the last three blood samples (Iest) was used. The image-derived input functions (Iica and Iest) were compared with the input function from blood sampling (Itp). The mean percentage error of the metabolic rate of [F]-2-fluoro-2-deoxy-D-glucose (MRFDG) was calculated for both Iica and Iest against that of Itp. RESULTS: In simulated studies, the mean percentage errors of MRFDG between true simulated and estimated values of Iest and Iica were 8.2% and 4.2%, respectively. In clinical studies, six clinical cases were collected. The mean percentage errors and standard deviations of MRFDG with Iest and Iica were 12.6+/-7.5% and 7.7+/-3.3%, respectively. CONCLUSIONS: We have proposed a technique for estimating image-derived input functions using independent component analysis without blood sampling. The results of our method were highly correlated with those from standard blood sampling, and more accurate than those of other methods proposed previously.     

A new subtraction method for obtaining myocardial perfusion images with oxygen-15 water and positron emission tomography

The myocardial positron emission tomograms which are obtained during the perfusion phase following bolus injection of O-15 water (H2(15)O) intravenously require subtraction of the blood pool activity overlaid upon the myocardium. Subtraction has been carried out using the blood pool images obtained in the same position following single inhalation of O-15 labeled carbon monoxide gas (C15O). However, because a difference in activity exists between the left ventricular (LV) cavity and the right ventricular (RV) cavity, simple subtraction of the LV cavity activity using C15O blood pool images induced significant over-subtraction in the right-side heart including the interventricular septum and RV wall. We developed a new method, "two-component subtraction," in which the C15O blood pool images were decomposed into the right-side and left-side components using the early phase images of the H2(15)O dynamics under the assumption that the whole activity of that phase was distributed in the right-side heart homogeneously. Thus we subtracted the blood pool spillover from RV and LV separately. This method provided myocardial perfusion images of high quality which were well correlated with N-13 ammonia images.     

Reproducibility of tumor perfusion measurements using 15O-labeled water and PET

PET and 15O-labeled water (H215O) can be used to noninvasively monitor tumor perfusion. This allows evaluation of the direct target of antiangiogenic drugs, that is, tumor vasculature. Because these drugs often result in consolidation rather than regression of the tumor mass, a change in perfusion might be a more sensitive way to evaluate response than are indirect size measures on a CT scan. However, to use the technique for serial imaging of individual patients, good reproducibility is essential. The purpose of the present study was to evaluate the reproducibility of quantitative H215O measurements. METHODS: Nine patients with non-small-cell lung cancer (NSCLC) were scanned twice within 7 d and before any therapy. All H215O scans were followed by an 18F-fluorothymidine scan to allow for adequate volume-of-interest (VOI) definition. VOIs were defined using a 3-dimensional threshold technique. Tumor perfusion and the volume of distribution (VT) were obtained using a 1-tissue-compartment model including an arterial blood volume component and an image-derived input function. The level of agreement between test and retest values was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman analyses. Possible dependency on absolute values and lesion size was assessed by linear regression. RESULTS: All primary tumors and more than 90% of clinically suspected locoregional metastases could be delineated. In total, 14 lesions in 9 patients were analyzed. Tumor perfusion showed excellent reproducibility, with an ICC of 0.95 and SD of 9%. The VT was only moderately reproducible, with an ICC of 0.52 and SD of 16%. No dependency was found on absolute values of perfusion (P = 0.14) and VT (P = 0.15). In addition, tumor volume did not influence the reproducibility of perfusion (P = 0.46) and VT (P = 0.25). CONCLUSION: Quantitative measurements of tumor perfusion using H215O and PET are reproducible in NSCLC. When patients are repeatedly being scanned during therapy, changes of more than 18% in tumor perfusion and 32% in VT (>1.96 x SD) are likely to represent treatment effects.