Circulating KL-6 levels in patients with drug induced pneumonitis.

BACKGROUND: The circulating level of KL-6/MUC1 is a sensitive marker for various interstitial lung diseases. Previous case reports have suggested that KL-6 may also be increased in some patients with drug induced pneumonitis. A study was undertaken to determine whether serum KL-6 could be a marker for particular types of drug induced pneumonitis. METHODS: The findings of high resolution computed tomographic (HRCT) chest scans of 30 patients with drug induced pneumonitis were reviewed separately by two independent observers. The pneumonitis was classified into four predominant patterns: widespread bilateral consolidation (diffuse alveolar damage, DAD; n=7), fibrosis with or without consolidation (chronic interstitial pneumonia, CIP; n=11), consolidation without fibrosis (bronchiolitis obliterans organising pneumonia or eosinophilic pneumonia, BOOP/EP; n=8), and diffuse ground glass opacities without fibrosis (hypersensitivity pneumonitis, HP; n=4). Serum KL-6 levels were measured by a sandwich enzyme linked immunosorbent assay. RESULTS: The overall sensitivity of serum KL-6 in detecting drug induced lung disease was 53.3%, which was lower than its sensitivity in detecting other interstitial lung diseases. However, the KL-6 level was increased in most patients with a DAD or CIP pattern (16/18; 88.9%) and was closely correlated with their clinical course. In contrast, serum KL-6 levels were within the normal range in all patients with a BOOP/EP or HP pattern. CONCLUSIONS: Particular patterns detected by HRCT scanning, such as DAD and CIP but not the BOOP/EP or HP patterns, are associated with increased circulating KL-6 levels in drug induced pneumonitis. Serum KL-6 levels may reflect the clinical activity of the particular disorders.

Reproducibility of the brain perfusion index for measuring cerebral blood flow using technetium-99m compounds.

We previously developed an alternative method for estimating the brain perfusion index (BPI) using technetium-99m compounds and spectral analysis (SA) for quantification of cerebral blood flow (CBF). In this study, we investigated the reproducibility of the BPI values obtained by SA (BPIS) using a double injection of technetium-99m ethyl cysteinate dimer without any intervention, and compared it with that of the BPI values obtained by graphical analysis (BPIG). The BPIS values in the first (x) and second sessions (y) correlated closely (y=0.921x+0.036; r=0.962; n=64; s.e.e.=0.058 min-1). Although the BPIG values in the first (x) and second sessions (y) also correlated (y=0.942x+0.040; r=0.916; n=64; s.e.e.=0.061 min-1), the correlation coefficient for BPIS was significantly higher than that for BPIG. The reproducibility was dependent on the injection dose ratio of the second session to the first (R). The difference in BPI between the first and second sessions tended to be smaller when 1.5

An anisotropic diffusion method for denoising dynamic susceptibility contrast-enhanced magnetic resonance images.

The purpose of this study was to present an application of a novel denoising technique for improving the accuracy of cerebral blood flow (CBF) images generated from dynamic susceptibility contrast-enhanced magnetic resonance imaging (DSC-MRI). The method presented in this study was based on anisotropic diffusion (AD). The usefulness of this method was firstly investigated using computer simulations. We applied this method to patient data acquired using a 1.5 T MR system. After a bolus injection of Gd-DTPA, we obtained 40-50 dynamic images with a 1.32-2.08 s time resolution in 4-6 slices. The dynamic images were processed using the AD method, and then the CBF images were generated using pixel-by-pixel deconvolution analysis. For comparison, the CBF images were also generated with or without processing the dynamic images using a median or Gaussian filter. In simulation studies, the standard deviation of the CBF values obtained after processing by the AD method was smaller than that of the CBF values obtained without any processing, while the mean value agreed well with the true CBF value. Although the median and Gaussian filters also reduced image noise, the mean CBF values were considerably underestimated compared with the true values. Clinical studies also suggested that the AD method was capable of reducing the image noise while preserving the quantitative accuracy of CBF images. In conclusion, the AD method appears useful for denoising DSC-MRI, which will make the CBF images generated from DSC-MRI more reliable.

Fractal analysis of cerebral blood flow distribution in Alzheimer's disease.

UNLABELLED: This study describes a method for quantifying cerebral blood flow (CBF) distribution in Alzheimer's disease (AD) from SPECT images obtained with (99m)Tc-hexamethylpropyleneamine oxime (HMPAO) by 3-dimensional fractal analysis (3D-FA). METHODS: HMPAO SPECT was performed on 68 patients with probable AD and 14 healthy control subjects. We delineated the CBF images using 4 cutoff levels (35%, 40%, 45%, and 50% of the maximal voxel radioactivity) and measured the total number of voxels in the areas surrounded by the contours obtained with each cutoff level. We calculated fractal dimensions from the relationship between the total number of voxels and the cutoff levels transformed into natural logarithms. RESULTS: The fractal dimensions (mean +/- SD) for patients with probable AD and healthy subjects were 0.74 +/- 0.33 and 0.52 +/- 0.09, respectively. A significant difference in the fractal dimension was found between groups (P = 0.001). Statistically significant correlations were obtained between the fractal dimension and the Mini-Mental State Examination score (r = -0.598; P < 0.0001) and between the fractal dimension and the AD Assessment Scale (r = 0.670; P < 0.0001). The fractal dimensions for subjects with clinical dementia rates (CDRs) of 0, 1, 2, and 3 were 0.52 +/- 0.09, 0.63 +/- 0.21, 0.77 +/- 0.23 (P < 0.05 vs. the group with a CDR of 1), and 1.43 +/- 0.49 (P < 0.0001 vs. the group with a CDR of 2), respectively. CONCLUSION: Quantification of CBF distribution on SPECT images in AD was possible using 3D-FA. The fractal dimension was well correlated with the cognitive impairment, as assessed in neuropsychologic tests. 3D-FA may be a useful method for objectively evaluating the progression of AD.

Hyperactivity of 99mTc-HMPAO within 6 hours in patients with acute ischemic stroke.

UNLABELLED: Intraarterial thrombolytic therapy has been used recently for treatment of acute ischemic stroke within 6 h after onset. Although hypoactivity of 99mTc-hexamethylpropyleneamine oxime (HMPAO) in stroke has been well documented, hyperactivity of HMPAO has not been evaluated in sufficient detail. The purpose of this study was to evaluate the incidence and clinical importance of hyperactivity of HMPAO in management of patients with acute ischemic stroke. METHODS: We retrospectively investigated HMPAO SPECT in 90 patients with acute ischemic stroke within 6 h after onset. The lesion-to-contralateral radioactivity ratios (L/Cs) were calculated on the SPECT images before treatment and were compared with the imaging results of CT or MRI (or both). RESULTS: Hyperactivity of HMPAO, accompanied by surrounding hypoactivity, was observed in 6 of 90 patients (7%) within 6 h after onset. The L/Cs ranged from 1.17 to 2.95. Two patients showed hyperactivity in the cortex and the other 4 patients showed hyperactivity in the basal ganglia. Angiography confirmed spontaneous recanalization of occluded vessels in accordance with the area of hyperactivity. In both patients with cortical hyperactivity, cerebral infarctions were revealed on follow-up CT; in 1 patient, hemorrhagic transformation developed after intraarterial thrombolytic therapy. In 3 of the 4 patients with hyperactivity in the basal ganglia, follow-up CT showed no infarction in the surrounding hypoperfused cortex (selective intraarterial thrombolytic therapy was performed on 2 patients), although various degrees of infarction were observed in the basal ganglia. Obvious infarctions developed in the basal ganglia and the cortex of the other patient. CONCLUSION: Hyperactivity of HMPAO could be seen in the basal ganglia and the cortex within 6 h after onset, reflecting spontaneous recanalization. The areas of hyperactivity may develop infarctions, whereas the accompanying areas of hypoactivity could be rescued by selective intraarterial thrombolytic therapy.

Twenty-four-hour Tl-201 delayed scan underestimates myocardial viability in patients with acute myocardial infarction after percutaneous transluminal coronary angioplasty.

BACKGROUND: Myocardial viability in area at risk of acute myocardial infarction (AMI) after reperfusion therapy may be underestimated by the 24-hour images due to reverse redistribution (r-RD). METHODS: Subjects were 37 AMI patients in whom Tc-99m pyrophosphate (PYP)/Tl-201 dual-isotope SPECT was positive. The 24-hour delayed scan was performed with only a Tl window. One month later, follow up rest Tl SPECT was performed to evaluate myocardial viability. In early (at PYP/Tl-201 dual-isotope SPECT), 24-hour, and one month follow up Tl studies, Tl uptake in the area of AMI was scored into four grades: 3 as normal to 0 as severely reduced. The scores were evaluated. RESULTS: Among the 37 AMI lesions, there were 16 r-RD, 3 RD, 16 fixed defect (FD) and 2 normal (positive PYP and normal Tl). Mean Tl scores were early; 1.4 +/- 1.1, 24-hr; 0.9 +/- 0.9 and one month; 1.3 +/- 1.1. The 24-hour Tl score was lower than the early and one month Tl scores (p < 0.01). CONCLUSION: Reverse redistribution is frequently observed in an area at risk where PYP SPECT was positive. Nuclear medicine physicians should be aware of the existence of frequent r-RD in Tl scan to avoid the underestimation of myocardial viability in the acute phase after PTCA.

Determination of arterial input function using fuzzy clustering for quantification of cerebral blood flow with dynamic susceptibility contrast-enhanced MR imaging.

An accurate determination of the arterial input function (AIF) is necessary for quantification of cerebral blood flow (CBF) using dynamic susceptibility contrast-enhanced magnetic resonance imaging. In this study, we developed a method for obtaining the AIF automatically using fuzzy c-means (FCM) clustering. The validity of this approach was investigated with computer simulations. We found that this method can automatically extract the AIF, even under very noisy conditions, e.g., when the signal-to-noise ratio is 2. The simulation results also indicated that when using a manual drawing of a region of interest (ROI) (manual ROI method), the contamination of surrounding pixels (background) into ROI caused considerable overestimation of CBF. We applied this method to six subjects and compared it with the manual ROI method. The CBF values, calculated using the AIF obtained using the manual ROI method [CBF(manual)], were significantly higher than those obtained with FCM clustering [CBF(fuzzy)]. This may have been due to the contamination of non-arterial pixels into the manually drawn ROI, as suggested by simulation results. The ratio of CBF(manual) to CBF(fuzzy) ranged from 0.99-1.83 [1.31 +/- 0.26 (mean +/- SD)]. In conclusion, our FCM clustering method appears promising for determination of AIF because it allows automatic, rapid and accurate extraction of arterial pixels. J. Magn. Reson. Imaging 2001;13:797-806.

Measurement of cerebral hemodynamics with perfusion-weighted MR imaging: comparison with pre- and post-acetazolamide 133Xe-SPECT in occlusive carotid disease.

BACKGROUND AND PURPOSE: We generated regional cerebral blood volume (rCBV) and regional cerebral blood flow (rCBF) studies from dynamic susceptibility contrast-enhanced MR images after an intravenous bolus injection of contrast agent (perfusion-weighted imaging [PWI]) by applying indicator dilution theory. We used a multishot echo-planar imaging (EPI) sequence to obtain adequate arterial input function (AIF). Our purpose was to compare the cerebral hemodynamics measured by PWI with the rCBF values and cerebral perfusion reserve obtained by xenon-133 single-photon emission CT (133Xe-SPECT). METHODS: Eight patients with chronic internal carotid artery occlusion or stenosis were examined. PWI data were acquired using a multishot EPI sequence, and the AIF was determined automatically. Our procedure was based on indicator dilution theory and deconvolution analysis. To eliminate the effect of superficial vessels, the automatic threshold selection method was used. RESULTS: AIF was adequate to generate rCBF and rCBV images. The rCBF and rCBV images by PWI were superior to 133Xe-SPECT scans in spatial resolution, and the rCBF values obtained by PWI correlated well with those obtained by 133Xe-SPECT. The regions with severely decreased perfusion reserve, which were determined by pre- and post-acetazolamide 133Xe-SPECT, showed significantly lower rCBF and higher rCBV by PWI than did regions with normal and moderately decreased perfusion reserve. CONCLUSION: The rCBF and rCBV images generated by our procedure using PWI data appear to provide important clinical information for evaluating the degree of cerebral perfusion reserve impairment in patients with chronic ischemia.

Late-phase enhancement of the upstream portion of pancreatic adenocarcinoma on dual-phase helical CT.

BACKGROUND: Late-phase enhancement of pancreatic parenchyma upstream (tail side) of pancreatic adenocarcinoma is found frequently on dual-phase helical computed tomography (CT). We measured the frequency of late-phase enhancement of the upstream portion of pancreatic adenocarcinoma and normal pancreatic parenchyma using dual-phase helical CT. METHODS: Twenty-one patients with pancreatic adenocarcinoma and nontumorous pancreas upstream of tumors were compared with 100 control patients without pancreatic disease. Early and late scans started at 25 and 75 s, respectively, after intravenous injection of contrast material. The attenuation values of normal and nontumorous pancreas upstream of tumors were assessed in three phases: precontrast, early, and late enhanced. Enhancement ratio (ER) was calculated as ER = (late phase - precontrast)/(early phase - precontrast). RESULTS: Late-phase enhancements (ER > 1.0) were seen in 86% of upstream pancreas and 10% of normal pancreas. The mean ER of upstream pancreas was significantly higher than that of normal pancreas (p < 0.01). CONCLUSION: Late-phase enhancement of the pancreas upstream of the tumor is frequently observed in patients with pancreatic adenocarcinoma. Late-phase enhancement and histology showed a correlation for chronic obstructing pancreatitis in five patients.

Two cases of pediatric bone disease (eosinophilic granuloma and Brodie's abscess) showing similar scintigraphic and radiographic findings.

Two 9-year-old patients with femoral bone lesions were referred to the authors' institution within a few days of each other. Both showed similar radiographic, magnetic resonance imaging, and scintigraphic findings. The radiographs showed osteolytic lesions in the right femoral diaphyses, and gadolinium-DTPA-enhanced magnetic resonance imaging revealed inhomogeneous enhancement. Tc-99m HMDP showed marked linear accumulation with relatively low central uptake in the right femoral shafts, and TI-201 scintigraphy showed considerable uptake corresponding to the area seen with Tc-99m HMDP. Histologic analysis confirmed eosinophilic granuloma in the first patient and Brodie's abscess in the second. The radiographic and scintigraphic findings in Brodie's abscess may be similar to those in eosinophilic granuloma.

Tc-99m PMT hepatobiliary scintigraphy in the differential diagnosis of extrahepatic metastases and hepatocellular carcinoma.

PURPOSE: The authors evaluated the utility of hepatobiliary scintigraphy for tissue characterization of extrahepatic metastases from hepatocellular carcinoma (HCC) using Tc-99m N-pyrydoxyl-5-methyltriptophane (Tc-99m PMT). METHODS: We examined 13 patients with HCC (29 extrahepatic metastases and 3 benign bone lesions) and 5 patients with other cancers (15 extrahepatic metastases). Thirty minutes to 6 hours after intravenous administration of Tc-99m PMT, planar (all 47 lesions) and SPECT (42 lesions) images were obtained. Accumulation of Tc-99m PMT in the lesion was evaluated visually by comparing bone scintigraphy, computed tomography, magnetic resonance imaging, or all of these. RESULTS: Findings were positive in 12 of 13 patients with HCC and extrahepatic metastases (16 of 29 on planar imaging and 21 of 26 on SPECT). Findings in all three benign bone lesions and 15 metastatic lesions from non-HCC primary lesions were negative (0 of 18 on planar imaging, 0 of 16 on SPECT). There were no false-positive findings in these lesions. Lesion-by-lesion sensitivity, specificity, accuracy, and positive and negative predictive values were 55%, 100%, 72%, 100%, and 58% by planar imaging and 81%, 100%, 88%, 100%, and 76% by SPECT, respectively. CONCLUSIONS: Because of the high specificity and reasonable sensitivity, Tc-99m PMT appears to be useful for the differential diagnosis of extrahepatic metastases from HCC. SPECT improves the detectability of small or faint accumulation in metastases from HCC.

Relationship between regional severity of emphysema and coronary heart disease.

We analyzed the relationship between regional severity of emphysema, which was evaluated by three-dimensional fractal analysis (3D-FA) of Technegas SPECT images, and coronary heart disease (CHD). For 22 patients with emphysema who underwent Technegas SPECT, we followed up CHD events. The follow-up period was 5.4+/-0.5 (mean +/- SD) years. We defined the upper-lung fractal dimension (U-FD) and lower-lung fractal dimension (L-FD) obtained with 3D-FA of Technegas SPECT images as the regional severity of emphysema. FD became greater with the progression of emphysematous change. During the follow-up period, CHD events occurred in 6 (27%) of the 22 patients. The ratio of U-FD to L-FD for patients with CHD events (0.87+/-0.22) was significantly smaller than for patients without CHD events (1.52+/-0.38) (p = 0.0015). These findings suggest that severer emphysema in the lower lung indicates a higher risk of CHD than that in the upper lung.

CT-guided treatment of ultrasonically invisible hepatocellular carcinoma.

New techniques of CT-guided management were introduced to ablate ultrasonically invisible hepatocellular carcinomas. In six patients with HCC, a total of six nodules (8-30 mm in diameter) were treated under the guidance of CT. These lesions were not visualized by sonography but were visualized as Lipiodol spots on CT after chemoembolization. Tumor localization was successful in all patients without difficulty, using a thin needle or hookwire under the guidance of CT. Two patients underwent subsequent hepatic resection and/or microwave coagulation therapy (MCT) through a small incision after hookwire placement. Four patients received percutaneous MCT (n = 2) or ethanol injection (PEI) (n = 2) at the time of localization. The postoperative CT with contrast enhancement indicated that tumor ablation was complete in four of the five nodules treated with MCT or PEI. However, in one nodule (30 mm in diameter) treated with PEI, tumor ablation was not complete. There were no complications. There has been no local tumor recurrence 6-46 months after treatment in any of the patients. In conclusion, these CT-guided procedures were effective in treating ultrasonically invisible hepatocellular carcinomas that otherwise would have remained untreated.

Hyperoxia-induced diffuse alveolar damage in pigs: correlation between thin-section CT and histopathologic findings.

PURPOSE: To determine whether lung abnormalities at thin-section computed tomography (CT) in experimental hyperoxic lung injury correlate with the pathologic phases of diffuse alveolar damage (DAD). MATERIALS AND METHODS: Eighteen juvenile pigs were exposed to more than 80% oxygen-for 24, 48, 72, 96, or 120 hours-or room air in sealed cages. Their removed lungs were inflated with air infused through the trachea and examined with thin-section CT. Two independent observers, without knowledge of the exposure times, compared 63 areas selected on the CT scans with the corresponding pathologic and histologic findings, which were evaluated independently by two pathologists. RESULTS: CT findings correlated well with histologic findings (rho = 0.86, P <.001), which corresponded to the pathologic phases of DAD. All areas of normal CT attenuation, eight of nine spared regions within areas of opacity, and two of 15 areas of ground-glass opacity corresponded to the early exudative pathologic phase of DAD. All areas that showed traction bronchiolectasis at CT corresponded to the early proliferative pathologic phase. There was good observer agreement regarding the interpretation of CT findings (kappa statistic, >0.60) and histologic results (>/=0.70). CONCLUSION: Thin-section CT findings reflect the pathologic phases of DAD, although the early exudative phase cannot be specifically depicted by thin-section CT. Traction bronchiolectasis on a CT scan suggests progression to the proliferative phase.

Quantitative analysis of technegas SPECT: evaluation of regional severity of emphysema.

UNLABELLED: The purpose of this study was to quantify the regional severity of emphysema by 3-dimensional fractal analysis of technegas (99mTc-carbon particle radioaerosol) SPECT images. METHODS: Technegas SPECT was performed on 22 patients with emphysema. The lungs were delineated using 4 cutoff levels (15%, 20%, 25%, and 30% of the maximal pixel radioactivity), and the total number of pixels was measured in the areas surrounded by the contours obtained with each cutoff level. We calculated fractal dimensions from the relationship between the total number of pixels and cutoff levels transformed into logarithms. Fractal dimension for total or regional lung was defined as the severity of emphysema. RESULTS: Total lung fractal dimension (T-FD), upper lung fractal dimension (U-FD), and lower lung fractal dimension (L-FD) for patients with emphysema were 1.84 +/- 0.46 (mean +/-SD), 2.22 +/- 0.61, and 1.77 +/- 0.49, respectively. U-FD was significantly greater than was L-FD. Patients with the ratio of U-FD to L-FD of <1.16 had a significantly greater percentage forced vital capacity (FVC) than did patients with the ratio of >1.16. Patients with an L-FD of <1.8 had a significantly greater forced expiratory volume in 1 s (FEV1)/FVC than did patients with that of >1.8. No significant difference was found between patient groups stratified by U-FD. CONCLUSION: The regional severity of emphysema was well shown by these fractal dimensions.

Development of a digital image database for chest radiographs with and without a lung nodule: receiver operating characteristic analysis of radiologists' detection of pulmonary nodules.

OBJECTIVE: We developed a digital image database (www.macnet.or.jp/jsrt2/cdrom_nodules.html ) of 247 chest radiographs with and without a lung nodule. The aim of this study was to investigate the characteristics of image databases for potential use in various digital image research projects. Radiologists' detection of solitary pulmonary nodules included in the database was evaluated using a receiver operating characteristic (ROC) analysis. MATERIALS AND METHODS: One hundred and fifty-four conventional chest radiographs with a lung nodule and 93 radiographs without a nodule were selected from 14 medical centers and were digitized by a laser digitizer with a 2048 x 2048 matrix size (0.175-mm pixels) and a 12-bit gray scale. Lung nodule images were classified into five groups according to the degrees of subtlety shown. The observations of 20 participating radiologists were subjected to ROC analysis for detecting solitary pulmonary nodules. Experimental results (areas under the curve, Az) obtained from observer studies were used for characterization of five groups of lung nodules with different degrees of subtlety. RESULTS: ROC analysis showed that the database included a wide range of various nodules yielding Az values from 0.574 to 0.991 for the five categories of cases for different degrees of subtlety. CONCLUSION: This database can be useful for many purposes, including research, education, quality assurance, and other demonstrations.

Two- and three-dimensional CT ventriculography: a new application of helical CT.

OBJECTIVE: We propose a new application of helical CT, CT ventriculography, which can produce two-dimensional (2D) and three-dimensional (3D) images of different cardiac phases (plus animation). We sought to determine the accuracy of CT ventriculography for assessing left ventricular volumes. MATERIALS AND METHODS: With a single breath-hold, the patient's entire heart was scanned with an ECG-gating technique (3-mm-thick collimation, 2 mm per rotation table speed, 0.8 sec per rotation, and 50 rotations through 10 cm in total). Using a 0.2-mm (0.08-sec) interval (10 slices per rotation) overlapping reconstruction, about 500 axial slices were obtained and reordered to separate different cardiac cycles. Then, 2D cardiac axes and 3D images were reconstructed and animated movies of the 2D and 3D images were produced. In 21 patients, the left ventricular end-diastolic volume, end-systolic volume, and ejection fraction were assessed and compared with left ventriculography. Correlations and agreements between CT and left ventriculography were determined. RESULTS: Close correlations between CT and left ventriculography were obtained (r = 0.95, 0.98, and 0.91, for end-diastolic volume, end-systolic volume, and left ventricular ejection fraction, respectively; p < 0.0001 for all values). The limits of agreement between CT and left ventriculography were 44.3 to -44.5 ml for end-diastolic volume, 19.8 to -29.0 ml for end-systolic volume, and 19.7% to -9.5% for left ventricular ejection fraction. CONCLUSION: This cardiac application of helical CT provides a clear morphology along the cardiac axes and 3D images and an assessment of left ventricular volumes (end-diastolic volume, end-systolic volume, and left ventricular ejection fraction).

Double-injection method for sequentially measuring cerebral blood flow with N-isopropyl-(123I)p-iodoamphetamine.

We investigated the accuracy of a double-injection method for sequentially measuring cerebral blood flow (CBF) with N-isopropyl-(123I)p-iodoamphetamine (IMP) in simulation studies based on patient data and in clinical studies. The unidirectional clearance of IMP from the blood to the brain (K1; nearly equal to CBF) in the first and second sessions was calculated by means of a microsphere model. The K1 values in the first session (K1I) were calculated from Cb(5)/Int_CaI, where Cb(5) and Int_CaI are values for brain radioactivity 5 min after the first injection and for arterial blood radioactivity obtained by 5-min continuous sampling. The K1 values in the second session (K1II) were calculated by means of the following four methods. Method 1: [Cb(tz + 5) - Cb(tz)]/[Int_CaII - Ca(tz) x 5], where Cb(tz+5) and Cb(tz) are the brain radioactivity levels 5 min after the second injection and at the time the second session was started (tz), respectively. Int_CaII and Ca(tz) are the arterial blood radioactivity levels obtained by 5-min continuous sampling after the second injection and at tz, respectively. Method 2: [Cb(tz + 5) - Cb(tz)]/[Int_CaI x R], where R is the injection dose ratio. Method 3: [Cb(tz + 5) - Cb(tz) x exp(- K1I x 5/lambda)]/Int_CaII, where lambda is the population averaged partition coefficient. Method 4: same as Method 3 except that K1I was replaced by K1II obtained by means of Method 2. Theoretically, Method 4 appeared to be the best of the four methods. The change in K1 during the second session obtained by Method 1 or 2 largely depended on R and tz, whereas Method 3 or 4 yielded a more reliable estimate than Method 1 or 2, without largely depending on R and tz. Since Method 2 was somewhat superior to other methods in terms of noninvasiveness and simplicity, it also had the potential for routine clinical use. The reproducibility of two sequential measurements of K1 was investigated with clinical data obtained without any intervention. The response of CBF to acetazolamide challenge was also assessed by the above four methods. The knowledge gained by this study may assist in selecting a method for sequentially measuring CBF with a double injection of IMP.