153Sm EDTMP for bone marrow ablation prior to stem cell transplantation for haematological malignancies.

This study examined the safety of adding 153Sm lexidronam to standard conditioning regimens in patients undergoing stem cell transplantation for marrow based haematological malignancies in whom total-body irradiation as part of conditioning was desirable but not feasible. Ten such patients were enrolled, seven with multiple myeloma. An escalating regimen of 19-45 GBq of 153Sm lexidronam was added 12-14 days prior to the standard transplantation regimen. Evaluation parameters included time to engraftment, status at day +100 by International Bone Marrow Transplant Registry (IBMTR) criteria and toxicity during this period. Absorbed marrow radiation doses were estimated using the MIRDOSE 3 program. No adverse events were attributable to 153Sm lexidronam. Of the seven patients with multiple myeloma, four achieved complete response, two partial response, and another had stable monoclonal band at 3 months post-transplant. One patient with Refractory Anaemic with Excess Blasts in transformation (RAEBt) died of a presumed fungal infection, whilst another with acute myeloid leukaemia relapsed, dying at day +153. A patient with low-grade lymphoma showed no evidence of residual disease at day +100. The total marrow absorbed dose was estimated to be 0.7+/-0.2 mGy x MBq(-1). Regional uptake was markedly non-uniform with poor uptake in the appendicular skeleton. Dose-limiting toxicity was not attained. At the activities used 153Sm lexidronam was not associated with additional toxicity in this population. Adequate absorbed radiation dose to appendicular marrow is unlikely to be deliverable by this approach alone.

Determination of right ventricular ejection fraction from reprojected gated blood pool SPET: comparison with first-pass ventriculography.

Gated blood pool (GBP) studies are widely available and relatively inexpensive. We have previously published a simple and convenient method for measuring left ventricle ejection fraction (EF) with increased accuracy from single-photon emission tomography (SPET) GBP scans. This paper describes an extension of this method by which right ventricular EF may also be measured. Gated SPET images of the blood pool are acquired and re-oriented in short-axis slices. Counts from the left ventricle are excluded from the short-axis slices, which are then reprojected to give horizontal long-axis images. Time-activity curves are generated from each pixel around the right ventricle, and an image is created with non-ventricular pixels "greyed out". This image is used as a guide in drawing regions of interest around the right ventricle on the end-diastolic and end-systolic long-axis images. In 28 patients, first-pass ventriculography studies were acquired followed by SPET GBP scans. The first-pass images were analysed a total of four times by two observers and the SPET images were analysed three times each by two observers. The agreement between the two techniques was good, with a correlation coefficient of 0.72 and a mean absolute difference between first-pass and reprojected SPET EFs of 4.8 EF units. Only four of the 28 patients had a difference of greater than 8 EF units. Variability was also excellent for SPET right ventricular EF values. Intra-observer variability was significantly lower for SPET than for first-pass EFs: standard error of the estimate (SEE)=5.1 and 7.3 EF units, respectively (P<0.05). Inter-observer variability was comparable in the two techniques (SEE=5.2 and 6.9 EF units for SPET and first-pass ventriculography, respectively).

Quantitative assessment of myositis in thigh muscles using magnetic resonance imaging.

Magnetic resonance (MR) imaging has been suggested as a technique for diagnosing and monitoring myositis, an inflammatory muscle disease. To date, the assessment of disease from MR images has been by subjective visual analysis. We describe here an objective, semi-automatic, computer-based method for quantifying the degree of disease from MR images, without the need for a radiologist or physician trained in the visual assessment of the MR images. The method is based on analysis of the histogram of intensity values produced from the MR images. The analysis yielded measures of the intensity and extent of disease. These two measures were combined to produce a calculated myositis index (CMI) which described the degree of disease evident from the MR images. This index was compared with a clinical assessment of the patient's condition, based on currently accepted, invasive and non-invasive, non-imaging criteria. Receiver operating characteristic (ROC) curve analysis showed that calculated myositis index agreed at least as well with clinical assessment as did visual analysis (receiver operating characteristic area = 0.93 and 0.94, p = not significant (NS), respectively, for separating remission from disease). Even using only two central MR slices for each patient, the receiver operating characteristic area for calculated myositis index was 0.92, implying that very short acquisition times are possible. We conclude that quantitative histogram analysis of MR images can be successfully performed with minimal operator input and using few MR slices. Agreement with more invasive clinical assessment is good and the method has the advantages of repeatability, objectivity, and decreased scan and analysis time.

13N-ammonia myocardial blood flow and uptake: relation to functional outcome of asynergic regions after revascularization.

OBJECTIVES: In this study we determined whether 13N-ammonia uptake measured late after injection provides additional insight into myocardial viability beyond its value as a myocardial blood flow tracer. BACKGROUND: Myocardial accumulation of 13N-ammonia is dependent on both regional blood flow and metabolic trapping. METHODS: Twenty-six patients with chronic coronary artery disease and left ventricular dysfunction underwent prerevascularization 13N-ammonia and 18F-deoxyglucose (FDG) positron emission tomography, and thallium single-photon emission computed tomography. Pre- and postrevascularization wall-motion abnormalities were assessed using gated cardiac magnetic resonance imaging or gated radionuclide angiography. RESULTS: Wall motion improved in 61 of 107 (57%) initially asynergic regions and remained abnormal in 46 after revascularization. Mean absolute myocardial blood flow was significantly higher in regions that improved compared to regions that did not improve after revascularization (0.63+/-0.27 vs. 0.52+/-0.25 ml/min/g, p < 0.04). Similarly, the magnitude of late 13N-ammonia uptake and FDG uptake was significantly higher in regions that improved (90+/-20% and 94+/-25%, respectively) compared to regions that did not improve after revascularization (67+/-24% and 71+/-25%, p < 0.001 for both, respectively). However, late 13N-ammonia uptake was a significantly better predictor of functional improvement after revascularization (area under the receiver operating characteristic [ROC] curve = 0.79) when compared to absolute blood flow (area under the ROC curve = 0.63, p < 0.05). In addition, there was a linear relationship between late 13N-ammonia uptake and FDG uptake (r = 0.68, p < 0.001) as well as thallium uptake (r = 0.76, p < 0.001) in all asynergic regions. CONCLUSIONS: These data suggest that beyond its value as a perfusion tracer, late 13N-ammonia uptake provides useful information regarding functional recovery after revascularization. The parallel relationship among 13N-ammonia, FDG, and thallium uptake supports the concept that uptake of 13N-ammonia as measured from the late images may provide important insight regarding cell membrane integrity and myocardial viability.

A pilot study: use of fludarabine for refractory dermatomyositis and polymyositis, and examination of endpoint measures.

OBJECTIVE: To study the effects of the adenine analog, fludarabine, on patients with refractory dermatomyositis and polymyositis, and to assess variables used in following myositis patients during medical intervention. METHODS: Patients whose myositis was not controlled by prednisone and at least one other immunosuppressive medication were entered into a pilot study during which they received 6 monthly cycles of intravenous fludarabine. Patients were assessed at baseline, every other month, and at month 7 for primary outcome measures of strength and function. Other measurements including peripheral blood cell subsets, muscle enzymes, and various assessments of disease activity were followed monthly during the fludarabine infusion period and for up to 6 months post therapy. RESULTS: Of 16 patients who entered the study, 4 patients were classified as improved, and 7 patients were classified as unchanged. Five patients who withdrew before month 7 were classified as treatment failures. Fludarabine caused a significant and prolonged lymphopenia without an increase in infectious complications over that seen with other immunosuppressive agents used for myositis. A sudden death of one patient at the end of the study was not thought to be drug related. Variables followed during the study emphasized the distinction between patient functional improvement and disease remission. CONCLUSION: A subset of patients with refractory myositis may benefit from fludarabine therapy and controlled trials are indicated. Refinement and validation of variables useful for following myositis patients await larger studies.

[18F]fluorodeoxyglucose single photon emission computed tomography: can it replace PET and thallium SPECT for the assessment of myocardial viability?

BACKGROUND: New high-energy collimators for single photon emission computed tomography (SPECT) cameras have made imaging of positron-emitting tracers, such as [18F]fluorodeoxyglucose (18FDG), possible. We examined differences between SPECT and PET technologies and between 18FDG and thallium tracers to determine whether 18FDG SPECT could be adopted for assessment of myocardial viability. METHODS AND RESULTS: Twenty-eight patients with chronic coronary artery disease (mean left ventricular ejection fraction [LVEF]=33+/-15% at rest) underwent 18FDG SPECT, 18FDG PET, and thallium SPECT studies. Receiver operating characteristic curves showed overall good concordance between SPECT and PET technologies and thallium and 18FDG tracers for assessing viability regardless of the level of 18FDG PET cutoff used (40% to 60%). However, in the subgroup of patients with LVEF< or =25%, at 60% 18FDG PET threshold value, thallium tended to underestimate myocardial viability. In a subgroup of regions with severe asynergy, there were considerably more thallium/18FDG discordances in the inferior wall than elsewhere (73% versus 27%, P<.001), supporting attenuation of thallium as a potential explanation for the discordant observations. When uptake of 18FDG by SPECT and PET was compared in 137 segments exhibiting severely irreversible thallium defects (scarred by thallium), 59 (43%) were viable by 18FDG PET, of which 52 (88%) were also viable by 18FDG SPECT. However, of the 78 segments confirmed to be nonviable by 18FDG PET, 57 (73%) were nonviable by 18FDG SPECT (P<.001). CONCLUSIONS: Although 18FDG SPECT significantly increases the sensitivity for detection of viable myocardium in tissue declared nonviable by thallium (to 88% of the sensitivity achievable by PET), it will occasionally (27% of the time) result in falsely identifying as viable tissue that has been identified as nonviable by both PET and thallium.

A "hybrid" method for measuring myocardial wall thickening from gated PET/SPECT images.

UNLABELLED: We introduce a hybrid index, HYB, which combines counts with geometric information to measure wall thickening from PET/SPECT gated images. Its accuracy is compared with that of a count-based index (MAX) and a geometric index (FWHM). METHODS: For each index, the index values versus thickness and the estimated thickening values versus true thickening were investigated using theoretical analyses, realistic simulated data obtained from clinical gated MR scans, phantom measurements and preliminary gated MRI and PET patient studies. Each index was studied for different spatial resolutions and noise and background conditions. The performance of each index was quantified using a parameter "Q" reflecting bias and variability of thickening estimates. RESULTS: HYB varied more linearly with thickness than MAX and FWHM, resulting in a better Q value than with MAX and FWHM for all noise, background and spatial resolutions. ROC analysis confirmed that HYB significantly increases the sensitivity and specificity for detection of wall thickening abnormalities (sensitivity = 100%; specificity = 85% for HYB, 95% and 50% for MAX and 100% and 0% for FWHM, respectively). CONCLUSION: Use of the hybrid index instead of conventional count-based or geometric indices should improve the classification of normal/abnormal wall thickening values in gated SPECT and PET.

Left ventricular ejection fraction: comparison of results from planar and SPECT gated blood-pool studies.

UNLABELLED: Global ejection fraction (EF) from planar gated blood-pool (GBP) imaging is a widely accepted measure of cardiac function. It has been suggested that planar GBP could be replaced by SPECT. In this article, we compare counts-based global EF measured from SPECT and planar images and investigate reasons for discrepancies between the two. METHODS: Twenty-three subjects were imaged with both planar and SPECT GBP. SPECT short-axis slices were projected to create reprojected images. Reprojected SPECT (rSPECT) images were created in both the true long-axis view and also in a view typical of planar studies (found to be 60 degrees from the true long-axis). Thus, angle of view effects on global EF could be investigated. In addition, we studied the effects of background and attenuation. RESULTS: Long-axis rSPECT EF correlated well with planar EF (r = 0.89) but EF values were significantly higher for rSPECT than for planar (slope = 1.4, intercept = -8 EF units; p < 0.001). We found that background correction may not be necessary with rSPECT, but neither background nor attenuation explained the observed discrepancy between rSPECT and planar EFs. This discrepancy was found to be caused by atrial overlap in the planar image and disappeared when the SPECT slices were reprojected at the same angle of view as the planar images. CONCLUSION: Global EF can be easily measured from rSPECT GBP images. Long-axis rSPECT EFs are, however, greater than planar EFs by a factor of 1.4 because atrial overlap causes a significant drop in planar EF in planar images. These results suggest that (long-axis) rSPECT EFs may be more accurate than planar EFs.

Measurement of myocardial wall thickening from PET/SPECT images: comparison of two methods.

PURPOSE: We compared two methods for measuring myocardial wall thickening from nuclear medicine perfusion scans. The first method uses the percent change in peak activity, and the second method models a profile measured across the myocardium. METHOD: Mathematical simulations of the myocardium were used. In addition, images with PET or SPECT resolution were created from real MR images. Known amounts of noise were then added. RESULTS: The percent peak thickening (% PT) is nonlinear with true percent thickening, especially for PET resolutions [7 mm full width at half-maximum (FWHM)]. For the peak method, low levels of noise (10%) introduced an error of 8%PT for PET and of 16%PT for SPECT. Additional smoothing reduced these errors. For the fitted model, at 10% noise, the error in thickening was large: 2.3 mm for PET and 7.8 mm for SPECT. CONCLUSION: The fitted model works well only with good resolution and low noise (e.g., 7 mm FWHM and 10%). The peak method is also sensitive to noise, especially for poorer resolutions. Additional smoothing gives more reliable results for the peak method but not the fitted method. The peak method is therefore the more generally reliable, but even this method may only allow classification of myocardial thickening into broad categories.

Artifactual inhomogeneities in myocardial PET and SPECT scans in normal subjects.

UNLABELLED: It has been well established that PET and SPECT scans of human myocardium are subject to partial volume related effects, which can cause artifactual regional variations in activity around the myocardium. This study investigated the sources and magnitude of such artifactual inhomogeneity in subjects with normal cardiac function. METHOD: Using multi-slice, gated MRI scans from 9 normal subjects, we examined separately the influences on measured activity of wall motion, axial resolution and the relationship between wall thickness and in-plane resolution. RESULTS: Two patterns of artifactual inhomogeneity were found: a depression in activity at the antero-apex and an elevation in activity in the free wall compared with the septum. Thus, in ungated PET images the true apical/septal ratio was artifactually reduced by a factor of 0.89 (0.92 for SPECT), while the true free wall/septal ratio was enhanced by a factor of 1.12 (1.19 for SPECT). Gating improved uniformity in end-systolic (ES) images but degraded uniformity in end-diastolic (ED) images. With gating, the true PET apical/septal ratio was artifactually reduced by only 0.97 at ES, and 0.82 at ED. Similar behavior was found for SPECT. Improvements in axial resolution were found to have little effect on artifactual variations. CONCLUSION: We find that the relationship between in-plane resolution and wall thickness, but not axial resolution, is of prime importance in determining the degree of artifactual inhomogeneity in ungated scans of normal human myocardium. Gating improved ES but degraded ED homogeneity.

Is fetal heart rate monitoring sufficiently sensitive to detect changes during labour?

Although fetal monitoring is a common clinical procedure, there is little quantitative evidence that it can detect changes occurring during labour. We present quantitative data comparing the first and second stage of labour, from 21 labours resulting in a normal fetal outcome. A range of fetal heart rate variables was calculated from the output of a fetal heart rate monitor. Significant changes were detected in baseline fetal heart rate (P less than 0.005), heart rate variability (P less than 0.05), number of dips (P less than 0.01) and their depth (P less than 0.01). The results encourage confidence in the sensitivity of fetal monitoring for the detection of changes in a number of fetal heart rate variables during the course of labour.

Comparison of methods for measuring fractal dimension.

Fractal dimension has been proposed as a useful method for characterizing medical images. The fractal dimension is calculated from the average radial power spectrum of the image. However, simpler methods of calculation have been proposed. This paper examines a very simple and easily implemented method which has been proposed for the calculation of fractal dimensions. Comparisons are made between the more rigorous method and the proposed simplification. It is found that the simpler method is a useful technique for calculating estimates of fractal dimension provided the range of dimensions of interest is small.

Properties of fetal heartbeat intervals during labour.

This study was designed to investigate the range of beat-to-beat changes in fetal inter-beat (RR) intervals during routine clinical monitoring in labour. Fetal RR intervals were automatically measured and collected from 10 fetuses. Intervals which were incorrectly measured were excluded, and the remaining 23,510 intervals were used to compile the distribution of beat-to-beat changes. The inter-quartile range of this distribution was 23 ms and the 99th centile fell at approximately 50 ms. No relationship could be established between beat-to-beat changes and the absolute RR interval. These findings differ from the results published by other workers on the basis of data obtained antenatally or during early labour. In addition, the results suggest possibilities for improving algorithms designed to enhance data quality in fetal heart rate monitoring.

4,6-dibenzamidopyrazolo[3,4-d]pyrimidine is a highly selective inhibitor of cytomegalovirus adsorption to cells.

The heterocycle, 4,6-dibenzamidopyrazolo[3,4-d]pyrimidine (DBAPP), inhibited cytopathology induced by human, mouse, and vervet monkey cytomegaloviruses (CMV) in vitro at 0.2 to 0.5 microM, but did not inhibit cell replication at less than or equal to 30 microM. Herpes simplex viruses were unaffected by the inhibitor. The antiviral agent ganciclovir was effective against these CMVs at 3-10 microM in parallel assays. DBAPP and ganciclovir were synergistic inhibitors when used in combination. The heterocycle was only active if applied to cells before virus replication, indicating that it inhibited virus adsorption. Cells pre-treated 1 h with 30 microM DBAPP, then extensively rinsed, were resistant to infection by mouse CMV even 3 days after removal of the inhibitor. Human and monkey CMVs were able to infect cells and replicate within 24 h of drug removal. When virus and DBAPP were combined together then dialyzed to remove the compound, mouse CMV infectivity was decreased 1.7 logs, whereas human CMV and monkey CMV infectivity titers were relatively unaffected. Treatment of mice with DBAPP twice a day for 7 days starting 6 h after mouse CMV inoculation caused a moderate increase in number of survivors at 30 mg/kg. Cell to cell spread of the virus may account for poor efficacy of the compound when added after virus infection. DBAPP may serve as a tool to explore aspects of CMV adsorption or to characterize the cellular component of the CMV receptor.

Double-antibody solid-phase enzyme immunoassay for the detection of staphylococcal enterotoxin A.

A simple double-antibody enzyme immunoassay that uses a microtechnique was developed for detecting staphylococcal enterotoxin A in food products. Sample preparation can be completed in less than 15 min. Assay sensitivity ranges from 0.4 ng (20-h test time) to 3.2 ng (1- to 3-h test time) of toxin per ml of prepared sample. Separation and detection of enterotoxin from spiked food products ranged between 72 and 98% of the amount added.

Application of the indirect enzyme-labeled antibody microtest to the detection and surveillance of animal diseases.

The rapid, indirect enzyme-labeled antibody (ELA) microplate test has been developed as a diagnostic and surveillance tool to aid in the control of animal disease. The test has been applied to viral (hog cholera), parasitic (trichinosis), and bacterial (brucellosis) diseases of animals. A correlation of greater than 95% was observed between the hog cholera ELA test and the serum neutralization test for hog cholera in greater than 2,000 field samples obtained during the 1976 epizootic in New Jersey. Serum samples from all of 56 swine naturally infected with Trichinella spiralis at a level considered dangerous to humans were ELA-positive, whereas only one of 360 packinghouse sera negative for T. spiralis was ELA-positive. Preliminary experiments with bovine brucellosis (Brucella abortus) indicate that the ELA test is more sensitive than other test methods currently in use. ELA procedures should soon become tests of choice for the detection of antibodies to animal disease agents.

Use of dogs as an assay for Clostridium perfringens enterotoxin.

Three techniques for using the dog as an assay organism for Clostridium perfringens enterotoxin are described. These are believed to be more convenient than ligated ileal-loop procedures.