Nizar A. Mullani

Assessment of coronary artery disease severity by positron emission tomography. Comparison with quantitative arteriography in 193 patients.

To assess the accuracy of positron emission tomography (PET) for evaluation of coronary artery disease (CAD), cardiac PET perfusion images were obtained at rest and with dipyridamole-handgrip stress in 193 patients undergoing coronary arteriography. PET images were reviewed by two independent readers blinded to clinical data. Subjective defect severity scores were assigned to each myocardial region on a 0 (normal) to 5 (severe) scale. Results were compared with arteriographic stenosis severity expressed as stenosis flow reserve (SFR), with continuous values ranging from 0 (total occlusion) to 5 (normal), calculated from quantitative arteriographic dimensions using automated detection of the vessel borders. There were 115 patients with significant CAD (SFR less than 3), 37 patients with mild CAD (3 less than or equal to SFR less than 4), and 41 patients with essentially normal coronaries (SFR greater than or equal to 4). With increasingly severe impairment of stenosis flow reserve, subjective PET defect severity increased. Despite wide scatter, a PET score of 2 or more was highly predictive of significant flow reserve impairment (SFR less than 3). For each patient, the score of the most severe PET defect correlated with the SFR of that patients most severe stenosis (rs = 0.77 +/- 0.06). For each of 243 stenoses, PET defect score correlated with the SFR of the corresponding artery (rs = 0.63 +/- 0.08). PET defect location closely matched the region supplied by the diseased artery, and readers agreed whether the most severe PET defect was less than or more than 2 for 89% of patients.

Phase I Study of Recombinant Human Endostatin in Patients With Advanced Solid Tumors

PURPOSE Endostatin, a 20-kd fragment of collagen XVIII, is a potent inhibitor of angiogenesis. We evaluated recombinant human endostatin (rh-Endo) in a phase I trial designed to assess safety, pharmacokinetics, and serum markers of angiogenesis in patients with solid tumors. PATIENTS AND METHODS Twenty-six patients were enrolled onto a dose-finding trial of rh-Endo administered as an intravenous bolus over a 20-minute period once daily. Three patients each were treated at dose levels of 15, 30, 60, 120, 180, and 600 mg/m(2)/d, and seven patients were treated at 300 mg/m(2)/d. Treatment consisted of a minimum of two 28-day cycles. Evaluations included noninvasive imaging, pharmacokinetics, and serum biomarkers. RESULTS Twenty-five patients were treated with rh-Endo. Treatment was well tolerated; there were no dose-limiting toxic effects. Bacteremia from frequent central line access was the most common problem. The pharmacokinetic disposition of rh-Endo was linear and best described using a two-compartmental open model. The overall mean half-life was 10.7 +/- 4.1 hours. A dose of 300 mg/m(2) achieved an area under the concentration-time curve associated with activity in preclinical models. In two patients, there was evidence of antitumor activity, but no responses were seen. Serum markers of angiogenic activity did not provide insight into rh-Endos activity. Serum antibodies were observed against both rh-Endo and the Pichia pastoris vector, but no allergic reactions were observed. CONCLUSION rh-Endo was safe and well tolerated. rh-Endo pharmacokinetic profiles achieved area under the concentration-time curves associated with activity in preclinical models. Evidence of minor antitumor activity was observed and further studies are indicated.

Noninvasive assessment of coronary stenoses by myocardial perfusion imaging during pharmacologic coronary vasodilation. VIII. Clinical feasibility of positron cardiac imaging without a cyclotron using generator-produced Rubidium-82

The purpose of this study was to determine the clinical feasibility of diagnosing significant coronary artery disease by positron imaging of myocardial perfusion without a cyclotron, using generator-produced rubidium-82 (82Rb). Fifty patients underwent positron emission tomography of the entire heart using a multislice positron camera and intravenous 82Rb or nitrogen-13 ammonia (13NH3) before and after intravenous dipyridamole combined with handgrip stress. Images were read by two observers blinded as to clinical or arteriographic data. Automated quantitative coronary arteriography was obtained for the arteriographic determination of coronary flow reserve, previously demonstrated to be a single integrated measure of stenosis severity accounting for all its geometric dimensions of length, absolute diameter, percent narrowing and asymmetry by quantitative analysis of cine films. Significant coronary artery disease was defined as an arteriographically determined coronary flow reserve of less than 3.0 based on all stenosis dimensions. Any single geometric measure of stenosis severity alone was an inadequate reference standard for comparison with perfusion images. Sensitivity of identifying patients with coronary artery disease having an arteriographically determined coronary flow reserve of less than 3.0 was 95% by positron imaging with a specificity of 100%. The single case that was missed, studied with 13NH3, had a 43% diameter narrowing of a small ramus intermedius off the left coronary artery with no significant narrowing of the major coronary arteries. Positron emission tomography of myocardial perfusion before and after intravenous dipyridamole combined with handgrip stress utilizing generator-produced 82Rb provides sensitive and specific diagnosis of reduced coronary flow reserve due to coronary artery disease in humans.

Development of Biologic Markers of Response and Assessment of Antiangiogenic Activity in a Clinical Trial of Human Recombinant Endostatin

PURPOSE Angiogenesis is a target for the treatment of cancer and other diseases, and its complex biology suggests that establishing the appropriate dose and schedule for antiangiogenic treatment will require extensive study. We present the initial results of a dose-finding clinical trial of recombinant human endostatin (rh-Endo) that examined potential surrogates for response to antiangiogenic therapy. PATIENTS AND METHODS Twenty-five patients were treated with escalating doses of rh-Endo. Positron emission tomography (PET) was used to assess tumor blood flow (with [15O]H2O) and metabolism (with [18F]fluorodeoxyglucose) before the start of therapy and then every 4 weeks. To directly assess the effects of rh-Endo on endothelial cells within the tumors, biopsy specimens of tumor tissue were obtained before therapy and again at 8 weeks and evaluated for endothelial cell and tumor cell apoptosis. RESULTS Tumor blood flow and metabolism as measured by PET scans generally decreased with increasing doses of rh-Endo; however, the effects were complex and in some analyses nonlinear. Tumor biopsy analysis revealed a significant increase in tumor cell apoptosis (P =.027) and endothelial cell apoptosis (P =.027) after 8 weeks of therapy. However, there was no statistically significant relationship between rh-Endo dose and induction of tumor cell or endothelial cell apoptosis. CONCLUSION These initial data suggest that rh-Endo has measurable effects on tumor blood flow and metabolism and induces endothelial and tumor cell apoptosis even in the absence of demonstrable anticancer effects. Further study and validation of these biomarkers in the context of antiangiogenic therapy will be required.

Brain glucose metabolism in chronic marijuana users at baseline and during marijuana intoxication

Despite the widespread abuse of marijuana, knowledge about its effects in the human brain is limited. Brain glucose metabolism with and without delta 9 tetrahydrocannabinol (THC) (main psychoactive component of marijuana) was evaluated in eight normal subjects and eight chronic marijuana abusers with positron emission tomography. At baseline, marijuana abusers showed lower relative cerebellar metabolism than normal subjects. THC increased relative cerebellar metabolism in all subjects, but only abusers showed increases in orbitofrontal cortex, prefrontal cortex, and basal ganglia. Cerebellar metabolism during THC intoxication was significantly correlated with the subjective sense of intoxication. The decreased cerebellar metabolism in marijuana abusers at baseline could account for the motor deficits previously reported in these subjects. The activation of orbitofrontal cortex and basal ganglia by THC in the abusers but not in the normal subjects could underlie one of the mechanisms leading to the drive and the compulsion to self-administer the drug observed in addicted individuals.

Frequency and Clinical Implications of Fluid Dynamically Significant Diffuse Coronary Artery Disease Manifest as Graded, Longitudinal, Base-to-Apex Myocardial Perfusion Abnormalities by Noninvasive Positron Emission Tomography

BACKGROUND Diffuse coronary atherosclerosis is the substrate for plaque rupture and coronary events. Therefore, in patients with mild arteriographic coronary artery disease without significant segmental dipyridamole-induced myocardial perfusion defects, we tested the hypothesis that fluid dynamically significant diffuse coronary artery narrowing is frequently manifest as a graded, longitudinal, base-to-apex myocardial perfusion abnormality by noninvasive PET. METHODS AND RESULTS In this study, 1001 patients with documented coronary artery disease by coronary arteriography showing any visible coronary artery narrowing underwent rest-dipyridamole PET perfusion imaging. Quantitative severity of dipyridamole-induced, circumscribed, segmental PET perfusion defects was objectively measured by automated software as the minimum quadrant average relative activity indicating localized flow limiting stenoses. Quantitative severity of the graded, longitudinal, base-to-apex myocardial perfusion gradient indicating fluid dynamic effects of diffuse coronary artery narrowing was objectively measured by automated software as the spatial slope of relative activity along the cardiac longitudinal axis. CONCLUSIONS In patients with mild arteriographic disease without statistically significant dipyridamole-induced segmental myocardial perfusion defects caused by flow-limiting stenoses compared with normal control subjects, there was a graded, longitudinal, base-to-apex myocardial perfusion gradient significantly different from normal control subjects (P=0. 001) that was also observed for moderate to severe dipyridamole-induced segmental perfusion defects (P=0.0001), indicating diffuse disease underlying segmental perfusion defects; 43% of patients with or without segmental perfusion defects demonstrated graded, longitudinal, base-to-apex perfusion abnormalities beyond +/-2 SD of normal control subjects, indicating diffuse coronary arterial narrowing by noninvasive PET perfusion imaging.

Effects of acute alcohol intoxication on cerebral blood flow measured with PET

Regional distribution of cerebral blood flow was assessed in a group of 13 normal social drinkers under baseline conditions and after acute alcohol intoxication. Blood flow measurements were done using 15O-labeled water and positron emission tomography (PET). Each subject underwent two control sessions under baseline conditions and two sessions after alcohol. Seven of the subjects were given 0.5 g/kg of alcohol and six were given 1 g/kg of alcohol p.o. The first and second post-alcohol scans were done 40 and 60 min after alcohol ingestion. The studies revealed that both the high and the low doses of alcohol reduced blood flow to the cerebellum. This effect was significant only for the high doses of alcohol, which also increased blood flow to the right temporal and the prefrontal cortex. The decrease in blood flow of the cerebellum could account for the muscular incoordination induced by alcohol.

PETT VI: a positron emission tomograph utilizing cesium fluoride scintillation detectors.

We designed and built a positron emission transverse tomograph (PETT VI), designed specifically for fast dynamic studies in the human brain, and for cardiac studies in experimental animals. The scintillation detectors incorporated into this device are fitted with cesium fluoride crystals. Cesium fluoride was selected for this purpose because its short fluoresence decay allows the use of a short coincidence resolving time with a concomitant reduction of unwanted random coincidences. PETT VI utilizes four rings of 72 detectors simultaneously yielding seven tomographic sections. The system can be operated in either a low or high resolution mode with intrinsic geometrical resolutions in the plane of section of 7.1 to 11.7 mm full width at half maximum (FWHM), for a slice thickness with a resolution at the center of 13.9 mm FWHM. The maximum sensitivity of the system for seven slices in the low resolution mode is 322,000 cps/μCi/cc in a 20 cm diameter phantom. The contribution of random coincidences before subtraction in PETT VI was found to be approximately 14% of the counts in the phantom image with a source of approximately 3.5 mCi of a positron emitting radionuclide dispersed in a 20 cm diameter tissue equivalent phantom with a concentration of 1 μCi/cc. The short coincidence resolving time of the system permits rapid data acquisition for attenuation corrections and clinical dynamic studies with data acquisition times of less than a minute.

Photon time-of-flight-assisted positron emission tomography

In positron emission tomography (PET), the annihilation radiation is usually detected as a coincidence occurrence that localizes the position of the annihilation event to a straight line joining the detectors. The measure of the difference between the time of flight (TOF) of the annihilation photons between their inception and their detection permits the localization of the position of the annihilation event along the coincidence line. The incorporation of TOF information into the PET reconstruction process improves the signal-to-noise ratio in the image obtained. The utilization of scintillation detectors utilizing cesium fluoride scintillators, fast photomultiplier tubes, and fast timing circuits allows sub-nanosecond coincidence timing resolution needed for the effective use of TOF in PET. Mathematical considerations and pilot experiments show that with state-of-the-art electronic components and through the application of proper reconstruction algorithms, the combination of TOF and PET positional data improves severalfold the signal-to-noise ratio with respect to conventional PET image reconstruction at the cost of increasing the amount of data to be processed. The construction of a TOF-assisted PET device is within the capability of state-of-the-art technology.

Design considerations for a positron emission transverse tomograph (PETT V) for imaging of the brain.

Imaging of the brain by positron emission tomography can be optimized for sensitivity by dedicating the design of the tomograph to this application. We have designed a multislice positron emission tomograph (PETT V) for imaging the human brain and the whole body of small experimental animals. The detector system of PETT V consists of a circular array of 48 NaI(Tl) scintillation detectors, each fitted with two photomultiplier tubes, with one dimensional positioning capability. Suitable sampling is achieved by rotation of the circular array of detectors and by a wobbling motion of the detector circle. The proposed system is capable of providing seven slices simultaneously, with a spatial resolution in the plane of the slice from 7 to 15 mm and with slice thicknesses of 7 and 14 mm. The minimum scanning time is 1 sec. The estimated overall sensitivity of PETT V is 350,000 counts/sec/mCi in a 20 cm diameter phantom for a resolution of approximately 1.5 x 1.5 cm. The system is under construction.