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Current imaging methods have focused on evaluation of myocardial anatomy and function. However, since myocardial metabolism and function are interrelated, metabolic myocardial imaging techniques, such as positron emission tomography, single photon emission tomography, and magnetic resonance spectroscopy present novel opportunities for probing myocardial pathology and developing new therapeutic approaches. Potential clinical applications of metabolic imaging include hypertensive and ischemic heart disease, heart failure, cardiac transplantation, as well as cardiomyopathies. Furthermore, response to therapeutic intervention can be monitored using metabolic imaging. Analysis of metabolic data in the past has been limited, focusing primarily on isolated metabolites. Models of myocardial metabolism, however, such as the oxygen transport and cellular energetics model and constraint-based metabolic network modeling, offer opportunities for evaluation interactions between greater numbers of metabolites in the heart. In this review, the roles of metabolic myocardial imaging and analysis of metabolic data using modeling methods for expanding our understanding of cardiac pathology are discussed.

This report documents the first use of magnetic resonance images (MRIs) of living dolphins to register functional brain scans, allowing for the exploration of potential mechanisms of unihemispheric sleep. Diazepam has been shown to induce unihemispheric slow waves (USW), therefore we used functional imaging of dolphins with and without diazepam to observe hemispheric differences in brain metabolism and blood flow. MRIs were used to register functional brain scans with single photon emission computed tomography (SPECT) and positron emission tomography (PET) in trained dolphins. Scans using SPECT revealed unihemispheric blood flow reduction following diazepam doses greater than 0.55 mg kg(-1) for these 180-200 kg animals. Scans using PET revealed hemispheric differences in brain glucose consumption when scans with and without diazepam were compared. The findings suggest that unihemispheric reduction in blood flow and glucose metabolism in the hemisphere showing USW are important features of unihemispheric sleep. Functional scans may also help to elucidate the degree of hemispheric laterality of sensory and motor systems as well as in neurotransmitter or molecular mechanisms of unihemispheric sleep in delphinoid cetaceans. The findings also demonstrate the potential value of functional scans to explore other aspects of dolphin brain physiology as well as pathology.

Silibinin, a flavonolignan from milk thistle, has intestinal cancer chemopreventive efficacy in rodents. It is a strong antioxidant and modulates the insulin-like growth factor (IGF) system by increasing circulating levels of IGF-binding protein 3 (IGFBP-3) and decreasing levels of IGF-I. Here, the hypothesis was tested that administration of oral silibinin generates agent levels in human blood and colorectal and hepatic tissues consistent with pharmacologic activity. Patients with confirmed colorectal adenocarcinoma received silibinin formulated with phosphatidylcholine (silipide) at dosages of 360, 720, or 1,440 mg silibinin daily for 7 days. Blood and biopsy samples of normal and malignant colorectum or liver were obtained before dosing, and blood and colorectal or hepatic tissues were collected at resection surgery after the final silipide dose. Levels of silibinin were quantified by high-pressure liquid chromatography-UV, and plasma metabolites were identified by liquid chromatography-mass spectrometry. Blood levels of IGFBP-3, IGF-I, and the oxidative DNA damage pyrimidopurinone adduct of deoxyguanosine (M1dG) were determined. Repeated administration of silipide was safe and achieved levels of silibinin of 0.3 to 4 micromol/L in the plasma, 0.3 to 2.5 nmol/g tissue in the liver, and 20 to 141 nmol/g tissue in colorectal tissue. Silibinin monoglucuronide, silibinin diglucuronide, silibinin monosulfate, and silibinin glucuronide sulfate were identified in the plasma. Intervention with silipide did not affect circulating levels of IGFBP-3, IGF-I, or M1dG. The high silibinin levels achieved in the human colorectal mucosa after consumption of safe silibinin doses support its further exploration as a potential human colorectal cancer chemopreventive agent.

Bottlenose dolphins were submitted to structural (CT) and functional (SPECT/PET) scans to investigate their in vivo anatomy and physiology with respect to structures important to hearing and echolocation. The spatial arrangement of the nasal passage and sinus air spaces to the auditory bullae and phonic lips was studied in two dolphins via CT. Air volume of the sinuses and nasal passages ranged from 267.4 to 380.9 ml. Relationships of air spaces to the auditory bullae and phonic lips support previous hypotheses that air protects the ears from echolocation clicks generated by the dolphin and contributes to dolphin hearing capabilities (e.g. minimum angular resolution, inter-aural intensity differences). Lung air may replenish reductions in sinus and nasal passage air volume via the palatopharyngeal sphincter, thus permitting the echolocation mechanism to operate at depth. To determine the relative extent of regional blood flow within the head of the dolphin, two dolphins were scanned with SPECT after an intravenous dose of 1850 MBq 99mTc-bicisate. A single dolphin received 740 MBq of 18F-2-fluoro-2-deoxyglucose (FDG) to identify the relative metabolic activity of head tissues. Substantial blood flow was noted across the dorsoanterior curvature of the melon and within the posterior region of the lower jaw fats. Metabolism of these tissues relative to others within the head was nominal. It is suggested that blood flow in these fat bodies serves to thermoregulate lipid density of the melon and jaw canal. Sound velocity is inversely related to the temperature of acoustic lipids (decreasing lipid density), and changes in lipid temperature are likely to impact the wave guide properties of the sound projection and reception pathways. Thermoregulation of lipid density may maintain sound velocity gradients of the acoustic lipid complexes, particularly in the outer shell of the melon, which otherwise might vary in response to changing environmental temperatures.

A 31-year-old man with a vagal nerve stimulator for seizure control was noted to have decreased metabolism within the thalamus as visualized by F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET). Some investigators think the thalamus plays an important role in the regulation of seizure activity. Vagal nerve stimulation (VNS) may reduce thalamic activity, which in turn may reduce seizure activity. However, because the thalamus has diffuse connections throughout the brain, its role in seizure activity is likely complex. Observing decreased thalamic activity during VNS is just 1 small step toward understanding this role.

Background: Type IV collagen, a heterotrimeric molecule that exists in six genetically distinct forms, alpha1(IV)-alpha6(IV) is a major structural component of basement membrane (BM) and acts as a scaffold for other BM constituents., Methods: Indirect immunofluorescence using alpha chain-specific monoclonal antibodies was employed to clarify basement membrane (BM) collagen IV distribution in two ameloblastoma, and for comparison, on oral mucosa and tooth germ., Results: Ameloblastoma BM expressed five of six genetically distinct forms of collagen IV: alpha1(IV), alpha2(IV), alpha5(IV) and alpha6(IV) chains occurred as intense linear stainings without disruption around neoplastic epithelium, and this expression pattern was fundamentally similar to oral mucosa BM; alpha4(IV) expression was rare and occurred around nests of primitive tumor cells or potentially invasive sites. The tooth germ demonstrated a stage- and position-specific collagen IV distribution: the inner enamel epithelium BM expressed alpha1(IV), alpha2(IV), and alpha4(IV) except in the cuspal predentine region; and the outer enamel epithelium BM expressed alpha1(IV), alpha2(IV), alpha5(IV), and alpha6(IV) chains., Conclusions: Results suggest that collagen IV alpha chain distribution in ameloblastoma BM plays an important role in tumor cytodifferentiation and progression.

The enzymatic synthesis of Gal-beta 1,3[GlcNAc-beta 1,6]-GalNAc-alpha 1-OBn (core 2-Bn) using a multi-enzyme system consisting of a beta-galactosidase (EC 3.2.1.23) from bovine testes and a recombinant core 2 beta 1,6-GlcNAc transferase (C2GnT, EC 2.4.1.102) was empirically optimized by the use of a genetic algorithm. After variation of seven relevant parameters and performance of 56 experiments, two local maxima regarding the selection criteria could be found after four generations of optimization. The selectivity of core 2-Bn formation showed values up to 90%.

Capillary electrophoresis is a powerful and versatile analytical tool due to the wide range of separation variables and separation methods possible. CE permits the combination of multiple separation mechanisms (e.g., chiral modifiers, polarity, pH) for the analysis of a large variety of compounds. The main advantage of CE (i.e., the broad range of separation variables) has thus far limited its application. This is due to the nonlinear influence and interactions of different parameters on separation quality, making it difficult to predict trends for the optimization of separation systems and hence hindering CE method development. In this paper, we present a means for rationalizing method development for CE separations using a genetic algorithm. We provide selected examples of separation enhancements achieved in the field of nucleotide and nucleotide sugar separation. An improved method for the enantioselective separation of amino acid derivatives (2-acetylamino-3-phenyl-propionic acid) will also be presented.

Purpose: The use of whole-body PET for re-staging of renal cell carcinoma has not been investigated. The aim of the current study was to examine the diagnostic accuracy and clinical usefulness of whole-body PET imaging for re-staging of renal cell cancer., Patients and Methods: Clinical PET was performed for re-staging in 36 patients with advanced renal cell cancer. Written reports of imaging studies (including CT, MRI, US, plain film and bone scan), patient history, and extensive chart notes were used to define the clinical stage before PET (pre-PET stage). The written PET report was used to define the clinical stage after PET (PET stage). Reports were used to determine the accuracy of PET for re-staging renal cell cancer and for defining biopsy proven lesions. Clinical parameters and biopsy proven lesions served as reference for the accuracy of PET for re-staging renal cell cancer., Results: PET classified the clinical stage correctly in 32/36 patients (89%) and was incorrect in 4/36 (11%) (sensitivity and specificity: 87% and 100%). In 20 patients, 25 suspicious lesions were biopsied within 3.2 +/- 6.7 months of the PET study. Of these, 17 were malignant and 8 were benign. PET correctly classified 21/25 (84%) of the biopsied lesions (sensitivity and specificity: 88% and 75%)., Conclusion: PET re-stages renal cell cancer with a diagnostic accuracy of 89%. Its diagnostic accuracy for classifying biopsy proven anatomic lesions as malignant or benign was 84%. These findings suggest that PET is useful in characterizing anatomic lesions of unknown significance in patients with renal cell cancer.

Context: Deficits in cerebral glucose utilization have been identified in patients with cognitive dysfunction attributed to various disease processes, but their prognostic and diagnostic value remains to be defined., Objective: To assess the sensitivity and specificity with which cerebral metabolic patterns at a single point in time forecast subsequent documentation of progressive dementia., Design, Setting, and Patients: Positron emission tomography (PET) studies of [(18)F]fluorodeoxyglucose in 146 patients undergoing evaluation for dementia with at least 2 years' follow-up for disease progression at the University of California, Los Angeles, from 1991 to 2000, and PET studies in 138 patients undergoing evaluation for dementia at an international consortium of facilities, with histopathological diagnoses an average of 2.9 years later, conducted from 1984 to 2000., Main Outcome Measures: Regional distribution of [(18)F]fluorodeoxyglucose in each patient, classified by criteria established a priori as positive or negative for presence of a progressive neurodegenerative disease in general and of Alzheimer disease (AD) specifically, compared with results of longitudinal or neuropathologic analyses., Results: Progressive dementia was detected by PET with a sensitivity of 93% (191/206) and a specificity of 76% (59/78). Among patients with neuropathologically based diagnoses, PET identified patients with AD and patients with any neurodegenerative disease with a sensitivity of 94% and specificities of 73% and 78%, respectively. The negative likelihood ratio of experiencing a progressive vs nonprogressive course over the several years following a single negative brain PET scan was 0.10 (95% confidence interval, 0.06-0.16), and the initial pattern of cerebral metabolism was significantly associated with the subsequent course of progression overall (P<.001)., Conclusion: In patients presenting with cognitive symptoms of dementia, regional brain metabolism was a sensitive indicator of AD and of neurodegenerative disease in general. A negative PET scan indicated that pathologic progression of cognitive impairment during the mean 3-year follow-up was unlikely to occur.

In heart failure (HF) patients, reflex renal vasoconstriction during exercise is exaggerated. We hypothesized that muscle mechanoreceptor control of renal vasoconstriction is exaggerated in HF. Nineteen HF patients and nineteen controls were enrolled in two exercise protocols: 1) low-level rhythmic handgrip (mechanoreceptors and central command) and 2) involuntary biceps contractions (mechanoreceptors). Renal cortical blood flow was measured by positron emission tomography, and renal cortical vascular resistance (RCVR) was calculated. During rhythmic handgrip, peak RCVR was greater in HF patients compared with controls (37 +/- 1 vs. 27 +/- 1 units; P < 0.01). Change in (Delta) RCVR tended to be greater as well but did not reach statistical significance (10 +/- 1 vs. 7 +/- 0.9 units; P = 0.13). RCVR was returned to baseline at 2-3 min postexercise in controls but remained significantly elevated in HF patients. During involuntary muscle contractions, peak RCVR was greater in HF patients compared with controls (36 +/- 0.7 vs. 24 +/- 0.5 units; P < 0.0001). The Delta RCVR was also significantly greater in HF patients compared with controls (6 +/- 1 vs. 4 +/- 0.6 units; P = 0.05). The data suggest that reflex renal vasoconstriction is exaggerated in both magnitude and duration during dynamic exercise in HF patients. Given that the exaggerated response was elicited in both the presence and absence of central command, it is clear that intact muscle mechanoreceptor sensitivity contributes to this augmented reflex renal vasoconstriction.

Preoperative localization of parathyroid adenomas in patients with hyperparathyroidism currently relies on a combination of computed tomography, magnetic resonance imaging, ultrasound, (99m)Tc-sestamibi scintigraphy, and venous sampling of parathyroid hormone. No procedure is universally reliable, however, and in reoperation for missed parathyroid adenomas, development of an optimal preoperative localization strategy becomes especially problematic. We report the case of a patient with hyperparathyroidism who required reoperation for a missed parathyroid adenoma despite preoperative localization with (99m)Tc-sestamibi scintigraphy. (99m)Tc-sestamibi scintigraphy was done 2.5 hours before reoperation. On reoperation, a gamma-detecting probe (C-Track; Care Wise Medical Corporation, Morgan Hill, CA) introduced through a right neck incision was used to localize a 4-cm adenoma within 45 minutes. No significant radiation hazard existed, and no special handling of the specimen was required. The patient's hyperparathyroidism resolved within 24 hours postoperatively. Therefore, this intraoperative technique may prove to be a useful adjunct to preoperative localization studies of parathyroid adenomas, particularly in patients requiring reoperation for persistent postsurgical hyperparathyroidism.

Background: Conflicting reports exist regarding the permanence of improved gastric emptying (GE) after fundoplication for gastroesophageal reflux in children., Methods: Changes in gastric volume (GV) and GE of a radiolabeled mixed meal induced by a Nissen fundoplication (NF) were compared with those with a NF plus pyloroplasty (NF + P). GE was measured preoperatively, 15 and 30 days postoperation, in 24 Sprague-Dawley rats; 12 had NF alone, and 12 had NF + P Results were expressed as percent gastric retention at 90 minutes (GR90). GV was measured at the same time periods in 20 additional rats., Results: NF rats had enhanced GE with reduction of preoperative GR90 from 37.6% to 23.7% at 15 days (P < .05); however, at 30 days the GR90 increased to 34.3%. NF + P rats had enhanced GE with reduction in GR90 from 37.2% to 20.8% at 15 days (P< .05), which persisted at 30 days (20.4%). Mean GV decreased from (1.36 mL/100 g body weight) preoperation to 0.86 at 15 days (P< .05) at 15 days in the NF group, and returned to 1.29 at 30 days. Mean GV decreased from 1.36 to 0.91 at 15 days in the NF + P rats and persisted at 0.90 at 30 days., Conclusion: In the rat model, NF enhances GE transiently, whereas NF + P produces long-term enhancement of GE.

Positron emission tomography (PET) is a biochemical-imaging tool that uses the uptake of the glucose analog 2-deoxy-2-[F-18] fluoro-D-glucose (FDG) to detect head and neck tumor proliferation. The aim of this study is to determine if quantitation of either primary tumor metabolic activity or tumor response using PET scans could predict local control and overall survival in patients with head and neck cancer undergoing primary radiotherapy. Twelve patients with squamous cell carcinomas of the head and neck underwent PET scans before and 6 weeks after completion of radiation therapy. Tumor metabolic activity was quantitated using the metabolic ratio method. Mean follow-up was 40 months (range: 18-55 months). In our series, tumors with metabolic rates greater than that of the cerebellum are associated with significantly better local control (p < 0.05) and survival. Posttreatment PET imaging was falsely positive in one patient with clinical signs of severe inflammation. Tumors with greater than 50% decrease in metabolic activity with irradiation had improved local control. Clinically, nine patients had excellent response to irradiation. These results suggest that pretreatment PET findings may have prognostic implications in determining which patients will achieve long-term local control with primary radiation therapy. This may help identify those at increased risk of recurrence that may benefit from more aggressive altered fractionation schemes or combined modality therapy.

Unlabelled: Receiver operating characteristic (ROC) and localization ROC (LROC) studies were performed to compare lesion detection at the borderline of detectability on images reconstructed with two-dimensional filtered backprojection (FBP) without attenuation correction (a common clinical protocol), three-dimensional FBP without attenuation correction, two-dimensional FBP with segmented attenuation correction and a two-dimensional iterative maximum a posteriori (MAP) algorithm using attenuation correction. Lung cancer was the model for the study because of the prominent role of 18F-fluorodeoxyglucose PET in the staging of lung cancer and the importance of lesion detection for staging., Methods: Simulated lung cancer lesions were added to two-dimensional and three-dimensional PET data from healthy volunteers. Data were reconstructed using the four methods. Four nuclear medicine physicians evaluated the images. Detection performance with each method was compared using ROC and LROC analysis. Jackknife analysis provided estimates of statistical significance for differences across all readers for the ROC results., Results: ROC and LROC results indicated statistically significant degradation in detection performance with three-dimensional acquisition (average area under ROC curves [Az] 0.51; average area under LROC curves [A(z,LROC)] 0.13) and segmented attenuation correction (average Az 0.59; average Az,LROC 0.29) compared with two-dimensional FBP without attenuation correction (average Az 0.79; average A(z,LROC) 0.54). ROC and LROC results indicated an improvement in detection performance with iterative MAP reconstruction (average Az 0.83; average A(z,LROC) 0.64) compared with two-dimensional FBP reconstruction; this improvement was not statistically significant., Conclusion: Use of segmented attenuation correction or three-dimensional acquisition with FBP reconstruction is not expected to improve detection of lung lesions on whole-body PET images compared with images with two-dimensional FBP without attenuation correction. The potential improvement in detection obtained with an iterative MAP reconstruction method is small compared with that obtained with two-dimensional FBP without attenuation correction.

Purpose: We compare the detection of metastatic disease by helical computerized tomography (CT), positron emission tomography (PET) with F-18 fluorodeoxyglucose and monoclonal antibody scan with 111indium capromab pendetide in patients with an elevated prostate specific antigen (PSA) after treatment for localized prostate cancer., Materials and Methods: A total of 45 patients with an elevated PSA (median 3.8 ng./ml.) were studied following definitive local therapy with radical prostatectomy in 33, radiation therapy in 9 and cryosurgery in 3. CT of the abdomen and pelvis, and whole body PET were performed in all patients, of whom 21 also underwent monoclonal antibody scan. Lymph nodes 1 cm. in diameter or greater on CT were considered abnormal and were sampled by fine needle aspiration in 12 patients., Results: PET and CT were positive for distant disease in 50% of 22 patients with PSA greater than 4, and in 4 and 17%, respectively, of 23 with PSA less than 4 ng./ml. The detection rate for metastatic disease was similar for CT and PET, and higher overall than that for monoclonal antibody scan. Monoclonal antibody scan was true positive in only 1 of 6 patients, while PET was true positive in 6 of 9 with CT guided fine needle aspiration proved metastases., Conclusions: CT and PET each detected evidence of metastatic disease in 50% of all patients with a high PSA or PSA velocity (greater than 4 ng./ml. or greater than 0.2 ng./ml. per month, respectively). Both techniques are limited for detecting metastatic disease in patients with a low PSA or PSA velocity. Our data suggest that monoclonal antibody scan has a lower detection rate than CT or PET.

Background/purpose: Nissen gastroesophageal fundoplication (GEF) increases gastric emptying (GE); however, the duration and the mechanisms for this improvement in GE remain unclear. The aim of this study was to evaluate the effects of a GEF on GE of a mixed meal, and to determine the correlation between GE and changes in intragastric pressure (IGP) and compliance., Methods: Using a radiolabeled mixed meal, GE was measured preoperatively 15 and 30 days after operation in 24 Sprague-Dawley rats divided into SHAM and GEF groups. Results were expressed as percent gastric retention at 90 minutes (GRg90), and time to evacuate 50% of the isotope meal (T1/2). Changes in IGP and compliance were determined at the same time-points using a different set of 20 rats., Results: Fifteen days after surgery, GR90 and T1/2 in the GEF group were reduced significantly when compared with preoperative values but returned to near preoperative values 30 days postoperation. In contrast, rats from the SHAM group showed no change in GR90 and T1/2 at 15 days and 30 days postoperation. Immediately after GEF, maximal distension of the stomach resulted in pressures 65% higher than those recorded before operation (20.2 v 11.7 mm Hg; P< .05), which persisted on the 15th postoperative day (17.7 v 10.7 mm Hg; P<.05). On the 30th postoperative day, however, there was no difference in the IGP between rats undergoing GEF compared with those undergoing a SHAM operation (11.7 v 12.0 mm Hg; P < .05). Similarly, mean gastric compliance decreased significantly immediately after and 15 days after GEF, but returned to preoperative levels 30 days after the operation., Conclusions: In a rat model, GEF produces a transitory increase in GE, which is related to a simultaneous decrease in gastric volume and compliance. However, 30 days after GEF, associated with an elevated IGP, gastric volume increases and GE returns to preoperative levels.

Background: Detection of myocardial viability is important in patients with ischemic cardiomyopathy. Restoration of blood flow to viable myocardium is associated with improved left ventricular function and improved patient prognosis. However, the prevalence of viable myocardium in patients with ischemic cardiomyopathy is unknown., Methods and Results: To determine the prevalence of myocardial viability, clinical [13N]ammonia/18F-deoxyglucose PET studies performed in 283 patients (age, 63+/-10 years) with ischemic heart disease (mean ejection fraction, 26+/-8%) were visually analyzed for the presence and extent of viable and nonviable myocardium. The myocardium was divided into 19 segments. The extent of viable myocardium was considered "functionally" significant if >/=5 segments ( approximately 25% of the left ventricular myocardium) exhibited a blood flow/metabolism mismatch and "prognostically" significant if 1 to 4 left ventricular segments did so. Of all patients, 41% had no evidence of viable myocardium, 55% had viable myocardium, and 4% had normal blood flow and metabolism within an enlarged left ventricle. Functionally significant viability was found in 27% and prognostically significant viability in 28% of the patients. Multivariate analysis revealed the presence of angina to be the only clinical parameter associated with the presence of functionally significant viability., Conclusions: Revascularization might improve patient prognosis in 55% and result in improved left ventricular function in 27% of all patients with ischemic cardiomyopathy.

Unlabelled: Several tracer kinetic methods have been proposed for quantification of regional myocardial blood flow (MBF) with 13N-ammonia and PET. Merits and limitations specific to each approach, however, generally are not clear, because they have not been evaluated in the same experimental environment. Therefore, we compared six different commonly used methods (11 modifications) to characterize the accuracy of each approach. The methods included the two-parameter model (method 1), the modified two-parameter model (method 2), the four-parameter model (method 3), the graphical analysis (method 4), the first-pass extraction method (method 5) and the dose uptake index (DUI; method 6)., Methods: Eleven studies in four dogs, 16 studies in eight healthy human volunteers and 14 studies in seven patients were performed using 13N-ammonia and PET. MBF in dogs was varied with dipyridamole and coronary occlusions and was measured independently and simultaneously with microspheres. Volunteers and patients were studied at baseline and after dipyridamole. MBF and DUI were estimated using a time-activity curve (Qi[t]) derived from dynamic images and regions of interest (ROls) and using the six methods. DUI was defined as Qi(t = 2 min) x weight/dose., Results: MBF estimated by methods 1-5 correlated well with microsphere MBF in dogs. MBF estimates by method 1 correlated well with those by methods 2, 4 and 5 and to a lesser degree with those by method 3 in both dog and human studies. DUI correlated poorly with MBF by microspheres and by methods 1-5 in both dog and human studies. MBF estimates by method 3 showed larger dispersion (SD/mean flow) and higher sensitivity to metabolites correction in arterial blood than those by methods 1, 2, 4 and 5., Conclusion: MBF can be measured accurately using 13N-ammonia PET and tracer kinetic methods. DUI is a poor indicator of MBF values. The results indicate that preference should be given to the two-parameter model, incorporating geometrical ROI representation (method 2) among the compartment models, and to the graphical analysis (method 4) among the noncompartmental approaches.

Objectives: The purpose of this study was to evaluate the predictive accuracy of positron emission tomography (PET) blood flow-F-18 fluorodeoxyglucose (FDG) imaging in coronary artery disease (CAD) patients with diabetes mellitus (DM)., Background: Positron emission tomography accurately predicts the postrevascularization improvement in left ventricular dysfunction in unselected patients with CAD. In diabetic patients, however, poor myocardial glucose utilization may limit the accuracy of the approach., Methods: Forty patients (64+/-10 years old; 19 with DM = group I; 21 without DM = group II) with reduced left ventricular ejection fraction (LVEF = 29+/-6%) were studied with N-13 ammonia and FDG PET before coronary revascularization. Studies were performed after intravenous injection of regular insulin (group I) or oral glucose administration (group II). Blood flow-FDG mismatches and matches were identified by polar map analysis in the three vascular territories of the left anterior descending, left circumflex and right coronary artery. Wall motion and LVEF were assessed by two-dimensional echocardiography before and 158+/-123 days after revascularization., Results: Of 107 vascular territories analyzed, 46 were classified as mismatch, 29 as match and 32 as normal. The FDG image quality, assessed by F-18 myocardium to blood pool activity ratios, and the predictive accuracy were similar in both groups; presence of a blood flow/FDG mismatch had a sensitivity of 92% (group I) and 94% (group II) and a specificity of 85% (group I) and 79% (group II) for an improvement in regional left ventricular function. A postrevascularization improvement in global left ventricular function was related to the extent of blood flow/FDG mismatch; LVEF increased from 30+/-7% to 35+/-7% (p = 0.017) in patients with one mismatch and from 27+/-4% to 41+/-7% (p < 0.001) in those with two mismatches., Conclusions: The predictive accuracy of blood flow/FDG imaging is maintained in patients with DM when a clinically acceptable study protocol, which guarantees good FDG image quality, is used. The extent of a blood flow/metabolism mismatch is correlated with the magnitude of the postrevascularization improvement in global left ventricular function.

Purpose: To determine the usefulness of technetium 99m diethyltriaminepentacetic acid (DTPA) radioaerosol inhalation-clearance scintigraphy for early detection of pulmonary complications of human immunodeficiency virus (HIV) disease in children., Materials and Methods: A total of 301 studies were performed in 132 HIV-positive children (group 1; mean age, 46.6 months). In children born to HIV-positive mothers (group 2), 273 studies were performed in 160 children who eventually were proved to be HIV negative (mean age, 10.3 months), and 80 studies were performed in 47 HIV-positive children (mean age, 15.6 months). Radioaerosol studies were performed by using commercially available radioaerosol nebulizers. Pulmonary clearance half-time was measured by using conventional gamma camera computer systems. Radioaerosol results were correlated with indexes of pulmonary health and function., Results: The HIV-negative, group 2 children had a mean radioaerosol clearance half-time (58.1 minutes; 162 studies in 108 children) similar to that reported in healthy adults. Group 1 children with pulmonary involvement exhibited a faster mean clearance half-time (28.6 minutes) than did children without evidence of pulmonary involvement from either group 1 or group 2 (P < .05). A faster pulmonary clearance rate did not simply reflect the presence of chest disease that also was detectable on radiographs (P = .3)., Conclusion: Quantitative DTPA radioaerosol clearance studies may provide useful information about pulmonary involvement in selected children with HIV disease.

Despite the large number of women with breast cancer and the importance of this disease in health care, only a relatively small number of published reports involve the application of 18-fluorodeoxyglucose (FDG) in the evaluation of patients with breast cancer. This report summarizes the results of these studies, presents the opinions from various clinical oncologists from both a university and community setting, and discusses the possible future implication of positron imaging technology in the management of breast cancer. The four potential areas of clinical application include (1) detection and differentiation of primary breast lesions, (2) staging of axillary lymph nodes, (3) detection of residual and metastatic disease, and (4) monitoring the response to chemotherapy.

The usefulness of positron-emission tomography (PET) for noninvasive assessment of several biological parameters of neoplastic tissue has been reviewed. Numerous radiotracers have been developed, whose particular distribution in the presence of cancer in vivo serves to distinguish medically relevant properties of the tumor cells with which they associate. That distribution is most accurately determined through use of a PET scanner, to localize and quantify the tracer molecules, in which have been incorporated positron-emitting isotopes. These tracers include hypoxia markers, receptor ligands, substrates for enzymatic modification by the products of expression of specific genes, and precursors of protein anabolism and carbohydrate catabolism. In addition, application of PET to evaluation of patients with some particular cancers has been examined, while placing special emphasis on the level of scientific rigor of the evidence underlying conclusions about appropriate use of PET in oncology., (Copyright 1998 W.B. Saunders Company.)

Background: The sentinel lymph node is defined as the first lymph node to receive drainage from a primary tumor. Based on this concept, the authors set out to evaluate whether the status of the sentinel lymph node can accurately predict whether breast tumor cells have metastasized to the axillary lymphatic basin., Methods: Radiolabeled dextran was injected into the site of the breast tumor. In the operating room, a portable gamma detector probe was used to identify the exact location of the sentinel lymph node(s). After identifying and excising the radioactive sentinel lymph node specimens, a routine axillary lymph node dissection was performed. All lymph nodes were then subjected to hematoxylin and eosin (H & E) staining, and the sentinel lymph nodes were subjected to additional cytokeratin immunohistochemistry., Results: Of the 41 patients who participated in the study, 18 had tumor metastasis to their axillary lymph nodes. In all 18 of these cases, the sentinel lymph node(s) contained cancer detected by either H & E staining or cytokeratin immunohistochemistry., Conclusions: The status of the sentinel lymph node(s) appears to predict accurately whether breast tumor cells have metastasized to the axillary lymphatic basin. This new, minimally invasive technique for staging breast carcinoma should be further validated in a large, multi-institutional clinical trial.

Unlabelled: The mouse model is currently being explored for various applications with PET imaging. Low resolution of current animal scanners relative to mouse size leads to difficulty in quantitating data from mouse PET images. We have, therefore, investigated methods for determining blood time-activity curves (TACs) from mouse PET studies done with fluorine-18-fluorodeoxyglucose (FDG)., Methods: Eight mice were fasted, the tail vein was injected with 150-300 microCi of FDG and dynamic images were acquired with a CTI/Siemens (Knoxville, TN) animal tomograph for 64.5 min. Concurrently, 11-14 left ventricle (LV) blood samples were drawn directly from the LV chamber. Organ TACs were obtained by drawing circular regions of interest (ROIs) of various sizes on images of the heart, liver and brain. For each mouse, the FDG model parameter K = (K1 x k3)/(k2 + k3) was estimated by a Patlak algorithm with various estimates of the blood TAC and, as a reference tissue TAC, the brain TAC., Results: Most partial-volume-corrected heart ROI TACs overestimated the LV samples. Blood TACs from heart images produced statistically different estimates of K than did the LV samples. The liver image-derived blood TACs yielded estimates of K that were comparable to those yielded by the LV samples. Estimates of K determined with two directly sampled LV points in conjunction with the liver image-derived TAC were not statistically different from the estimates obtained with the LV samples. The size and location of ROIs on images of the liver minimally affected the TACs., Conclusion: We have shown that it is experimentally possible to obtain a blood TAC from mouse studies by repeatedly sampling from the LV. We have also shown that images of the liver can be used to reliably estimate the blood TAC. Future FDG PET studies with the mouse model will benefit from this demonstrated ability to noninvasively quantitate blood TACs directly from FDG PET images.

Unlabelled: This study assessed the diagnostic accuracy of whole-body PET on a patient and lesion basis using 18F-fluorodeoxyglucose (FDG) for the detection of tumor foci in patients with suspected recurrent or metastatic lesions of breast carcinoma., Methods: Whole-body FDG-PET imaging was performed on 57 patients with a previous history of breast carcinoma who were referred for a clinical suspicion of disease recurrence. Whole-body PET images were scored from 1 (definitely negative) to 5 (definitely positive) by three independent observers, and discrepancies were resolved by a fourth observer. Patients were clinically followed for up to 24 mo to assess the accuracy of PET diagnosis by biopsy, follow-up imaging and other diagnostic tests., Results: PET scans showed that there were 41 sites indicating recurrent or metastatic disease in 29 patients. There were 38 sites in 28 patients that showed no evidence for malignant disease. On a patient basis, with scores 4 or 5 considered to be positive, sensitivity and specificity were 93% and 79%, respectively. The corresponding positive and negative predictive values were 82% and 92%. On a lesion basis, with scores 4 or 5 considered to be positive, the sensitivity was 85% and specificity 79%. The area index in receiver operating characteristic analysis was 0.91 for patient-based analysis and 0.88 for lesion-based analysis. To determine the cause for false-negative and false-positive findings more precisely, false-negative lesions with scores of 3 or lower and false-positive lesions with scores of 4 or higher were analyzed. Bone metastases had a significantly larger proportion of false-negative lesions than other nonosseous malignant sites (p < 0.05). False-positive lesions were due to muscle uptake (n = 5), inflammation (n = 4), blood pool activity in the great vessels (n = 2), bowel uptake (n = 1) and unknown causes (n = 6)., Conclusion: The whole-body FDG-PET scan is a useful diagnostic test for detecting recurrent or metastatic lesions of breast carcinoma. However, the sensitivity for metastases to bone appears to be lower than that to other organs. Specificity may be improved by more strict attention to patient preparation and better recognition of physiologic skeletal muscle or artifactual uptakes.

Purpose: Early experience has shown that positron-emission tomography (PET) is a useful technique for the detection of occult squamous cell carcinoma of the head and neck. Although highly sensitive, PET lacks definition of anatomic detail and therefore does not localize pathology precisely. To circumvent this limitation, a computerized coregistration technique has been developed at the University of California-Los Angeles to correlate PET and magnetic resonance images (MRI). This method allows accurate, precise anatomic localization of areas of heightened glucose metabolism, including subclinical tumors., Materials and Methods: The technique uses a coregistration computer program that precisely superimposes the PET scan with the corresponding MRI image., Results: Two cases are presented in which PET-MRI coregistration was used to anatomically define the areas of heightened glucose metabolism. Large tumors were selected because the precision of the method can be verified., Conclusion: The coregistration technique is a valuable addition to PET imaging, particularly in its ability to anatomically localize PET findings. The most important application of this technique is to facilitate the biopsy of subclinical lesions identified on PET.

Unlabelled: Contamination of working areas by 99mTc DTPA aerosol is of concern to nuclear medicine technologists. This study sought to determine the extent of 99mTc DTPA contamination to technologists, and to localize sources of aerosol leakage so that methods could be identified that would minimize contamination., Methods: Fifty to eighty millicuries 99mTc DTPA, diluted to a volume of 4-5 ml with normal saline, were injected into the nebulizing chamber of two commercially available inhalation aerosol systems. The patient's nostrils were clamped and a damp washcloth was wrapped around the patient's mouth. An alcohol swab was placed in the exit port of the exhaust filter in each delivery system, and the technologist involved wore a face mask during the inhalation phase. The patient breathed DTPA-labeled aerosol by mouth until the counting rate in the lungs was four times greater than the counting rate from the pulmonary perfusion phase. Connecting joints of the delivery system were then wipe tested. Last, a Geiger-Mueller detector (pancake probe) was used to survey all device components. Readings above 0.05 mR/hr were considered contaminated., Results: The patient was the greatest source of leakage as determined by the damp washcloth, followed by the joints of the tubes of the delivery system and, finally, the system's exhaust filter. Contamination readings from face masks worn by technical personnel during the lung ventilation studies were slightly greater than 0.05 mR/hr., Conclusion: The findings support trace levels of contamination to both the technologist and room while performing 99mTc DTPA aerosol ventilation studies. Comparative data using the two delivery systems revealed little difference in sources of leakage and little variation in contamination measurements.

Purpose: We provide scientists and clinicians with an introduction to the basic principles and methods of positron emission tomography (PET) and summarize the recent research and clinical applications of PET in the urological field. Specifically, we introduce PET so that the reader can understand and objectively review current and future articles that involve this imaging technology., Materials and Methods: The recent applications of PET in urology in the published literature were searched and reviewed., Results: In prostate carcinoma preliminary studies using radiotracer 18-fluoro-2-deoxyglucose (FDG) demonstrated that PET cannot reliably differentiate between primary prostate cancer and benign prostatic hyperplasia, and that PET is not as sensitive as bone scintigraphy for the detection of osseous metastases. However, PET may have a role in the detection of lymph node metastases in patients with prostate specific antigen relapse after primary local therapy. In renal cell carcinoma recent studies have shown the ability of FDG PET to detect primary and metastatic lesions and to monitor response to therapy. In the staging of testicular cancer FDG PET has been used to differentiate viable carcinoma from benign teratomas and/or fibrotic or necrotic changes., Conclusions: Current developments in PET technology that accurately stage the extent of tumor before surgery as well as monitor effectiveness or ineffectiveness of new or current therapies may make PET a valuable tool in research and in the management of urological diseases.

The use of dissolved hydrogen as an early warning signal of digester failure and a control parameter to operate anaerobic digesters was investigated. A sensitive, on-line method was developed for measuring trace levels of dissolved hydrogen in a semi-permeable membrane, situated within the biomass of a 1 L laboratory anaerobic digester, using trace reduction gas analysis. At normal operating conditions, the dissolved hydrogen partial pressure (2 to 8 Pa) was found to be linearly correlated with the loading rate of the digester, and was a sensitive indicator of the effect of shockloads as well as gradual overloading. An increase in hydrogen partial pressure above a critical concentration of 6.5-7 Pa indicated the initial stage of digester overloading (i.e., volatile fatty acids accumulation). A H(2)-based computer control system, using a critical hydrogen partial pressure of 6.5 Pa as the setpoint, was found to be effective for the safe operation of a laboratory digester close to its maximum sustainable loading rate. The existence of a relationship between hydrogen level and organic loading rate was also confirmed on a 600 m(3) industrial digester, with digester overloading occurring at hydrogen concentrations above 7 Pa. The results suggest that the dissolved hydrogen concentration is capable of being a sensitive on-line parameter for the automated management of anaerobic digesters near their maximum sustainable loading capacity. (c) 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 56: 626-634, 1997.

Background: Evidence is accumulating that specific "triggers," such as intense psychological stress, may precipitate myocardial infarction and sudden death. Patients with advanced heart failure have increased resting sympathoexcitation, which has been directly related to increased mortality. The impact of triggers on sympathetic nerve activity and regional blood flow in heart failure has not been examined in patients with heart failure., Methods and Results: Twenty-seven patients with heart failure (NYHA functional class III or IV) and 26 age-matched normal control subjects were studied. Muscle sympathetic nerve activity, heart rate, mean arterial pressure, forearm blood flow, and renal blood flow were measured during mental stress testing with mental arithmetic and Stroop color word test. Patients with heart failure had elevated levels of resting muscle sympathetic nerve activity and heart rate. Mental stress significantly increased muscle sympathetic nerve activity and heart rate in both patients with heart failure and control subjects, although the magnitude of increases tended to be blunted in patients with heart failure. Nevertheless, absolute levels of sympathetic activity in patients with heart failure remained significantly higher than levels in control subjects during mental stress. The decrease in renal blood flow in patients with heart failure was similar to that of control subjects, despite greater resting renal vasoconstriction. The increase in forearm blood flow during mental stress testing in patients with heart failure was blunted compared with that of control subjects., Conclusions: Patients with heart failure do not have augmented muscle sympathetic nerve activity responses to mental stress, despite elevated resting levels of sympathetic activity, but they do have markedly higher absolute levels of sympathetic nerve activity during mental stress as well as at rest.

Background: Lung clearance of 99mTc-labeled diethylenetriamine pentaacetate (DTPA) is a sensitive test of altered alveolar epithelial permeability that has been found to be increased in smokers of tobacco, as well as a small number of healthy smokers of crack cocaine, suggesting the possibility of subclinical crack-related lung injury., Study Objective: To evaluate further whether habitual smoking of cocaine alone alters alveolar permeability, whether crack smoking adds to or potentiates the effects of tobacco and/or marijuana, and whether experimental cocaine smoking acutely alters DTPA lung clearance., Design: Observational cohort study (habitual cocaine smoking) and single-blind crossover study (experimental cocaine administration)., Subjects: Fourteen habitual smokers of cocaine alone (CS), 19 smokers of cocaine and tobacco (CTS), 3 smokers of cocaine and marijuana, 12 smokers of cocaine, tobacco, and marijuana (CMTS), and 5 smokers of marijuana plus tobacco (MTS). Results obtained in the crack-smoking subjects were compared with data previously obtained in 10 nonsmokers (NS), 9 smokers of tobacco alone (TS), 10 smokers of marijuana alone (MS), and 4 additional MTS., Methods: Subjects underwent measurements of DTPA radioaerosol lung clearance after refraining from marijuana and/or cocaine for > 12 h and from tobacco for >2 h. Ten of the 48 crack users were tested on two days 1 to 2 weeks apart within 2 h of experimental smoking of three physiologically active or inactive doses (total 98.8+/-15.5 or 8.5+/-2.5 mg, respectively) of cocaine base. Lung clearance half-times (T1/2) were computed from time-activity curves for each lung., Results: T1/2 values for each lung in CS and MS were comparable to those of NS, while TS, MTS, CTS, and CMTS had significantly shorter clearance rates than NS (p<0.01; three-way analysis of variance). No additive or interactive effects on T1/2 were noted among tobacco, cocaine, and/or marijuana. No acute effect of experimental cocaine smoking on T1/2 was noted., Conclusion: Whereas regular smoking of tobacco alone or with other substances increases alveolar epithelial permeability, habitual smoking of cocaine and/or marijuana has no measurable effect on alveolar permeability in the absence of tobacco nor any additive effect to that of tobacco alone.

Medical imaging technology is rapidly expanding and the role of each modality is being redefined constantly. PET has been around since the early sixties and gained clinical acceptance in oncology only after an extreme number of scientific publications. Although PET has the unique ability to image biochemical processes in vivo, this ability is not fully used as a clinical imaging tool. In this overview, the role of PET in relation to other tumor imaging modalities will be discussed and the reported results in the literature will be reviewed. In predicting the future of PET, technical improvements of other imaging modalities need to be dealt with. The fundamental physical principles for image formation with computed tomography (CT), ultrasound (US), magnetic resonance imaging (MRI), photon-emission tomography (PET), and single photon emission CT (SPECT) will not change. The potential variety of radiopharmaceuticals which may be developed is unlimited, however, and this provides nuclear imaging techniques with a significant advantage and adaptive features for future biologic imaging. The current applications of PET in oncology have been in characterizing tumor lesions, differentiating recurrent disease from treatment effects, staging tumors, evaluating the extent of disease, and monitoring therapy. The future developments in medicine may use the unique capabilities of PET not only in diagnostic imaging but also in molecular medicine and genetics. The articles discussed in this review were selected from a literature search covering the last 3 years, and in which comparisons of PET with conventional imaging were addressed specifically. PET studies with the glucose analogue fluorine-18-labeled deoxyglucose (FDG) have shown the ability of detecting tumor foci in a variety of histological neoplasms such as thyroid cancer, breast cancer, lymphoma, lung cancer, head and neck carcinoma, colorectal cancer, ovarian carcinoma, and musculoskeletal tumors. Also, the contribution of the whole body PET (WBPET) imaging technique in diagnosis will be discussed. In the current health care environment, a successful imaging technology must not only change medical management but also demonstrate that those changes improve patient outcome.

The bradykinin analog, RMP-7, was investigated for its ability to increase selectively the transport of 68Ga ethylenediamine tetraacetic acid (EDTA) into recurrent malignant gliomas in nine patients. For each patient, two position emission tomography (PET) studies (one with and one without RMP-7) were performed. For studies with RMP-7, 10 to 300 ng/kg of the compound was infused into the supraophthalmic carotid artery over 15 minutes. In each PET study, a sequence of PET scans was initiated simultaneously with an intravenous bolus of 68Ga EDTA (5-10 mCi). Arterial samples were taken to provide the input function. All PET scans were coregistered to the magnetic resonance (MR) images of the patient. Regions of interest were defined for tumor and normal tissue regions on MR images and were copied to the coregistered PET dynamic images to provide brain tissue-time activity curves. The constant (Ki) for the transport of gallium-68 from plasma to brain tissue was determined using a simple compartmental model. Intracarotid infusion of RMP-7 significantly increased transport into tumor regions with an average increase of 46 +/- 42% (mean +/- standard deviation, p < 0.05). Permeability in normal tissue regions was not significantly increased. Tumors in three of six patients treated with 300 ng/kg RMP-7 and carboplatin had at least a 50% reduction in tumor volume as measured by MR imaging. Intracarotid infusion of RMP-7 is a novel technique for selective delivery of antitumor compounds into brain tumors.

Unlabelled: Accurate staging of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) is important for treatment management. In this study, the utility of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) whole-body PET was evaluated as an imaging modality for initial staging or restaging of 7 HD and 11 NHL patients., Methods: Whole-body PET-based staging results were compared to the patient's clinical stage based on conventional staging studies, which included combinations of CT of the chest, abdomen and pelvis, MRI scans, gallium scans, lymphangiograms, staging laparatomies and bone scans., Results: Accurate staging was performed in 17 of 18 patients using a whole-body PET-based staging algorithm compared to the conventional staging algorithm in 15 of 18 patients. In 5 of 18 patients, whole-body PET-based staging showed additional lesions not detected by conventional staging modalities, whereas conventional staging demonstrated additional lesions in 4 of 18 patients not detected by whole-body PET. The total cost of conventional staging was $66,292 for 16 CT chest scans, 16 CT abdominal/pelvis scans, three limited MRI scans, four bone scans, five gallium scans, two laparotomies and one lymphangiogram. In contrast, scans cost $36,250 for 18 whole-body PET studies and additional selected correlative studies: one plain film radiograph, one limited CT, one bone marrow scan, one upper GI and one endoscopy., Conclusion: A whole-body FDG-PET-based staging algorithm may be an accurate and cost-effective method for staging or restaging HD and NHL.

During static exercise, several reflex systems that increase sympathetic nerve activity, heart rate, arterial pressure, and cardiac output are activated. At rest, the renal circulation receives the most blood flow per tissue weight of any organ in the body. However, the renal circulatory response to static exercise has not been studied in humans because of technical limitations in methods for measuring rapid changes in renal blood flow. The aim of this study was to determine the renal blood flow response to static exercise in healthy humans and, specifically, to clarify the reflex mechanisms underlying this response. Renal cortical blood flow was measured using dynamic positron emission tomography and the blood flow agent oxygen-15 water. Graded handgrip exercise, posthandgrip circulatory arrest, and administration of intra-arterial adenosine were performed to clarify the mechanisms controlling renal blood flow during static exercise. The major new findings in this study are that in healthy humans (1) renal cortical blood flow decreases (basal versus handgrip, 4.4 +/- 0.1 versus 3.5 +/- 0.1 mL.min-1.g-1; P = .008) and renal cortical vascular resistance increases (basal versus handgrip, 17 +/- 1 versus 26 +/- 2 U; P = .01) in response to static handgrip exercise; (2) central command and/or the mechanoreflex contributes importantly to the early decrease in renal blood flow (basal versus handgrip, 4.2 +/- 0.2 versus 3.5 +/- 0.3 mL.min-1.g-1; P = .04) and to the increase in renal cortical vascular resistance (basal versus handgrip, 20 +/- 1 versus 25 +/- 2 U; P = .04); (3) the muscle metaboreflex contributes to further decreases in renal blood flow (basal versus posthandgrip circulatory arrest, 4.3 +/- 0.1 versus 3.5 +/- 0.2 mL.min-1.g-1; P = .002) and increases in renal cortical vascular resistance (basal versus handgrip, 18 +/- 1 versus 25 +/- 3 U; P = .002); and (4) exogenous adenosine activates the muscle metaboreflex producing reflex renal vasoconstriction and decreased renal blood flow, which may implicate endogenous adenosine generated during ischemic exercise as a potential activator of the muscle metaboreflex during ischemic handgrip exercise.

Unlabelled: The extraction of pure arterial time-activity curves (TACs) from dynamic PET images of a small animal heart using factor analysis of dynamic structures (FADS) was found to be unsuccessful due to the small size of the cardiac chamber that causes extensive mixture of TACs of different structures., Methods: In this study, we used digital phantoms of the left ventricle (LV cavity size: 1-2 cm) and small monkey (LV cavity size: approximately 2 cm) dynamic FDG PET studies to evaluate FADS for extracting the pure blood-pool TACs by adding a single blood sample (taken at a late scan time) constraint., Results: In the digital phantom studies, spillover fractions in the extracted blood-pool TACs using FADS without a blood sample constraint (FADS(-)) and with a blood sample constraint (FADS(+)) were 3%-91% and < 3%, respectively. In the monkey studies (n = 4), FADS(+) extracted blood-pool TACs matched well with the arterialized well counter measurements (% differences of curve integration; FADS(-) < 82%; FADS(+) < 9%). The microparameters (K1*, k2*, k3*, k4*) and macroparameters (Knlr), obtained from the FADS(+) blood-pool TACs, were similar to those obtained from plasma samples in a three-compartment model fitting (% differences of Knlr:phantom studies < 5%; monkey studies < 9%)., Conclusion: The FADS technique with a single-blood sample has the potential to extract the pure blood-pool TACs directly from dynamic PET images of a small animal without multiple blood sampling, region of interest definition or spillover correction.

Background: [13N]Ammonia has been validated in dog studies as a myocardial blood flow tracer. Estimates of myocardial blood flow by [13N]ammonia were highly linearly correlated to those by the microsphere and blood sample techniques. However, estimates of myocardial blood flow with [13N]ammonia in humans have not yet been compared with those by an independent technique. This study therefore tested the hypothesis that the [13N]ammonia positron emission tomographic technique in humans gives estimates of myocardial blood flow comparable to those obtained with the [15O]water technique., Methods and Results: A total of 30 pairs of positron emission tomographic flow measurements were performed in 30 healthy volunteers; 15 volunteers were studied at rest and 15 during adenosine-induced hypermia. Estimates of average and of regional myocardial blood flow by the [13N]ammonia and the [15O]water approaches correlated well (y = 0.02 + 1.02x, r = .99, P < .001 SEE = 0.023 for average and y = 0.06 + 1.00x, r = .97, P < .001, SEE = 0.025 for regional values) over a flow range of 0.45 to 4.74 mL.min-1.g-1. At rest, mean myocardial blood flow was 0.64 +/- 0.09 mL.min-1.g-1 for [13N]ammonia and 0.66 +/- 0.12 mL.min-1.g-1 for [15O]water (P = NS). For adenosine-induced hyperemia, mean myocardial blood flow was 2.63 +/- 0.75 mL.min-1.g-1 for [13N]ammonia and 2.73 +/- 0.77 mL.min-1.g-1 for [15O]water (P = NS). The coefficient of variation as an index of the observed heterogeneity of myocardial blood flow averaged, for [13N]ammonia, 9 +/- 4% at rest and 12 +/- 7% during stress and, for [15O]water, 14 +/- 11% at rest and 16 +/- 9% during stress. The coefficients of variation for [15O]water were significantly higher than those for [13N]ammonia (P = .004 at rest and P = .03 during stress)., Conclusions: The two approaches yield comparable estimates of myocardial blood flow in humans, which supports the validity of the [13N]ammonia method in human myocardium previously shown only in animals. However, the [15O]water approach reveals a greater heterogeneity (presumably method-related), which might limit the accuracy of sectorial myocardial blood flow estimates in humans.

Unlabelled: We developed a method to improve the quantitative precision of FDG-PET scans in cancer patients. The total-lesion evaluation method generates a correlation coefficient (r) constrained Patlak parametric image of the lesion together with three calculated glucose metabolic indices: (a) the total-lesion metabolic index ("KT-tle", ml/min/lesion); (b) the total-lesion voxel index ("VT-tle", voxels/lesion); and (c) the global average metabolic index ("KV-tle", ml/min/voxel)., Methods: The glucose metabolic indices obtained from conventional region of interest (ROI) and multiplane evaluation were used as standards to evaluate the accuracy of the total-lesion evaluation method. Computer simulations and four patients with metastatic melanoma before and after chemotherapy were studied., Results: Computer simulations showed that the total-lesion evaluation method has improved precision (% s.d. < 0.6%) and accuracy (approximately 10% error) compared with the conventional ROI method (% s.d. approximately 5%; approximately 25% error). The KT-tle and VT-tle indices from human FDG-PET studies using the total-lesion evaluation method showed excellent correlations with the corresponding values obtained from the conventional ROI methods and multiplane evaluation (r approximately 1.0) and CT lesion volume measurements., Conclusion: This method is a simple but reliable way to quantitatively monitor tumor FDG uptake. The method has several advantages over the conventional ROI method: (a) less sensitive to the ROI definition, (b) no need for image registration of serial scan data and (c) includes tumor volume changes in the global tumor metabolism.

Unlabelled: In this study, factor analysis of dynamic structures (FADS) was used to extract the "pure" blood-pool time-activity curves (TACs) and to generate parametric myocardial blood flow (MBF) images (pixel unit: ml/min/g)., Methods: Ten dynamic 13N-ammonia dog PET studies (three baseline, five hyperemia and two occlusion) were included. Three factors (TACs) and their corresponding factor images (the right ventricular and left ventricular blood pools and myocardial activities) were extracted from each study. The left ventricular factors matched well with the plasma TACs. The factor images of myocardium were then converted to a parametric images of MBF using a relationship derived from a two-compartment model., Results: MBF estimates obtained from FADS correlated well with MBF estimates obtained with the two-compartment model (r = 0.98, slope = 0.84) and microsphere techniques (r = 0.96, slope = 0.94). FADS-generated MBF parametric images have better image quality and lower noise levels compared to those generated with Patlak graphical analysis., Conclusion: Regional MBF can be measured accurately and noninvasively with 13N-ammonia dynamic PET imaging and FADS. The method is simple, accurate and produces parametric images of MBF without requiring blood sampling and spillover correction.

Unlabelled: Arterial sampling in dynamic PET studies can be eliminated by using left ventricular or aortic time-activity curves (TAC) obtained from user drawn regions of interest (ROIs) after appropriate spillover correction. In this study, we evaluated the feasibility of extracting the "pure" arterial TAC from dynamic PET images using factor analysis of dynamic structures (FADS)., Methods: Computer simulations were used to study the performance of the FADS algorithm with positivity constraints. Ten canine 13N-ammonia and two human FDG-PET dynamic studies were used to extract the blood TACs from FADS. Plasma samples and compartmental model fittings were used to validate the accuracy of the FADS-generated blood factors., Results: We found that FADS with positivity constraints was sufficient to extract the blood factor from the composite dynamic images. The "pure" blood-pool TACs that matched well with the arterialized well counter measurements were generated from FADS in the canine and human studies., Conclusion: FADS has the potential to accurately extract "pure" blood TAC from dynamic PET images, allowing reliable quantitation of biological information from PET studies without blood sampling, ROI drawing or spillover correction.

Unlabelled: To evaluate the effects of hematopoietic cytokines on bone marrow glucose metabolism noninvasively, we studied serial quantitative FDG-PET images in 18 patients with metastatic melanoma and normal bone marrow who were undergoing granulocyte-macrophage colony-stimulating factor (GMCSF) or macrophage colony-stimulating factor (MCSF) administration as an adjunct to chemotherapy., Methods: All patients received 14 days of cytokine therapy in three groups: four patients were treated with GMCSF (5 micrograms/kg/d SQ), eight patients were treated with GMCSF (5 micrograms/kg/d SQ) and monoclonal antibody (MAbR24) and six patients were treated with MCSF (80 micrograms/kg/d IVCI) and MAbR24. Dynamic FDG-PET imaging was performed over the lower thoracic or upper lumbar spine at four time points in each patient., Results: Baseline glucose metabolic rates in the bone marrow of these three groups of patients were similar (5.2 +/- 0.7, 4.4 +/- 0.8 and 4.8 +/- 1.2 micrograms/min/g as mean value and standard deviations, respectively). In both GMCSF and GMCSF + R24 groups, rapid increases in bone marrow glucose metabolic rates were observed during therapy. After GMCSF was stopped, bone marrow glucose metabolic rates rapidly decreased in both groups. The glucose metabolic response in these two groups was not significantly different by pooled t-statistics (p = 0.105). In the MCSF+R24 group, the increase of glucose metabolic rate on Days 3 and 10 was 35% and 31% above baseline on the average, but was not significant., Conclusion: The results support the use of parametric FDG-PET imaging for noninvasive quantitation of bone marrow glucose metabolic changes to hematopoietic cytokines in vivo.

Background: Coronary arteriography is considered the "gold standard" for evaluating the severity of a coronary stenosis. Because the resistance to blood flow through a stenotic lesion depends on a number of lesion characteristics, the physiological significance of coronary lesions of intermediate severity is often difficult to determine from angiography alone. This study of patients with coronary artery disease seeks to determine the relation between myocardial blood flow and flow reserve measured by positron emission tomography (PET) and the percent area stenosis on quantitative coronary arteriography., Methods and Results: We studied 28 subjects: 18 patients with coronary artery disease (66 +/- 8 years) and 10 age-matched healthy volunteers (64 +/- 13 years) with dynamic N-13 ammonia PET imaging at rest and after dipyridamole (0.56 mg/kg). The percent cross-sectional area stenosis was quantified on the coronary arteriograms as described by Brown et al. In the 18 patients, a total of 41 non-infarct-related coronary vessels were analyzed. Myocardial blood flows in normal regions of patients with coronary artery disease were not different than those in healthy volunteers, both at rest and after dipyridamole. As a result, the myocardial flow reserve was also similar in both groups (2.4 +/- 0.4 versus 2.6 +/- 0.7, respectively; P = NS). Quantitative PET estimates of hyperemic blood flow (r = .81, P < .00001), flow reserve (r = .78, P < .00001), and an index of the "minimal coronary resistance" (r = .78, P < .00001) were inversely and nonlinearly correlated with the percent area stenosis on angiography. Of note, PET estimates of myocardial flow reserve successfully differentiated coronary lesions of intermediate severity (50% to 70% and 70% to 90%; 2.4 +/- 0.4 versus 1.8 +/- 0.5, respectively; P = .04)., Conclusions: In patients with coronary artery disease, non-invasive measurements of myocardial blood flow and flow reserve by PET are inversely and nonlinearly related to stenosis severity as defined by quantitative angiography. Importantly, coronary lesions of intermediate severity have a differential flow reserve that decreases as stenosis increases that can be detected noninvasively by PET, thus allowing better definition of the functional importance of known coronary stenosis.

Unlabelled: The standard approach for evaluating FDG-PET kinetic studies is based upon an assumption that tissue within a representative region of interest (ROI) is relatively homogeneous in terms of FDG kinetics. In neoplasms and other disease states, tissue within an ROI may be grossly heterogeneous, due to adjacent infarcted tissue and other causes. We have developed a method employing two ROIs (one over the tumor and another over a "reference region") to deal with this level of heterogeneity., Methods: The method is based on the regular FDG model but consists of six variable parameters (6P model) which uses the kinetics in the reference region to account for the normal tissue within the tumor ROI, so that the kinetic data only associated with the tumor can be estimated. Monte Carlo simulations and human PET FDG studies were used to analyze the performance of the 6P model., Results: The narrower 95% confidence intervals of parameter estimates, which centered at the true tumor rate constants, and the smaller correlation matrix of the 6P model showed the better performance of the 6P model compared to the standard "homogeneous" four-parameter FDG model. Computer simulations further showed that the 6P model can accurately estimate the microparameters (rate constants: K1* (ml/min/g), k2* (min-1), k3* (min-1), k4* (min-1)) and the macroparameter (K (ml/min/g)) of tumor cells regardless of the percent weight of tumor cells in the lesions., Conclusions: The new method can produce more reliable and accurate estimates of tumor glucose metabolic rates with dynamic PET FDG studies.

Unlabelled: The liver plays an important role in glucose homeostasis. PET studies with 2-[F-18]fluoro-2-deoxy-D-glucose (FDG) of the liver (e.g., in neoplasms) require an understanding of the effects of dietary conditions on hepatic FDG uptake., Methods: Twenty studies were performed on 10 normal volunteers (ages 24 +/- 4) after fasting 4 to 19 hr and again after oral consumption of 100 g of dextrose to investigate tracer kinetic model configurations of FDG in the normal liver and to evaluate the impact of oral glucose on liver in normal subjects. Dynamic PET images were acquired for about 1 hr using a Siemens/CTI 931 tomograph., Results: A three-compartment model with an input function delay time parameter was the statistically preferred model configuration. The model estimated transport rate constant from plasma to liver, K1, increased significantly (p < 0.05) from 0.864 +/- 0.136 ml/min/g in fasting studies to 1.058 +/- 0.269 ml/min/g in postglucose studies. Glucose loading also significantly increased (p < 0.01) the rate constant for FDG phosphorylation, k3, from 0.005 +/- 0.003 min-1 in fasting studies to 0.013 +/- 0.007 min-1 in postglucose administration and, consequently, significantly increased both the phosphorylation fraction (k3/(k2 + k3)) and the influx constant (K1k3/(k2 + k3)). No significant differences in the liver-to-plasma transport rate constant, k2, dephosphorylation constant, k4, or distribution volume of FDG (K1/(k2 + k3)) were observed., Conclusion: Dynamic FDG-PET studies can be used to evaluate kinetics of liver glucose metabolism. The results indicate that dietary conditions have a significant effect on hepatic FDG kinetics. Because of the higher net FDG uptake by normal liver after glucose loading, fasting conditions are preferred for FDG liver tumor studies to increase the tumor-to-background contrast.

Quantitative indexes based on regions of interest ratios from preoperative thallium-201 SPECT and F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans were compared for their ability to predict the histological grade of cerebral gliomas. Of the five different ratios used to determine the index for each PET scan, the ratio of tumour versus ipsilateral hemisphere in the same plane as the tumour showed the most significant correlation with glioma grade (p < 0.001). A large study of 62 thallium-201 SPECT scans showed equally good correlation with glioma grade (p < 0.0005). The use of thallium-201 SPECT for detection of tumour recurrence had 100% sensitivity in this series, while PET scans had 90.9% sensitivity. Patients with a rate of change in serial thallium indexes of 0.475 +/- 0.278 per month survived 5.93 +/- 2.25 months from onset of index increase, while those with little change in the index (0.069 +/- 0.063 per month) survived 17.93 +/- 5.25 months from onset of index increase. Results indicate thallium-201 SPECT correlates well with tumour grade and is equally efficient as PET in screening for glioma recurrence.

Positron emission tomography (PET) is an imaging technique that can produce high-quality tomographic images reflective of the metabolic characteristics of imaged tissue. Among the many positron-emitting tracers utilized in conjunction with PET is [18F]fluoride ion; it is actively taken up in bone in proportion to bone metabolic activity, analogous to standard nuclear medicine bone scanning agents such as technetium methylenediphosphonate ([99mTc]MDP). Whole-body imaging with PET and [18F]fluoride ion generates tomographic images that are useful in mapping patterns of bone metabolism, as well as identifying extraosseous site of bone formation or calcification. We report the case of a patient with polyostotic fibrous dysplasia, metastatic osteogenic sarcoma, and a breast mass, who presented with pulmonary nodules, in whom [18F] fluoride ion/PET imaging was useful in confirming the nature of the pulmonary nodules.

Positron emission tomography (PET) of the brain and heart has made important contributions in clinical and research applications in the fields of neurology and cardiology. The more recent applications of PET in tumor imaging has marked oncology as the next frontier in PET; however, the dilemma of rising health care cost will challenge the application of new technologies. This challenge can be approached by innovative and appropriate use of sophisticated technology in both the research and clinical realms. The current developments of PET imaging technology to accurately stage the extent of tumor, as well as monitor the effectiveness or ineffectiveness of new or current therapies will be an extremely valuable tool in research and in the cost effective management of cancer patients. In the future, the oncologist may be able to adjust the chemotherapy to the tumor response based on PET imaging. In other situations, PET may be able to predict that no existing therapy will elicit a durable response, resolving the patients' and families' uncertainty of whether extreme therapeutic measures would have made a significant difference. This paper reviews some of the recent developments and areas of research in tumor PET imaging, and describes some of the practical and technical aspects involved with FDG tumor quantitation and whole body PET imaging.