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Objectives Innate immune dysfunction after major burn injuries increases the susceptibility to organ failure. Lipid mediators of inflammation resolution, e.g., resolvin D2, have been shown recently to restore neutrophil functionality and reduce mortality rate in a rat model of major burn injury. However, the physiological mechanisms responsible for the benefic activity of resolvin D2 are not well understood. Design Prospective randomized animal investigation. Setting Academic research setting. Subjects Wistar male rats. Interventions Animals were subjected to a full-thickness burn of 30% total body surface area. Two hours after burn, 25 ng/kg resolvin D2 was administered IV and repeated every day, for 8 days. At day 10 post burn, 2 mg/kg of lipopolysaccharide was administered IV, and the presence of renal and hepatic injuries was evaluated at day 11 post burn by histology, immunohistochemistry, and relevant blood chemistry. Measurements and main results In untreated animals, we found significant tissue damage in the kidneys and liver, consistent with acute tubular necrosis and multifocal necrosis, and changes in blood chemistry, reflecting the deterioration of renal and hepatic functions. We detected less tissue damage and significantly lower values of blood urea nitrogen (26.4 ± 2.1 vs 36.0 ± 9.3 mg/dL; p ≤ 0.001), alanine aminotransferase (266.5 ± 295.2 vs 861.8 ± 813.7 U/L; p ≤ 0.01), and total bilirubin (0.13 ± 0.05 vs 0.30 ± 0.14 mg/dL; p ≤ 0.01) in resolvin D2-treated rats than in untreated animals. The mean blood pressure of all animals was above 65 mm Hg, indicating adequate tissue perfusion throughout the experiments. We measured significantly larger amounts of chromatin in the circulation of untreated than of resolvin D2-treated rats (575.1 ± 331.0 vs 264.1 ± 122.4 ng/mL; p ≤ 0.05) and identified neutrophil extracellular traps in kidney and liver tissues from untreated rats, consistent with the tissue damage. Conclusions Pathologic changes in kidney and liver tissues in a rat model of major burn and endotoxin insults are ameliorated by resolvin D2.

Objective Recent studies have suggested that epidermal burn injuries are associated with inflammation and immune dysfunction. Simvastatin has been shown to possess potent anti-inflammatory properties. Thus, we hypothesized that simvastatin protects against burn-induced apoptosis in the spleen via its anti-inflammatory activity. Methods Wild-type, tumor necrosis factor alpha knockout (TNF-α KO) and NF-κB KO mice were subjected to full-thickness burn injury or sham treatment. The mice then were treated with or without simvastatin, and the spleen was harvested to measure the extent of apoptosis. Expression levels of TNF-α and NF-κB were also determined in spleen tissue and serum. Results Burn injury induced significant splenic apoptosis and systemic cytokine production. Simvastatin protected the spleen from apoptosis, reduced cytokine production in the serum, and increased the survival rate. Simvastatin decreased burn-induced TNF-α and NF-κB expression in the spleen and serum. TNF-α and NF-κB KO mice demonstrated lower levels of apoptosis in spleen in response to burn injury. Simvastatin did not further decrease burn-caused apoptosis and mortality in either strain of KO mice. Conclusions Simvastatin reduces burn-induced splenic apoptosis via downregulation of the TNF-α/NF-κB pathway.

Previous studies from our laboratories revealed a reduced rate of whole-blood (WB) glutathione (GSH) synthesis in severely burned patients. To determine whether WB GSH metabolism is an indicator of the status of GSH metabolism in one or more of the major organs, we used a burn rabbit model to determine GSH concentrations and rates of synthesis in WB, liver, lungs, kidney, and skeletal muscle. L-[1- 13 C]-cysteine was infused intravenously for 6 h in rabbits at 3 days post-burn and in sham burn controls. WB and organ 13 C-enrichment of cysteine and GSH was determined by gas chromatography/mass spectrometry. Plasma cysteine metabolic flux was increased significantly (P < 0.01) following burn injury. WB, liver, and lung GSH concentrations (P = 0.054, P < 0.05, and P < 0.05, respectively) and fractional rates of GSH synthesis (P < 0.05, P< 0.01, and P< 0.05, respectively) were reduced at 3 days post-burn. Kidney was unaffected. There also appears to be an increased rate of GSH transport out of the liver after burn injury. Hence, there is a differential impact of burn injury on tissue and organ GSH status, with WB qualitatively reflecting the changes in lung and liver. It will be important to determine whether these changes are due to alterations in the intrinsic capacity for GSH synthesis and/or availability of amino acid precursors of GSH.

The main aim of this study was to examine the relationship between dopamine transporter (DAT) binding in the striatum in individuals with and without attention-deficit/hyperactivity disorder (ADHD), attending to the 3'-untranslated region of the gene (3'-UTR) and intron8 variable number of tandem repeats (VNTR) polymorphisms of the DAT (SLC6A3) gene.Subjects consisted of 68 psychotropic (including stimulant)-naïve and smoking-naïve volunteers between 18 and 55 years of age (ADHD n = 34; control subjects n = 34). Striatal DAT binding was measured with positron emission tomography with 11C altropane. Genotyping of the two DAT (SLC6A3) 3'-UTR and intron8 VNTRs used standard protocols.The gene frequencies of each of the gene polymorphisms assessed did not differ between the ADHD and control groups. The ADHD status (t = 2.99; p.004) and 3'-UTR of SLC6A3 9 repeat carrier status (t = 2.74; p.008) were independently and additively associated with increased DAT binding in the caudate. The ADHD status was associated with increased striatal (caudate) DAT binding regardless of 3'-UTR genotype, and 3'-UTR genotype was associated with increased striatal (caudate) DAT binding regardless of ADHD status. In contrast, there were no significant associations between polymorphisms of DAT intron8 or the 3'-UTR-intron8 haplotype with DAT binding.The 3'-UTR but not intron8 VNTR genotypes were associated with increased DAT binding in both ADHD patients and healthy control subjects. Both ADHD status and the 3'-UTR polymorphism status had an additive effect on DAT binding. Our findings suggest that an ADHD risk polymorphism (3'-UTR) of SLC6A3 has functional consequences on central nervous system DAT binding in humans.

There is increasing evidence that the liver is one of the main targets for organ dysfunction after thermal injury. Most of patients suffering from severe burn trauma also have hepatic dysfunction [1, 2]. However, it is not clear whether thermal injury induces programmed cell death in the remote liver, or if an imbalance between hepatic cellular proliferation and apoptosis leads to homeostatic dysfunction of the liver [3, 4]. Simvastatin, a 3-hydroxy 3-methyl-glutaryl coenzyme-A (HMG-CoA) reductase inhibitor, has clinically been shown to reduce hepatic complications, including hepatic dysfunction and failure in severely burned patients [5]. These effects of statins have been shown to be related both directly and indirectly to blocking HMG-CoA reductase activity [6, 7]. Simvastatin interferes with the synthesis of farnesylpyrophosphate. Farnesylpyrophosphate is needed for many biosynthetic pathways, including the synthesis of ubiquinone, a component of the mitochondrial respiratory chain, and post-translational lipidation of proteins. These pathways are all involved in cellular apoptosis [8]. However, the underlying mechanism(s) remain obscure. The primary use of statins is to treat hypercholesterolemia [9]; however, accumulating data suggest that statins also exert anti-inflammatory effects by decreasing the formation of pro-inflammatory cytokines, chemokines, and reactive oxygen species [10, 11]. Burn injury can induce significant inflammatory reactions in the liver, which may trigger or promote hepatic cellular apoptosis. However, it is not known whether statins suppress susceptibility to burn-induced hepatic apoptosis via their anti-inflammatory properties. Clinically, statins have been shown to decrease the morbidity and mortality rate in burn patients which is attributable to reduction of liver complications [12]. Therefore we hypothesize that the protective role of statins on liver is related to a reduction of apoptosis and it is necessary to evaluate the effects of statin on hepatocyte apoptosis. Tumor necrosis factor-α (TNF-α), a key mediator of the effects of burn injury, has been shown to promote leukocyte recruitment and to induce hepatocyte apoptosis in some disease conditions [13, 14]. TNF-α initiates cellular apoptosis as a potent extracellular stimulator. Downstream of the apoptotic TNF-α signaling pathway, caspase-3 plays a crucial role in the guidance of cells to undergo apoptosis [15]. Cleavage of procaspase-3 leads to active casepase-3 expression. Furthermore, Slotta and colleagues have found that simvastatin can reduce TNF-α expression and apoptosis in endotoxin-induced liver injury [16, 17]. It is not clear if burn injury promotes TNF-α expression in the liver or if simvastatin affects hepatocellular apoptosis via the TNF-α/caspase-3 pathway. In the present study, we hypothesized that treatment with simvastatin reduces burn-induced apoptosis and may exert this anti-apoptotic activity by reducing pro-inflammatory cytokines, specifically, TNF-α and caspase-3. To test this hypothesis, we used an experimental model in which mice were exposed to thermal injury and then treated with simvastatin.

Hypermetabolism is a prominent feature of burn injury, and altered mitochondria function is presumed to contribute to this state. Recently, brown adipose tissue (BAT) was found to be present not only in rodents but also in humans, and its activity is associated with resting metabolic rate. In this report, we elucidate the relationship between burn injury-induced hypermetabolism and BAT activity and the possible role of the mitochondria-targeted peptide SS31 in attenuating burn injury-induced hypermetabolism by using a rat burn injury model. We demonstrate that burn injury induces morphological changes in interscapular BAT (iBAT). Burn injury was associated with iBAT activation, and this effect was positively correlated with increased energy expenditure. BAT activation was associated with augmentation of mitochondria biogenesis, and UCP1 expression in the isolated iBAT mitochondria. In addition, the mitochondria-targeted peptide SS31 attenuated burn injury-induced hypermetabolism, which was accompanied by suppression of UCP1 expression in isolated mitochondria. Our results suggest that BAT plays an important role in burn injury-induced hypermetabolism through its morphological changes and expression of UCP1.

Purpose We investigated the metabolic response of lung cancer to radiotherapy or chemoradiotherapy by 18F-FDG PET and its utility in guiding timely supplementary therapy. Methods Glucose metabolic rate (MRglc) was measured in primary lung cancers during the 3 weeks before, and 10–12 days (S2), 3 months (S3), 6 months (S4), and 12 months (S5) after radiotherapy or chemoradiotherapy. The association between the lowest residual MRglc representing the maximum metabolic response (MRglc-MMR) and tumor control probability (TCP) at 12 months was modeled using logistic regression. Results We accrued 106 patients, of whom 61 completed the serial 18F-FDG PET scans. The median values of MRglc at S2, S3 and S4 determined using a simplified kinetic method (SKM) were, respectively, 0.05, 0.06 and 0.07 μmol/min/g for tumors with local control and 0.12, 0.16 and 0.19 μmol/min/g for tumors with local failure, and the maximum standard uptake values (SUVmax) were 1.16, 1.33 and 1.45 for tumors with local control and 2.74, 2.74 and 4.07 for tumors with local failure (p

Presently, there are no effective treatments for several diseases involving the central nervous system (CNS). While several novel molecular approaches are being developed, many of them require delivery of macromolecular or supramolecular agents to the CNS tissues protected by the blood–brain and blood–arachnoid barriers. A variety of approaches that are being developed for overcoming or bypassing the barriers are based on complex transfer processes. The delivery of biopharmaceuticals and other macromolecules and particulates to the CNS, especially through the leptomeningeal (intrathecal) route, includes a variety of stages, such as leptomeningeal propagation, drainage to the systemic circulation, and penetration into the CNS. The investigation of complex pharmacokinetics that includes convective, as well as diffusional and active transfer processes, greatly benefit from real-time non-invasive in vivo monitoring of the drug transport. Pharmacological positron emission tomography (PET) imaging, which enables such monitoring, plays an increasingly significant role in drug delivery and biopharmacology. PET is a powerful tool for quantitative in vivo tracking of molecules labeled with positron-emitting radionuclides. The high sensitivity, format, and accuracy of the data (similar to those of conventional tissue sampling biodistribution studies) make PET a readily adoptable pharmacological technique. In contrast to the conventional studies, PET also allows for longitudinal nonterminal same-animal studies. The latter may not only improve the data statistics, but also enable preclinical studies (especially in large and/or rare animals) not feasible under the conventional approach. This paper is intended to demonstrate the character of data that can be obtained by PET and to demonstrate how the main patterns of the leptomeningeal route pharmacokinetics can be investigated using this method. Examples of data processing are taken from our recent studies of five model proteins in rats and nonhuman primates.

In mice, it has been demonstrated that at 7 days after burn injury, injection of lipopolysaccharide (LPS) is more lethal than the same dose at 1 day after injury. In the present study, we examined the effect of LPS injection to mice burned 7 days previously on glucose metabolism ([(18)F] 2-fluoro-2-deoxy-D-glucose [(18)FDG] uptake) in vivo. CD-1 male mice (25-28 g, Charles River Breeding Laboratories, Wilmington, MA) were anesthetized, backs shaven, and subjected to dorsal full thickness burn on 25% TBSA. Sham-treated animals were used as controls. Six days after burn injury, all mice were fasted overnight. One half of the burned and sham controls were subsequently injected IP with LPS (10 mg/kg; Escherichia coli). The remaining animals were injected with saline IP. Two hours later, all mice were injected IV with 50 μCi of (18)F FDG. One hour later, the animals were euthanized, and biodistribution was measured. Tissues were weighed, and radioactivity was measured with a well-type γ counter. Results were expressed as %dose/g tissue, mean ± SEM. The combination of burn 7 days previously and LPS significantly increased mortality compared to animals with burn alone, LPS alone, or sham controls. Burn injury 7 days previously caused a significant decrease in (18)FDG uptake by the brain compared to sham controls. The combination of LPS and burn injury 7 days previously produced a significant increase in (18)FDG uptake by brown adipose tissue and heart compared with either treatment separately. LPS produced a significant increase in (18)FDG uptake by lung, spleen, and gastrointestinal tract of the sham animals, changes that were different in mice burned 7 days previously and injected with LPS. The present results suggest that burn injury 7 days previously predisposes mice to alterations in (18)FDG uptake produced by LPS. These changes may relate, in part, to the increased lethality of LPS injection in previously burned mice.

Treatment with statins, inhibitors of HMG-CoA reductase, extends the survival of septic mice. However, the molecular mechanisms underlying the cholesterol-lowering, independent beneficial effects of statins in sepsis are poorly understood. The inhibition of protein isoprenylation, namely farnesylation and geranylgeranylation, has been proposed as a mediator of the pleiotropic protective effects of statins, although direct evidence is lacking. Major features of sepsis-induced immune suppression include T-cell dysfunction, which is characterized by apoptosis of splenic T cells, increased CD4(+)Foxp3(+) regulatory T cells (Tregs), and suppression of type 1 helper T-cell response [e.g., interferon-γ (IFN-γ) secretion] in mice. Here, we show that the induction of sepsis by cecal ligation and puncture (CLP) resulted in increases in farnesyltransferase activity and farnesylated proteins in the spleen relative to sham operation. Treatment with farnesyltransferase inhibitor N-[4-[2(R)-amino-3-mercaptopropyl]amino-2-phenylbenzoyl]methionine methyl ester trifluoroacetate salt (FTI-277) (25 mg/kg b.wt. i.p.) at 2 h after CLP blocked the increase in farnesylated proteins and improved survival and bacterial clearance of septic mice. FTI-277 reverted to or mitigated sepsis-induced apoptosis in spleen and thymus, increased splenic CD4(+)Foxp3(+) Tregs, and suppressed IFN-γ secretion and proliferation of splenocytes in response to anti-CD3+CD28 antibodies in mice. Moreover, FTI-277 promoted macrophage phagocytotic activity in septic mice. These results indicate that elevation in protein farnesylation plays a role in derangements in immune function and mortality of septic mice. These findings suggest that prevention of immune dysfunction might contribute to FTI-277-induced improvement in survival of septic mice. These data highlight protein farnesyltransferase as a novel potential molecular target to reduce the mortality of patients with sepsis.

BackgroundNeuroimaging research has demonstrated medial prefrontal cortex (mPFC) hyporesponsivity and amygdala hyperresponsivity to trauma-related or emotional stimuli in post-traumatic stress disorder (PTSD). Relatively few studies have examined brain responses to the recollection of stressful, but trauma-unrelated, personal events in PTSD. In the current study, we sought to determine whether regional cerebral blood flow (rCBF) abnormalities in mPFC and amygdala in PTSD could be observed during the recollection of trauma-unrelated stressful personal events.MethodParticipants were 35 right-handed male combat veterans (MCVs) and female nurse veterans (FNVs) who served in Vietnam: 17 (seven male, 10 female) with current military-related PTSD and 18 (nine male, nine female) with no current or lifetime PTSD. We used positron emission tomography (PET) and script-driven imagery to study rCBF during the recollection of trauma-unrelated stressful versus neutral and traumatic events.ResultsVoxelwise tests revealed significant between-group differences for the trauma-unrelated stressful versus neutral comparison in mPFC, specifically in the anterior cingulate cortex (ACC). Functional region of interest (ROI) analyses demonstrated that this interaction in mPFC represented greater rCBF decreases in the PTSD group during trauma-unrelated stressful imagery relative to neutral imagery compared to the non-PTSD group. No differential amygdala activation was observed between groups or in either group separately.ConclusionsVeterans with PTSD, compared to those without PTSD, exhibited decreased rCBF in mPFC during mental imagery of trauma-unrelated stressful personal experiences. Functional neuroanatomical models of PTSD must account for diminished mPFC responses that extend to emotional stimuli, including stressful personal experiences that are not directly related to PTSD.

Background Hyperglycemia with insulin resistance is commonly seen in severely burned patients and tight glycemia control with insulin may be beneficial in this condition. The most potent insulinotropic hormone, gucagon-like peptide 1 (GLP-1), stimulates insulin secretion in a glucose-dependent manner. Because infusion of GLP-1 never reduces glucose levels to below ∼70 mg/dL, the risk of hypoglycemia by using insulin is reduced. In this study we investigated the metabolic effects of GLP-1 infusion after burn injury in an animal model. Methods Male CD rats were divided in 3 groups: burn injury with saline, burn injury with GLP-1 treatment, and sham burn (SB). Burn injury was full thickness 40% total body surface area. The burn injury with GLP-1 treatment group received GLP-1 infusion via osmotic pump. Fasting blood glucose, plasma insulin, and plasma GLP-1 levels were measured during intraperitoneal glucose tolerance tests. Expressions of caspase 3 and bcl-2 were evaluated in pancreatic islets. In a subset of animals, protein metabolism and total energy expenditure were measured. Results Fasting GLP-1 was reduced in burn injury with saline compared to SB or burn injury with GLP-1 treatment. Burn injury with GLP-1 treatment showed reduced fasting blood glucose, improved intraperitoneal glucose tolerance test results, with increased plasma insulin and GLP-1 responses to glucose. GLP-1 reduced protein breakdown and total energy expenditure in burn injury with GLP-1 treatment versus burn injury with saline, with improved protein balance. Increased expression of caspase 3 and decreased expression of bcl-2 in islet cells by burn injury were ameliorated by GLP-1. Conclusion Burn injury reduced plasma GLP-1 in association with insulin resistance. GLP-1 infusion improved glucose tolerance and showed anabolic effects on protein metabolism and reduced total energy expenditure after burn injury, possibly via insulinotropic and non insulinotropic mechanisms.

With the growing number of biotechnology products and drug delivery systems entering preclinical and clinical studies, pharmacological imaging studies with PET play an increasingly significant role. Such studies often require investigation of slow and complex pharmacokinetics (PK). This suggests labeling of the drug candidate with radionuclides that have long physical half-lives. Among the currently available PET positron emitters, ¹²⁴I has the longest physical half-life (4.2 days). This, combined with the well-investigated behavior of iodine in vivo, makes ¹²⁴I very attractive for pharmacological studies. However, the high energy of the positrons emitted by ¹²⁴I and the presence of single photons in the ¹²⁴I emission can potentially introduce limitations in the quantitative analysis of the images. The objective of this research was to determine whether the use of ¹²⁴I as a PET label provides data quality suitable for PK studies. The study was carried out using MicroPET P4 scanner (Siemens/Concorde Microsystems). Spatial resolution, count-rate performance, sensitivity and scatter fraction were measured using a line source and a cylindrical phantom. Model animal studies in rats and cynomolgus monkeys were carried out using human recombinant proteins. The proteins were labeled with ¹²⁴I, up to 185 MBq/mg. The transaxial and axial spatial resolutions in the center of the camera were satisfactory and higher for OSEM3D/MAP than FORE-2DFBP (FWHM 2.52 vs 3.31 mm, and 3.10 vs 3.69 mm). Linearity of the true coincidence count-rate was observed up to 44 MBq. Animal studies demonstrated excellent delineation and resolution of even very small organs. At optimal doses, 2-10 MBq per animal for rodents and 4-10 MBq per kg of body weight for larger animals, the quality of numerical data was appropriate for PK analysis in all experimental timeframes from minutes (dynamic studies) to 10 days. Overall, the data suggest that ¹²⁴I is an excellent label for quantitative pharmacological PET imaging studies.

Background Armodafinil, prescribed principally to treat narcolepsy, is undergoing assessment of therapeutic potential for other neuropsychiatric disorders and medical conditions. The neurochemical substrates and mechanisms of armodafinil are unresolved. We investigated the hypothesis that armodafinil enhances wakefulness by modulating the activities of the dopamine transporter (DAT). With positron emission tomography imaging, we determined DAT occupancy and changes in extracellular dopamine by armodafinil in vivo. Methods Twelve subjects were enrolled. Plasma armodafinil levels were obtained. In vivo armodafinil occupancy of the DAT in striatum was detected by [ 11 C]altropane and changes in extracellular dopamine were detected by indirect displacement of [ 11 C]raclopride in human subjects at different times after drug administration. Results Armodafinil (100 mg by mouth [PO]) occupied striatal DAT (34.0 ± 9.0% at 1 hour, 40.4 ± 9.5% at 2.5 hours, n = 6) and 250 mg occupied striatal DAT (60.5 ± 7.4% at 1 hour, 65.2 ± 6.1% at 2.5 hours, n = 6). In addition, armodafinil was associated with changes in extracellular dopamine (17.8 ± 30.1% [100 mg PO] and 7.0 ± 8.6% [250 mg PO] at 2.5 hours, n = 6). Conclusions Occupancy of the DAT and changes in extracellular dopamine in vivo further implicates the actions of armodafinil on DAT as a potential candidate for its therapeutic improvement of wakefulness and other conditions.

Despite significant advances in burn resuscitation and wound care over the past 30 years, morbidity and mortality from thermal injury remain high. Limited donor skin in severely burned patients hinders effective wound excision and closure, leading to infectious complications and prolonged hospitalizations. Even with large-volume fluid resuscitation, the systemic inflammatory response syndrome compromises end-organ perfusion in burn patients, with resultant multiorgan failure. Stem cells, which enhance wound healing and counteract systemic inflammation, now offer potential therapies for these challenges. Through a review of the literature, this article seeks to illustrate applications of stem cell therapy to burn care and to highlight promising areas of research.

The lipophilic cationic compound, (4-[18F]fluorophenyl)triphenylphosphonium ion (18F-FTPP) was synthesized and evaluated as a potential positron emission tomography (PET) myocardial perfusion agent. 18F-FTPP was prepared from (4-nitrophenyl)triphenylphosphonium nitrate and ammonium [18F]fluoride by nucleophilic aromatic substitution and was purified by high performance liquid chromatography before use. Biodistribution studies were performed in rats at 5, 30, 60 min (five rats per time point). Three rats were evaluated by microPET imaging after injection of 18F-FTPP. In addition, microPET imaging in rabbits (three) was performed before and after occlusion of the left anterior descending (LAD) artery with 13NH3 (111 MBq) and 18F-FTPP (74 MBq). Biodistribution data in rats showed rapid blood clearance and high levels of accumulation in the heart; 75:1 heart-to-blood ratio at 30 min. Uptake of radioactivity in the heart was 1.64% ID/G, 1.51% ID/g, and 1.57% ID/g at 5, 30, and 60 min. At 5, 30, and 60 min, lung activity was 0.69% ID/g, 0.03% ID/g, and 0.38% ID/g, and liver uptake was 0.34% ID/g, 0.18% ID/g, and 0.17% ID/g. Heart-to-lung ratios at 5, 30, and 60 min were 2, 5, and 4. Bone accumulation was minimal. MicroPET imaging in both rats and rabbits after injection of 18F-FTPP demonstrated an initial spike of activity in the myocardium corresponding to blood flow followed by a plateau after 1 min. Region of interest analysis of microPET images of normal and LAD-occluded rabbits with 13NH3 and 18F-FTPP indicated similar distributions of the two tracers in both normal and altered blood flow regions. The excellent heart-to-blood ratio of 18F-FTPP and its correlation with 13NH3 distribution in normal and LAD-occluded rabbits suggest that this radiopharmaceutical may have potential as a PET agent for characterizing mitochondrial damage and/or myocardial blood flow.

The purpose of this study is to assess which of five bowel preparation regimes offers superior bowel distension and to assess if these regimes adversely affect FDG activity on PET/CT imaging. The study conformed to HIPAA regulations. Ninety patients were divided into five groups of 18 who received no oral contrast agent (group A); 900 ml of water orally (group B); or 900, 1,350, or 1,800 ml of LDB (groups C, D, E, respectively). PET/CT examinations were assessed quantitatively (bowel diameter, SUV) and qualitatively (visual assessment grading scale) for bowel distension and FDG activity by two blinded readers. ANOVA was utilized to determine if a statistically significant difference (SSD) existed between the groups in terms of distension and FDG uptake. Qualitatively superior bowel distension was observed in group C (LDB) compared to B (water) and greater distension was noted with increased volumes of LDB in C, D, and E. Quantitatively there was an SSD in mean distension between groups C and B (P0.001 except duodenum). Qualitatively and quantitatively there was no significant difference in bowel FDG uptake among the groups (P0.05). LDB as an oral contrast agent provides superior bowel distension over water and does not induce increased FDG bowel activity.

Purpose To assess the safety and efficacy of neoadjuvant bevacizumab with standard chemoradiotherapy in locally advanced rectal cancer and explore biomarkers for response. Patients and Methods In a phase I/II study, 32 patients received four cycles of therapy consisting of: bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; fluorouracil infusion (225 mg/m2/24 hours) during cycles 2 to 4; external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks); and surgery 7 to 10 weeks after completion of all therapies. We measured molecular, cellular, and physiologic biomarkers before treatment, during bevacizumab monotherapy, and during and after combination therapy. Results Tumors regressed from a mass with mean size of 5 cm (range, 3 to 12 cm) to an ulcer/scar with mean size of 2.4 cm (range, 0.7 to 6.0 cm) in all 32 patients. Histologic examination revealed either no cancer or varying numbers of scattered cancer cells in a bed of fibrosis at the primary site. This treatment resulted in an actuarial 5-year local control and overall survival of 100%. Actuarial 5-year disease-free survival was 75% and five patients developed metastases postsurgery. Bevacizumab with chemoradiotherapy showed acceptable toxicity. Bevacizumab decreased tumor interstitial fluid pressure and blood flow. Baseline plasma soluble vascular endothelial growth factor receptor 1 (sVEGFR1), plasma vascular endothelial growth factor (VEGF), placental-derived growth factor (PlGF), and interleukin 6 (IL-6) during treatment, and circulating endothelial cells (CECs) after treatment showed significant correlations with outcome. Conclusion Bevacizumab with chemoradiotherapy appears safe and active and yields promising survival results in locally advanced rectal cancer. Plasma VEGF, PlGF, sVEGFR1, and IL-6 and CECs should be further evaluated as candidate biomarkers of response for this regimen.

(82)Rb cardiac PET allows the assessment of myocardial perfusion with a column generator in clinics that lack a cyclotron. There is evidence that the quantitation of myocardial blood flow (MBF) and coronary flow reserve (CFR) with dynamic (82)Rb PET is feasible. The objectives of this study were to determine the accuracy and reproducibility of MBF estimates from dynamic (82)Rb PET by using our methodology for generalized factor analysis (generalized factor analysis of dynamic sequences [GFADS]) and compartment analysis.Reproducibility was evaluated in 22 subjects undergoing dynamic rest and dipyridamole stress (82)Rb PET studies at a 2-wk interval. The inter- and intraobserver variability of MBF quantitation with dynamic (82)Rb PET was assessed with 4 repeated estimations by each of 4 observers. Accuracy was evaluated in 20 subjects undergoing dynamic rest and dipyridamole stress PET studies with (82)Rb and (13)N-ammonia, respectively. The left ventricular and right ventricular blood pool and left ventricular tissue time-activity curves were estimated by GFADS. MBF was estimated by fitting the blood pool and tissue time-activity curves to a 2-compartment kinetic model for (82)Rb and to a 3-compartment model for (13)N-ammonia. CFR was estimated as the ratio of peak MBF to baseline MBF.The reproducibility of the MBF estimates in repeated (82)Rb studies was very good at rest and during peak stress (R(2)= 0.935), as was the reproducibility of the CFR estimates (R(2) = 0.841). The slope of the correlation line was very close to one for the estimation of MBF (0.986) and CFR (0.960) in repeated (82)Rb studies. The intraobserver reliability was less than 3% for the estimation of MBF at rest and during peak stress as well as for the estimation of CFR. The interobserver reliabilities were 0.950 at rest and 0.975 at peak stress. The correlation between myocardial flow estimates obtained at rest and those obtained during peak stress in (82)Rb and (13)N-ammonia studies was very good (R(2) = 0.857). Bland-Altman plots comparing CFR estimated with (82)Rb and CFR estimated with (13)N-ammonia revealed an underestimation of CFR with (82)Rb compared with (13)N-ammonia; the underestimation was within +/-1.96 SD.MBF quantitation with GFADS and dynamic (82)Rb PET demonstrated excellent reproducibility as well as intra- and interobserver reliability. The accuracy of the absolute quantitation of MBF with factor and compartment analyses and dynamic (82)Rb PET was very good, compared with that achieved with (13)N-ammonia, for MBF of up to 2.5 mL/g/min.

Objectives This study tests the hypothesis that absolute measurement of adenosine (Ado)-stimulated myocardial blood flow (MBFado) is superior to measurement of relative tracer uptake for identification of hemodynamically significant coronary artery disease (CAD). Background Positron emission tomography measurement of absolute myocardial blood flow (MBF) (13N-ammonia) with Ado has the capability to more accurately assess hemodynamic severity of CAD than measurement of relative tracer content (TC) (nCi/ml) during Ado, which by definition depends on at least 1 normal zone to which others are compared. Methods A total of 27 patients (20 male, 58 ± 11 years, mean ± SD) with known or suspected CAD and 21 normal subjects (13 male, 38 ± 10 years) were studied. Parametric (K1) MBF images and TC sum images were analyzed. A stenosis ≥70% defined significant CAD. The receiver-operator characteristic curve (ROC) analysis area under the curve (AUC) compared MBF and TC results. Cut-point analysis for sensitivity, specificity, and accuracy showed the best MBF criteria for CAD as MBFado Results The ROC analysis of PET parameters showed that MBFado was superior to Conclusions Measurement of Ado-stimulated absolute MBF is superior to relative measurement of myocardial tracer retention for identification of CAD and can be accomplished with a single MBFado measurement.

Purpose We determined whether evaluation of treatment response is feasible by measuring metabolic tumor volume parameters on 18F-FDG (Fluorodeoxyglucose) PET–CT (Positron emission tomography–Computed tomography). We compared the response evaluation based on metabolic tumor volume parameters to a histopathologic and clinical response evaluation (clinical response criteria: RECIST criteria = Response evaluation criteria in solid tumors, and WHO criteria = World health organization). Patients and methods A total of 51 study subjects with adenocarcinomas (Type I due to Siewert classification) of the esophagus underwent PET–CT scans before and after neoadjuvant chemoradiotherapy. Tumor volume, maximum and mean standardized uptake values (SUV) were assessed before and after chemoradiotherapy. Furthermore, the total lesion glycolysis (TLG) was calculated by multiplying the tumor volume by the mean SUV of the volume. Clinical response evaluation was performed with endoscopic ultrasound and CT using RECIST and WHO criteria. The reference standard for treatment response was the postsurgical histopathology. Results The decrease of tumor volume between the pre- and post-treatment PET–CT scans was a better predictor of histopathologic response and survival than the decrease of the SUV and of the clinical response evaluation based on RECIST and WHO criteria. The highest accuracy, however, was achieved when using the TLG for the identification of treatment responders. A decrease of the TLG by >78% between pre- and post-therapy scans predicted histopathologic response with a sensitivity and specificity of 91% and 93%, respectively. Conclusions Tumor volume and TLG can be used to assess treatment response and survival in patients with esophageal adenocarcinoma.

Functional neuroimaging studies suggest that a lateral network in the brain is associated with the sensory aspects of pain perception while a medial network is associated with affective aspects. The highest concentration of opioid receptors is in the medial network. There is significant evidence that endogenous opioids are central to the experience of pain and analgesia. We applied an integrative multimodal imaging approach during acupuncture. We found functional magnetic resonance imaging signal changes in the orbitofrontal cortex, insula, and pons and [11C]diprenorphine positron emission tomography signal changes in the orbitofrontal cortex, medial prefrontal cortex, insula, thalamus, and anterior cingulate cortex. These findings include brain regions within both the lateral and medial pain networks.

Background: Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD). Objectives: To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features. Methods: Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio. Results: Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function. Conclusions: Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism. GLOSSARY: AAL = Automated Anatomic Labeling; AD = Alzheimer disease; ADRC = Alzheimer’s Disease Research Center; AMNART = American version of the National Adult Reading Test; ANCOVA = analysis of covariance; BDS = Blessed Dementia Scale; CAA = cerebral amyloid angiopathy; CDR = Clinical Dementia Rating; CDR-SB = Clinical Dementia Rating Sum of Boxes; DLB = dementia with Lewy bodies; DVR = distribution volume ratio; FCSRT = Cued Selective Reminding Test; FRSRT = Free Selective Reminding Test; HY MGH = Massachusetts General Hospital; MMSE = Mini-Mental State Examination; NC = normal control; NFT = neurofibrillary tangle; NPIQ = Neuropsychiatric Inventory Questionnaire; NS = not significant; PD = Parkinson disease; PDD = Parkinson disease dementia; PiB = Pittsburgh Compound B; ROI = region of interest; SPM2 = Statistical Parametric Mapping; UKPDSBRC = UK Parkinson’s Disease Society Brain Bank Research Center; UPDRS = United Parkinson’s Disease Rating Scale; WAIS-R = Wechsler Adult Intelligence Scale–Revised.

We investigated the utility of metabolic tumor width parameters in predicting response to chemoradiotherapy and in predicting disease-free survival in patients with esophageal cancer. Furthermore, we evaluated the possible confounding effect of therapy-induced esophagitis on the evaluation of treatment response. Forty-nine patients with squamous cell carcinoma, who had undergone positron emission tomography/computed tomography (PET/CT) exams before and after neoadjuvant chemoradiotherapy, were included in the study. In the slice with the maximum 2-deoxy-2-[F-18]fluoro-D: -glucose (FDG) uptake of the tumor, the following metabolic tumor width parameters were measured: Area of the tumor, maximum diameter of the tumor, maximum and mean standardized uptake value (SUV). Furthermore, the "diameter-SUV index" was calculated by multiplying the tumor diameter by the mean SUV.The decrease of the metabolic tumor diameter between pre- and post-treatment PET/CT scans was the single best predictor of treatment response and tumor-free survival. However, the accuracy of predicting response and survival was even higher when using the decrease of the "diameter-SUV index" as the metabolic criterion for treatment response. A decrease by more than 55% of the diameter-SUV index identified pathologic responders (n = 22) with a sensitivity of 91% and a specificity of 93%. Radiation esophagitis was found to have a significant impact on the assessment of treatment response when evaluating therapy response based on the maximum SUV, whereas no confounding effect of radiation esophagitis was seen when evaluating therapy response based on the tumor diameter or the diameter-SUV index.The present study shows that tumor width parameters, especially the tumor diameter or the combination of diameter and SUV in the "diameter-SUV index", are valuable for predicting tumor-free survival and treatment response independent from the presence of radiation esophagitis.

Objectives: To compare low-radiation dose nonenhanced fluorine 18 fluorodeoxyglucose (F-18 FDG) positron emission tomography (PET)/computed tomography (CT) (NE-PET/CT), contrast-enhanced fluorine 18 fluorodeoxyglucose PET/CT (CE-PET/CT), and gadolinium-enhanced liver magnetic resonance imaging (MRI) for the detection and characterization of liver lesions in patients with colorectal cancer (CRC). Methods: In this retrospective review of imaging database of CRC patients with suspected liver metastases, 33 patients (22 men, 11 women; mean age, 63 years) evaluated with low-radiation dose NE-PET/CT, CE-PET/CT, and liver MRI were studied. The final diagnosis was established either by pathological examination or follow-up imaging over a period of at least 6 months for lesion stability or growth. The liver lesions were characterized on an ordinal scale of 0 to 6 (0 = absent, 1 = definitely benign, and 6 = definitely malignant). Receiver operating characteristic analysis was performed to compare performance of the 3 imaging methods. Results: A total of 110 lesions were present on follow-up. The detection rate on low-radiation dose NE-PET/CT, CE-PET/CT, and MRI was 73.6%, 90.9%, and 95.4%, respectively. Magnetic resonance imaging (P < 0.001) and CE-PET/CT (P < 0.001) had a higher detection rate than low-radiation dose NE-PET/CT. There was no significant statistical difference in lesion detection between MRI and CE-PET/CT (P = 0.11). The sensitivity, specificity, and accuracy for characterization of detected liver lesions on low-radiation dose NE-PET/CT were 67%, 60%, and 66%, respectively; those on CE-PET/CT were 85%, 100%, and 86%, respectively; and those on MRI were 98%, 100%, and 98%, respectively. Comparative receiver operating characteristic analysis showed an area under curve of 0.74 for low-radiation dose NE-PET/CT, 0.86 for CE-PET/CT, and 0.97 for MRI. There were statistically significant differences in the accuracy of MRI, low-radiation dose NE-PET/CT, and CE-PET/CT for lesion characterization. Conclusions: When performing PET/CT, optimal detection and characterization of liver lesions require the use of a fused contrast-enhanced CT. Magnetic resonance imaging and CE-PET/CT have similar lesion detection rates. Magnetic resonance imaging is the best test for liver lesion characterization in patients with CRC.

To determine if low-dose attenuation correction computed tomography (CTAC) 1) provides images with acceptable anatomic definition and noise compared with standard-dose CTAC and 2) provides acceptable positron emission tomographic attenuation correction.Positron emission tomography/computed tomography was performed on 78 patients. Forty-three patients underwent CTAC with tube current based on a standard weight-based scale. A second group of 35 patients underwent CTAC with tube current based on a low-dose weight-based scale. In a blinded review, two radiologists rated each examination for anatomic definition and image noise at 4 major anatomic levels using a 5-point scale. To evaluate for correct positron emission tomographic attenuation correction at the standard and reduced radiation doses on CTAC, water phantom studies using both imaging techniques were performed and compared.Patients who underwent low-dose CTAC received a mean 60.6% reduction in radiation dose compared with those who underwent standard-dose CTAC (P.0001). Low-dose CTAC demonstrated statistically significant poorer ratings for anatomic detail and noise at each of the 4 anatomic levels (P.0001) compared with standard-dose CTAC. Scans were graded acceptable for diagnostic interpretation if scores for image noise and anatomic definition were greater than 3 at all anatomic levels. There was a significant difference between the number of acceptable diagnostic scans in the standard-dose group (88.4%) compared with the low-dose group (17.1%) (P.0001). There was no statistical difference in attenuation correction values in low-dose and standard-dose attenuation correction maps of the water phantom.Low-dose CTAC significantly reduced the effective dose while providing optimal positron emission tomographic attenuation correction. However, because of decreased image quality, low-dose CTAC was not acceptable for diagnostic interpretation.

We studied the pattern of striatal dopamine release during performance of an explicit motor memory task in healthy volunteers. The release was estimated by dynamically measuring concentration of a dopamine ligand using a positron emission tomography camera. An increased release of endogenous dopamine in the dorsomedial aspect of posterior putamen and in the anterior part of the caudate bilaterally was observed, during task performance. As we have earlier observed dopamine release in all of these areas, except the right putamen, in an implicit motor memory task, it seems that the striatal dopaminergic network for implicit and explicit motor memories are essentially similar.

For almost three decades, noninvasive radionuclide procedures for the evaluation of renal disease have been important components of nuclear medicine practice. With the introduction of new imaging agents and procedures, these techniques can provide valuable data on perfusion and function of individual kidneys. In general, these procedures are easy to perform and carry a low radiation burden and sedation is not required. Moreover, radionuclide imaging of the genitourinary tract has become an invaluable asset to clinicians in the evaluation of renal parenchyma and urologic abnormalities.

Inflammation plays an important role in the pathophysiology of atherosclerotic disease. We have previously shown that the targeted photosensitizer chlorin (e6) conjugated with maleylated albumin (MA-ce6) is taken up by macrophages via the scavenger receptor with high selectivity. In a rabbit model of inflamed plaque in New Zealand white rabbits via balloon injury of the aorto-iliac arteries and high cholesterol diet we showed that the targeted conjugate showed specificity towards plaques compared to free ce6. We now show that an intravascular fiber-based spectrofluorimeter advanced along the -iliac vessel through blood detects 24-fold higher fluorescence in atherosclerotic vessels compared to control rabbits (p < 0.001 ANOVA). Within the same animals, signal derived from the injured iliac artery was 16-fold higher than the contralateral uninjured iliac (p < 0.001). Arteries were removed and selective accumulation of MA-ce6 in plaques was confirmed using: (1) surface spectrofluorimetry, (2) fluorescence extraction of ce6 from aortic segments, and (3) confocal microscopy. Immunohistochemical analysis of the specimens showed a significant correlation between MA-ce6 uptake and RAM-11 macrophage staining (R = 0.83, p < 0.001) and an inverse correlation between MA-ce6 uptake and smooth muscle cell staining (R=−0.74, p < 0.001). MA-ce6 may function as a molecular imaging agent to detect and/or photodynamically treat inflamed plaques.

Sequential learning is an important aspect of cognitive processing. Neuropharmacological evidence acquired in laboratory animals suggests that striatal dopaminergic mechanisms may be important for processing of this form of learning. However, because experiments conducted on dopamine deficient patients have reported contradictory evidence, the role of dopamine and the striatum remains unclear in human sequential learning. We used a newly developed dynamic molecular imaging technique to determine whether striatal dopamine is released during performance of a sequential learning task. In this study we localized striatal regions where dopamine receptor ligand (11C-raclopride) was displaced from receptor sites, during performance of a motor sequence learning (serial reaction time) task. The results suggest that the task induces release of endogenous dopamine in the posterior two-third of dorsomedial aspect of left putamen and the anterior part of the body of caudate bilaterally. The activations of the left putamen and the right caudate coincided with the activations observed earlier during performance of a motor planning task. Since these activations are associated with the selection and execution of a response, the activation in the left caudate, which was not observed in motor planning, is probably associated with the detection of a change in the ‘context’, and in the formulation of a new ‘rule’. Thus, the results suggest that sequential learning involves two striatal dopaminergic mechanisms, one for the detection of a change in context, and the other for selection and execution of the response.

The advancement of positron emission tomography (PET) depends on the development of new radiotracers that will complement 18 F-FDG. Copper-64 ( 64 Cu) is a promising PET radionuclide, particularly for antibody-targeted imaging, but the high in vivo lability of conventional chelates has limited its clinical application. The objective of this work was to evaluate the novel chelating agent SarAr (1- N -(4-aminobenzyl)-3, 6,10,13,16,19-hexaazabicyclo[6.6.6] eicosane-1,8-diamine) for use in developing a new class of tumor-specific 64 Cu radiopharmaceuticals for imaging neuroblastoma and melanoma. The anti-GD2 monoclonal antibody (mAb) 14.G2a, and its chimeric derivative, ch14.18, target disialogangliosides that are overexpressed on neuroblastoma and melanoma. Both mAbs were conjugated to SarAr using carbodiimide coupling. Radiolabeling with 64 Cu resulted in >95% of the 64 Cu being chelated by the immunoconjugate. Specific activities of at least 10 μCi/μg (1 Ci = 37 GBq) were routinely achieved, and no additional purification was required after 64 Cu labeling. Solid-phase radioimmunoassays and intact cell-binding assays confirmed retention of bioactivity. Biodistribution studies in athymic nude mice bearing s.c. neuroblastoma (IMR-6, NMB-7) and melanoma (M21) xenografts showed that 15–20% of the injected dose per gram accumulated in the tumor at 24 hours after injection, and only 5–10% of the injected dose accumulated in the liver, a lower value than typically seen with other chelators. Uptake by a GD2-negative tumor xenograft was significantly lower (64 Cu-SarAr-mAb system described here is potentially applicable to 64 Cu-PET imaging with a broad range of antibody or peptide-based imaging agents.

Objective Cerebrovascular deposition of β-amyloid (cerebral amyloid angiopathy [CAA]) is a major cause of hemorrhagic stroke and a likely contributor to vascular cognitive impairment. We evaluated positron emission tomographic imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB) as a potential noninvasive method for detection of CAA. We hypothesized that amyloid deposition would be observed with PiB in CAA, and based on the occipital predilection of CAA pathology and associated hemorrhages, that specific PiB retention would be disproportionately greater in occipital lobes. Methods We compared specific cortical PiB retention in 6 nondemented subjects diagnosed with probable CAA with 15 healthy control subjects and 9 patients with probable Alzheimer's disease (AD). Results All CAA and AD subjects were PiB-positive, both by distribution volume ratio measurements and by visual inspection of positron emission tomographic images. Global cortical PiB retention was significantly increased in CAA (distribution volume ratio 1.18 ± 0.06) relative to healthy control subjects (1.04 ± 0.10; p = 0.0009), but was lower in CAA than in AD subjects (1.41 ± 0.17; p = 0.002). The occipital-to-global PiB ratio, however, was significantly greater in CAA than in AD subjects (0.99 ± 0.07 vs 0.86 ± 0.05; p = 0.003). Interpretation We conclude that PiB-positron emission tomography can detect cerebrovascular β-amyloid and may serve as a method for identifying the extent of CAA in living subjects. Ann Neurol 2007

PURPOSE: To investigate the feasibility and value of positron emission tomography and computed tomography (PET/CT) for treatment verification after proton radiotherapy.METHODS AND MATERIALS: This study included 9 patients with tumors in the cranial base, spine, orbit, and eye. Total doses of 1.8-3 GyE and 10 GyE (for an ocular melanoma) per fraction were delivered in 1 or 2 fields. Imaging was performed with a commercial PET/CT scanner for 30 min, starting within 20 min after treatment. The same treatment immobilization device was used during imaging for all but 2 patients. Measured PET/CT images were coregistered to the planning CT and compared with the corresponding PET expectation, obtained from CT-based Monte Carlo calculations complemented by functional information. For the ocular case, treatment position was approximately replicated, and spatial correlation was deduced from reference clips visible in both the planning radiographs and imaging CT. Here, the expected PET image was obtained from an analytical model.RESULTS: Good spatial correlation and quantitative agreement within 30% were found between the measured and expected activity. For head-and-neck patients, the beam range could be verified with an accuracy of 1-2 mm in well-coregistered bony structures. Low spine and eye sites indicated the need for better fixation and coregistration methods. An analysis of activity decay revealed as tissue-effective half-lives of 800-1,150 s.CONCLUSIONS: This study demonstrates the feasibility of postradiation PET/CT for in vivo treatment verification. It also indicates some technological and methodological improvements needed for optimal clinical application.

Objective: To determine if computer registration improves the image fusion of hybrid positron emission tomography (PET)/ computed tomography (CT) data sets in the thorax acquired during different breathing maneuvers. Methods: Hybrid PET/CT scans were acquired with varying CT respiratory instructions. The scans of 64 patients with 5 different breathing maneuvers were reviewed, including expiration, suspended breath hold, quiet breathing, small breath in, and regular breath in. The PET/CT data sets were reviewed before registration, after linear registration, and combined linear/nonlinear registration. Each PET/CT data set was graded for the quality of alignment at 5 anatomical locations (diaphragm, aortic arch, heart, thoracic spine, and lung apices) and rated from 1 (very poor) to 5 (excellent). The Kruskal-Wallis test was used to compare alignment between the breathing protocols, and Wilcoxon signed rank test was used to compare the registration techniques. Results: The quality of anatomical alignment between superimposed (nonregistered) PET and attenuation correction CT (CTAC) acquired during expiration, suspended breath hold, and quiet breathing was excellent, with no significant changes in alignment following registration. The quality of anatomical alignment between superimposed (nonregistered) PET and CTAC acquired during inspiration showed significant misalignment at the heart (P = 0.001, P < 0.0001) and diaphragm (P = 0.0001, P

Positron emission tomography (PET) with 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) has been shown to be sensitive in the detection of many bowel malignancies, but its specificity is lower because of various physiologic and pathologic patterns of bowel FDG uptake. PET-computed tomography (CT) can be useful in localizing and characterizing foci of increased FDG uptake within the bowel. As the use of PET-CT in the staging and monitoring of oncologic disease continues to expand, familiarity with these patterns of bowel FDG uptake is essential and can help determine the need for and the relative urgency of further testing. Although a variety of imaging protocols are used for PET-CT, the use of negative oral contrast agent allows improved bowel distention while eliminating potential artifacts caused by high-density oral contrast agents. In addition, correlation with the CT portion of the combined PET-CT examination can sometimes help identify the cause of focal or segmental bowel uptake. The radiologist should be aware of potential pitfalls in the evaluation of FDG-avid foci within the abdomen, including bowel motility and low-attenuation lesions mimicking bowel. Nevertheless, even though the precise role of combined PET-CT for bowel assessment has yet to be determined, the application of sound basic principles of image interpretation will help ensure the accurate interpretation of bowel findings seen with this combined modality.

Objective: To relate cerebral perfusion abnormalities to subsequent changes in clinical status among patients with mild cognitive impairment (MCI). Methods: Perfusion single photon emission computed tomography (SPECT) images were acquired in 105 elderly patients without dementia with MCI, using 99mTc-HMPAO. Clinical outcome after a 5-year follow-up period was heterogeneous. Results: Baseline SPECT data differed in those patients with MCI who were later diagnosed with Alzheimer’s disease (the converter group) from those patients with MCI who experienced clinically evident decline but did not progress to a diagnosis of Alzheimer’s disease within the follow-up period (the decliner group), from patients with MCI who had no clinical evidence of progression (the stable group), and from a group of 19 normal subjects (the control group). The most consistent decreases in relative perfusion in converters compared with the normal, stable and decliner groups were observed in the caudal anterior cingulate, and in the posterior cingulate. In addition, converters showed increased relative perfusion in the rostral anterior cingulate in comparison to the stable and decliner groups. A group of patients with Alzheimer’s disease were also included for purposes of comparison. The group of patients with Alzheimer’s disease at baseline differed from each of the other groups, with temporoparietal regions showing the most significant reductions in perfusion. Conclusions: These results suggest that clinical heterogeneity in MCI is reflected in SPECT perfusion differences, and that the pattern of perfusion abnormalities evolves with increasing clinical severity.

The interpretation of images obtained in the abdomen and pelvis can be challenging, and the coregistration of positron emission tomographic (PET) and computed tomographic (CT) scans may be especially valuable in the evaluation of these anatomic areas. PET-CT represents a major technologic advance, consisting of generally complementary modalities whose combined strength tends to overcome their respective weaknesses. However, this combined functional-structural imaging approach raises a number of controversial questions and presents some unique interpretative challenges. Accurate PET-CT scan interpretation requires awareness of the various pitfalls associated with the imaging components, both individually and in combination. The results of recent PET-CT studies have been very encouraging, but larger prospective studies will be needed to establish optimal hybrid scanning protocols. Applying sound imaging principles, paying attention to detail, and staying abreast of advances in this exciting new modality are necessary for harnessing the full diagnostic power of abdominopelvic PET-CT.

Viable dopamine neurons in Parkinson's disease express the dopamine transporter (DAT) and release dopamine (DA). We postulated that potent DAT inhibitors, with low affinity for the serotonin transporter (SERT), may elevate endogenously released extracellular dopamine levels to provide therapeutic benefit. The therapeutic potential of eight DAT inhibitors was investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated cynomolgus monkeys (Macaca fascicularis), with efficacy correlated with DAT occupancy as determined by positron emission tomography imaging in striatum. Four potent DAT inhibitors, with relatively high norepinephrine transporter, but low SERT affinities, that occupied the DAT improved activity in parkinsonian monkeys, whereas three high-affinity DAT inhibitors with low DAT occupancy did not. 2beta-Carbomethoxy-3alpha-(3,4-dichlorophenyl)-7beta-hydroxy-8-methyl-8-azabicyclo[3.2.1.]octane (O-1163) occupied the DAT but had short-lived pharmacological effects. The benztropine analog difluoropine increased general activity, improved posture, reduced body freeze, and produced sleep disturbances at high doses. (1R)-2beta-(1-Propanoyl)-3alpha-(4-fluorophenyl)tropane (O-1369) alleviated parkinsonian signs in advanced parkinsonian monkeys, by increasing general activity, improving posture, reducing body freeze, and sedation, but not significantly reducing bradykinesia or increasing locomotor activity. In comparison with the D(2)-D(3) DA receptor agonist quinelorane, O-1369 elicited oral/facial dyskinesias, whereas quinelorane did not improve posture or reduce balance and promoted stereotypy. In conclusion, DAT inhibitors with therapeutic potential combine high DAT affinity in vitro and high DAT occupancy of brain striatum in vivo with enduring day-time effects that do not extend into the nighttime. Advanced parkinsonian monkeys (80% DAT loss) respond more effectively to DAT inhibitors than mild parkinsonian monkeys (46% DAT loss). The therapeutic potential of dopamine transport inhibitors for Parkinson's disease warrants preclinical investigation.

2Department of Hematology and Oncology, Massachusetts General Hospital, Boston, MA 02114. e report a case of osseous flare response in the thoracic spine, correlating its appearance on 18F-FDG and 18F-fluoride ion PET, CT, technetium-99m medronate (99mTc-MDP) bone scanning, and gadolinium-enhanced MRI. Osteoblastic flare phenomenon has been described in detail using 99mTc-MDP scintigraphy [1]. The flare response refers to an increase in uptake after the initiation of therapy, corresponding with sites of osteoblastic activity at treated metastases. Planar 18F-fluoride ion scintigraphy [2] was largely abandoned in favor of 99mTcMDP for metastatic evaluation of the skeleton because of its more favorable photon energies for whole-body gamma camera imaging. However, after the inception of cross-sectional 18F-fluoride ion PET [3], the increasing availability of PET has renewed interest in this agent because of its increased spatial resolution and contrast and, thus, its increased sensitivity compared with planar imaging or SPECT with diphosphonates [4].

Although introduction of hybrid positron emission tomography/computed tomography (PET/CT) scanners represents an important development in field of radiology, the alliance of functional imaging with structural imaging has raised many controversial issues. The present review describes some of the important issues in hybrid PET/CT such as specific indications, protocols that deliver diagnostic quality CT scans while ensuring radiation dose associated with hybrid PET/CT examination are minimized, and the feasibility, desirability, and timing of oral and intravenous contrast administration. The issues of clinical indications for hybrid PET/CT versus PET alone will be discussed as well as the role of the CT component (ie, for diagnosis or transmission source alone) are discussed. The logistics of hybrid PET/CT scan interpretation, including the roles of radiologists and nuclear medicine physicians, will be discussed. This review describes the pertinent medical literature and discusses our experience with suitable examples.

Objective: The abuse potential of methylphenidate has been related to the drug’s capacity to produce a rapid onset of blockade of the presynaptic dopamine transporter in the brain. An oral once-aday osmotic controlled-release formulation of methylphenidate produces a more gradual rise in plasma methylphenidate concentration, compared with immediate-release methylphenidate. The authors hypothesized that osmotic-release methylphenidate would also produce a slower onset of blockade of the presynaptic dopamine transporter and would be associated with a lower risk for detection and likeability, compared to immediaterelease methylphenidate. Method: Twelve healthy adults were randomly assigned to receive single doses of immediate-release methylphenidate or osmotic-release methylphenidate. Doses predicted to produce equivalent maximum concentration (Cmax) values were selected (40 mg of immediate-release methylphenidate and 90 mg of osmoticrelease methylphenidate). Plasma dmethylphenidate levels and responses to detection/likeability questionnaire items were obtained hourly for 10 hours after administration of methylphenidate on two separate occasions for each subject. Dopamine transporter receptor occupancies were measured at hours 1, 3, 5, and 7 by using a carbon-11-labeled imaging agent (Altropane) and positron emission tomography. Results: Despite similar Cmax values for both formulations, osmotic-release methylphenidate was associated with a longer time to maximum concentration, longer time to maximum CNS dopamine transporter occupancy, and no detection/likeability, compared with immediate-release methylphenidate. Conclusions: The findings suggest that the abuse potential of oral methylphenidate is strongly influenced by the rate of delivery and not solely by the magnitude of plasma concentration or brain transporter occupancy. These results advance understanding of the underlying central effects of methylphenidate in humans and identify a potentially less abusable methylphenidate formulation.

We assessed improvements in performance in detection and estimation tasks due to a novel brain single photon computed tomography collimator. Data were acquired on the CeraSPECT{sup TM} scanner using both new and standard collimators. The new variable focusing collimator SensOgrade{sup TM} samples the projections unequally, with central regions more heavily represented, to compensate for attenuation of counts from central brain structures. Furthermore, it utilizes more of the cylindrical crystal surface. Two phantom studies were performed. The first phantom was a 21-cm-diameter cylindrical background containing nine spheres ranging from 0.5 to 5 cm{sup 3} in volume. {sup 99m}Tc sphere to background activity ratio was 10:1. Twenty-nine 10-min datasets were acquired with each collimator. The second phantom was the Radiology Support Devices (Long Beach, CA) striatal phantom with striatal-background ratios of 10:1 on the left and 5:1 on the right. Twenty-nine 4-min datasets were acquired with each collimator. Perfusion imaging using {sup 99m}Tc-HMPAO was also performed in three healthy volunteers using both collimators under identical simulations. Projections were reconstructed by filtered backprojection with an unwindowed ramp filter. The nonprewhitening matched filter signal-to-noise ratio (NPW-SNR) was computed as a surrogate for human performance in detecting spherical lesions. Sphere activity concentration, radius, and locationmore » coordinates were simultaneously estimated by fitting images to an assumed model using an iterative nonlinear algorithm. Resolution recovery was implicit in the estimation procedure, as the point spread function was incorporated into the model. NPW-SNR for sphere detection was 1.5 to 2 times greater with the new collimator; for the striatal phantom the improvement in SNR was 54%. The SNR for estimating sphere activity concentration improved by 46 to 89 % for spheres located more than 5 cm from the phantom center. Images acquired with the standard collimator were too noisy in the central regions to allow estimation of sphere activity. In {sup 99m}Tc-HMPAO human studies, SNR was improved by 21 to 41 % in the cortex, 66% in the basal ganglia, and 74% in the thalamus. The new collimator leads to substantially improved detection and estimation performance throughout the brain. The higher sensitivity will be particularly important for dynamic imaging.« less

Objective: To determine the prevalence of lipomatous hypertrophy of the interatrial septum (LHIS) on CT and its metabolic pattern on 18F fluorodeoxyglucose (FDG)-positron emission tomography (PET). Method and materials: Eight hundred two CT PET scans were reviewed. Patients were included if the interatrial septum was ≥ 1 cm and excluded if there was evidence of malignancy in the adjacent lung, hilum, or mediastinum. CT scans were fused with PET scans, and the mean standardized uptake value (SUV) was calculated over the LHIS, chest wall (CW) fat, and mediastinal blood pool. CT scans were reviewed for presence of excessive fat in the mediastinum, pericardial, peridiaphragmatic, peritoneal, and retroperitoneal regions and for the presence of emphysema. Medical records were reviewed for body mass index (BMI) and history of arrhythmia. Results: Twenty-three of 802 patients (2.8%) had LHIS on CT (9 women and 14 men); average age was 75.6 years (range, 58 to 95 years). Average BMI of 17 patients (± SD) was 31 ± 4.9 (range, 22.1 to 39.9). Mean CT values were as follows: thickening of LHIS, 1.47 ± 0.35 cm (range, 1.07 to 2.25 cm); LHIS, − 79.6 + 24.5 Hounsfield unit (HU) [range, − 11 to – 121 HU]. LHIS was dumbbell shaped in 18 patients. Mean SUVs were as follows: LHIS, 1.84 ± 0.10 (range, 0.48 to 3.48); CW fat, 0.36 + 0.37 (range, 0.04 to 1.98); blood pool, 1.74 + 0.51 (range, 0.25 to 2.71). The SUV of LHIS was greater than the SUV of CW wall fat in all patients (p r = 0.883). Those with dumbbell-shaped LHIS (p Conclusion: The SUV of LHIS was greater than the SUV of CW fat in all patients. LHIS with greater thickness or dumbbell shape had greater FDG uptake. These findings on CT and PET are important to recognize in order to avoid false-positive FDG-PET interpretations.

To retrospectively determine whether alignment of registered positron emission tomographic (PET) and computed tomographic (CT) data sets obtained independently varies significantly from alignment of data sets acquired from a combined PET/CT scanner.The study was approved by the institution's Human Research Committee with a waiver of informed consent and complied with HIPAA. Whole-body combined PET/CT data sets and separate routinely positioned thoracic CT data sets were obtained from 12 patients (six men, six women; mean age, 48.6 years; range, 24-62 years). Separate PET and thoracic CT data sets matched for patient positioning and respiration were acquired on the same day for nine patients (four men, five women; mean age, 71 years; range, 51-90 years). Computer nonlinear registration was performed on PET and CT data sets from combined PET/CT (fusion group 1), PET data sets from combined PET/CT with unmatched thoracic CT (fusion group 2), and data sets from separate PET and CT matched for patient positioning and respiration (fusion group 3). Quality of alignment was assessed by two radiologists in consensus blinded to the source of registered data in each fusion group at the following anatomic locations: diaphragm, aortic arch, heart, thoracic spine, and lung apices. Results were compared by using the Wilcoxon paired signed rank and unpaired rank sum tests.Quality of alignment did not significantly differ between fusion group 1 and fusion group 3. Fusion group 1 provided significantly better alignment in two of five anatomic locations (P = .008 for diaphragm and P = .031 for heart) than fusion group 2. Fusion group 3 provided significantly better alignment in two of five anatomic locations (P = .037 for diaphragm and P = .009 for heart) than fusion group 2.Thoracic anatomic alignment does not significantly differ between registered PET and CT data sets acquired on a combined PET/CT scanner or from separate PET and CT scanners obtained on the same day when carefully matched for anatomic positioning and respiration.

We tested the hypothesis that sildenafil increases myocardial dilator reserve in humans with ischemic heart disease.Positron emission tomography measured myocardial blood flow in 14 patients with ischemic heart disease. Patients were studied twice, in double-blind, placebo-control, cross-over design with sildenafil (or placebo) given approximately 2-3 h before measurements of hemodynamics and myocardial blood flow: at rest, with cold pressor stress and with adenosine. All myocardial segments of each patient with myocardial blood flow1.65 ml/min per g with adenosine under placebo conditions were combined into one abnormal zone for that patient. Segments with myocardial blood flow1.65 ml/min per g were averaged and combined into a normal zone for that patient.At rest, rate pressure product (heart rate x systolic arterial pressure, mmHg/min) was comparable, as was abnormal zone myocardial blood flow (ml/min per g; 0.76+/-0.48 placebo versus 0.64+/-0.20 sildenafil, both P=NS; mean+/-SD). Both rate pressure product and myocardial blood flow increased (P0.01) with cold pressor stress (11+/-3 K and 1.14+/-0.59 placebo versus 10+/-3 K and 1.21+/-0.62 sildenafil). However, sildenafil failed to improve the myocardial blood flow response to cold pressor stress in abnormal or normal zones. In contrast, abnormal zone myocardial blood flow reserve with adenosine and sildenafil (2.6+/-0.7) exceeded that with adenosine and placebo (2.0+/-1.3, P0.04, paired sign test).Sildenafil improves myocardial blood flow dilator response to adenosine in abnormal zones, possibly by augmenting nitric oxide-mediated increases in cGMP because adenosine response in part is nitric oxide dependent. Failure to improve myocardial blood flow response to cold pressor stress suggests that alpha-adrenergic constriction may offset enhanced nitric oxide effects. Clinically, the data suggest sildenafil may exert an anti-ischemic effect in patients with coronary artery disease.