Serial Positron Emission Tomography Research Articles

Tumor Metabolism and Blood Flow Changes by Positron Emission Tomography: Relation to Survival in Patients Treated With Neoadjuvant Chemotherapy for Locally Advanced Breast Cancer

Patients with locally advanced breast carcinoma (LABC) receive preoperative chemotherapy to provide early systemic treatment and assess in vivo tumor response. Serial positron emission tomography (PET) has been shown to predict pathologic response in this setting. We evaluated serial quantitative PET tumor blood flow (BF) and metabolism as in vivo measurements to predict patient outcome. Fifty-three women with primary LABC underwent dynamic [(18)F]fluorodeoxyglucose (FDG) and [(15)O]water PET scans before and at midpoint of neoadjuvant chemotherapy. The FDG metabolic rate (MRFDG) and transport (FDG K(1)) parameters were calculated; BF was estimated from the [(15)O]water study. Associations between BF, MRFDG, FDG K(1), and standardized uptake value and disease-free survival (DFS) and overall survival (OS) were evaluated using the Cox proportional hazards model. Patients with persistent or elevated BF and FDG K(1) from baseline to midtherapy had higher recurrence and mortality risks than patients with reductions. In multivariable analyses, BF and FDG K(1) changes remained independent prognosticators of DFS and OS. For example, in the association between BF and mortality, a patient with a 5% increase in tumor BF had a 67% higher mortality risk compared with a patient with a 5% decrease in tumor BF (hazard ratio = 1.67; 95% CI, 1.24 to 2.24; P < .001). LABC patients with limited or no decline in BF and FDG K(1) experienced higher recurrence and mortality risks that were greater than the effects of clinical tumor characteristics. Tumor perfusion changes over the course of neoadjuvant chemotherapy measured directly by [(15)O]water or indirectly by dynamic FDG predict DFS and OS.

Extensive necrosis of visceral melanoma metastases after immunotherapy

BackgroundThe prognosis for metastatic melanoma remains poor even with traditional decarbazine or interferon therapy. 5-year survival is markedly higher amongst patients undergoing metastatectomy. Unfortunately not all are suitable for metastatectomy. Alternative agents for systemic therapy have, to date, offered no greater rates of survival beyond traditional therapy. A toll-like receptor 9 agonist, PF-3512676 (formerly known as CPG 7909) is currently being evaluated for its potential.Case presentationWe present the case of a 54-year-old Caucasian male with completely resected metastatic cutaneous melanoma after immunotherapy. The patient initially progressed during adjuvant high-dose interferon, with metastases to the liver, spleen, and pelvic lymph nodes. During an 18-month treatment period with PF-3512676 (formerly known as CPG 7909), a synthetic cytosine-phosphorothioate-guanine rich oligodeoxynucleotide, slow radiologic disease progression was demonstrated at the original disease sites. Subsequent excision of splenic and pelvic nodal metastases was performed, followed by resection of the liver metastases. Histologic examination of both hepatic and splenic melanoma metastases showed extensive necrosis. Subsequent disease-free status was demonstrated by serial positron emission tomography (PET).ConclusionExisting evidence from phase I/II trials suggests systemic treatment with PF-3512676 is capable of provoking a strong tumor-specific immune response and may account for the prolonged tumor control in this instance.

The Influence of Changes in Tumor Hypoxia on Dose-Painting Treatment Plans Based on 18F-FMISO Positron Emission Tomography

To evaluate how changes in tumor hypoxia, according to serial fluorine-18-labeled fluoro-misonidazole (18F-FMISO) positron emission tomography (PET) imaging, affect the efficacy of intensity-modulated radiotherapy (IMRT) dose painting. Seven patients with head and neck cancers were imaged twice with FMISO PET, separated by 3 days, before radiotherapy. Intensity-modulated radiotherapy plans were designed, on the basis of the first FMISO scan, to deliver a boost dose of 14 Gy to the hypoxic volume, in addition to the 70-Gy prescription dose. The same plans were then applied to hypoxic volumes from the second FMISO scan, and the efficacy of dose painting evaluated by assessing coverage of the hypoxic volumes using Dmax, Dmin, Dmean, D95, and equivalent uniform dose (EUD). Similar hypoxic volumes were observed in the serial scans for 3 patients but dissimilar ones for the other 4. There was reduced coverage of hypoxic volumes of the second FMISO scan relative to that of the first scan (e.g., the average EUD decreased from 87 Gy to 80 Gy). The decrease was dependent on the similarity of the hypoxic volumes of the two scans (e.g., the average EUD decrease was approximately 4 Gy for patients with similar hypoxic volumes and approximately 12 Gy for patients with dissimilar ones). The changes in spatial distribution of tumor hypoxia, as detected in serial FMISO PET imaging, compromised the coverage of hypoxic tumor volumes achievable by dose-painting IMRT. However, dose painting always increased the EUD of the hypoxic volumes.

Measuring the effect of amantadine in chronic anoxic minimally conscious state

The effect of pharmacological agents on recovery in chronic disorders of consciousness remains unsatisfactory.1 Amantadine, a dopaminergic agonist, has been suggested to behaviourally improve recovery from both a vegetative state...

Abstract 2672: Serial in vivo Non-invasive Imaging of Intramyocardially Injected Autologous Mesenchymal Stem Cells, Modified for Transgene Expression of Positron-Emission Tomography (PET) Reporter in Porcine Myocardial Infarction

Objective. The aim of our study was to elaborate an in vivo tracking method of the intramyocardially injected msenchymal stem cells (MSCs), modified for transgene expression of trifusion protein (lentiviral vector, expressing renilla luciferase /RL/, red fluoroscein protein /RFP/ and herpes simplex truncated thymidine kinase /tTK, positron emmission tomography PET-reporter gene/) using serial PET imaging in pig myocardial infarction (MI). Methods. Bone marrow (100 ml) was harvested from pigs immediately before induction of MI by percutaneous balloon occlusion of the LAD followed by reperfusion. The MSCs were selected and cultivated. The lentiviral vector LV-RL-RFP-tTK was inoculated into the MSCs under control of CMV promoter. The cells with the highest fluorescence intensity (after achieving appr. 50% transfection efficacy) were sorted, and tracked in vitro by PET using 9-(4-[18F]fluoro-3-hydroxymethylbutyl)-guanine (18FHBG). The transfected MSCs (at least 3 mio MSCs/ pigs) were then injected direct intramyocardially using NOGA electromagnetic guidance in pigs in 10 locations of the infarct border zone (min. 0.3 million cells/injection), followed by PET imaging 30 hours and 7 days later, after intravenous injection of 5 mCi 18FHBG. Results. The in vitro 18FHBG uptakes of the transgene modified MSCs by PET were 10 times larger than the control JY human B-lymphoblasts and T lymphocytes. The minimum number of the cells detectable with PET was 0.2 million. MRI of the pigs revealed a mean global EF of 47+/-3.5%. PET imaging displayed diffuse distribution of the injected MSCs with high activity of the PET tracer in the anterior wall and septum at 30h, and less tracer activity in the injections sites with diffuse distribution in the pericardium and pleura indicating the wandering of the living cells at 7 days. PET imaging did not show 18FHBG accumulation in the infarcted heart of the control animals. Myocardial histology with RL and RFP staining confirmed the distribution of the injected MSCs through an elongated track around the injected area, 9 days after delivery. Conclusion. In vivo tracking of gene-modified porcine MSCs by PET imaging is feasible and allows serial noninvasive imaging of homing and propagation of MSCs in pigs after MI.

Autologous Mesenchymal Stem Cell Therapy Delays the Progression of Neurological Deficits in Patients With Multiple System Atrophy

We evaluated the feasibility and safety of therapy with mesenchymal stem cells (MSCs) through consecutively intra-arterial and three repeated intravenous injections and compared the long-term prognosis between MSC-treated (n=11) and control multiple system atrophy (MSA) patients (n=18). The MSC-treated patients showed significantly greater improvement on the unified MSA rating scale (UMSARS) than the control patients at all visits throughout the 12-month study period. Orthostasis in UMSARS I items and cerebellar dysfunction-related items of UMSARS II items were significantly different in favor of MSC treatment compared to controls. Serial positron emission tomography scan in the MSC-treated group showed that increased fluorodeoxyglucose uptake from baseline was noted in cerebellum and frontal white matters. No serious adverse effects related to MSC therapy occurred. This study demonstrated that MSC therapy in patients with MSA was safe and delayed the progression of neurological deficits with achievement of functional improvement in the follow-up period.

Optimizing Dual-Time and Serial Positron Emission Tomography and Single Photon Emission Computed Tomography Scans for Diagnoses and Therapy Monitoring

A region's early and late tracer uptake activities, QE and QL, within a dual-time scan (i.e. using two frames) or in serial scans (as for monitoring therapeutic response), are popular quantitative diagnostic aids, especially in oncology. In this paper, maximum performance is sought from their joint use. QL/QnE is introduced as a tumor marker with an empirical n. This generalizes traditional data weighting having n=1 for QL/QE, the retention index (RI), with its associated % difference. Using patient data, iterative guessing finds an optimal n that maximizes a measure of diagnostic performance: D=(difference of normal and abnormal marker means)/(their combined SD), which may be computed from values of QL/QnE, as well as of QL, QE, and RI each used alone. For 2-deoxy-2-[F-18]fluoro-D-glucose(FDG)-positron emission tomography (PET) dual-time protocols, another approach to optimization-selection of scan times-is investigated by simulations using the Sokolov model. A meta-analysis of 12 PET and single photon emission computed tomography (SPECT) studies with various tracers, cancers, and scan classes (dual-time or serial) finds ns from 0.5 to 1.1. The optimal D necessarily exceeds the best (or any) computed using QE, QL, or RI: negligibly to by as much as 0.6 (or 1.5). The increases in optimal receiver operating curve area (Az) over the best (or any) traditional marker range from negligible to 0.07 (or 0.4). QE alone usually has the lowest D and Az. Statistically significant performance improvement of QL/QnE over QE and QL is shown for most studies. Contrasting with an optimal n, another value n0 can also be found where D=0. Occasionally, n0 can be close to 1, and RI then will have a small D and poor performance. Simulation with kinetic modeling of FDG dual-time scans for liver and liver metastases demonstrates worst and best scan times. Indicated for these imaging protocols are QE at very early cellular transport associated times and QL rather late when phosphorylation/dephosphorylation dominate. Benefits from choosing optimal times in dual-time protocols, especially in combination with choosing optimal ns, can be significant. A protocol-dependent optimizing parameter n in an improved classification marker can easily be identified in a learning set of scans having normals and abnormals. Finding this parameter below 1.0 in most all studies suggests that a popularly used QL/QE may often overweight early activities. Additionally, QL/QE may sometimes be a poor marker choice and underestimate a protocol's diagnostic capability. Subsequent use of the proposed QL/QnE in settings similar to that of the learning set gives improved diagnostic performance over traditional approaches, although by widely varying amounts. Additionally, a method of seeking optimal scan times is demonstrated and suggests significant gains in dual-time protocol performances are possible.

Tumor metabolism, blood flow changes, and prognosis by positron emission tomography: A prospective cohort of locally advanced breast cancer patients

506 Background: Breast cancer patients with locally advanced tumors receive preoperative chemotherapy to provide early systemic treatment and assess in-vivo tumor response. Positron emission tomography (PET) has been used to follow tumor response to therapy, as pathologic response is predictive of patient outcome. We evaluated the prognostic utility of serial quantitative PET tumor blood flow (BF) and metabolism measurements. Methods: Fifty-five women with a primary diagnosis of locally advanced breast carcinoma (LABC) underwent dynamic [18F]-FDG and [15O]-water PET scans prior to and at midpoint of neoadjuvant chemotherapy. The FDG metabolic rate (MRFDG), transport (K1), and flux (Ki) parameters were calculated, and tumor blood flow was estimated from the [15O]-water study. Associations between tumor BF and MRFDG measurements and disease-free survival (DFS) and overall survival (OS) were evaluated using the Cox proportional hazards model. Results: Patients that had an increase in BF and K1, from baseline to mid-therapy measurements, had elevated recurrence and mortality risks compared to patients that had reductions in BF and MRFDG values. In multivariate analysis, changes in BF and K1 remained independent prognostic indicators of DFS and OS survival. Conclusions: PET measurements of tumor response prior to completion of neoadjuvant chemotherapy were predictive of patient outcome. Patients that failed to have a decline in BF and K1 experienced higher risks of recurrence and mortality that was largely independent of clinical tumor characteristics assessed in this study. These results suggest that tumor perfusion, measured directly by [15O]-water or indirectly by dynamic FDG PET, is highly predictive of outcome in neoadjuvantly treated breast cancer. No significant financial relationships to disclose.

Thalamic metabolism and symptom onset in preclinical Huntington's disease.

The neural basis for the transition from preclinical to symptomatic Huntington's disease (HD) is unknown. We used serial positron emission tomography (PET) imaging in preclinical HD gene carriers (p-HD) to assess the metabolic changes that occur during this period. Twelve p-HD subjects were followed longitudinally with [11C]-raclopride and [18F]-fluorodeoxyglucose PET imaging, with scans at baseline, 18 and 44 months. Progressive declines in striatal D2-receptor binding were correlated with concurrent changes in regional metabolism and in the activity of an HD-related metabolic network. We found that striatal D2 binding declined over time (P < 0.005). The activity of a reproducible HD-related metabolic covariance pattern increased between baseline and 18 months (P < 0.003) but declined at 44 months (P < 0.04). These network changes coincided with progressive declines in striatal and thalamic metabolic activity (P < 0.01). Striatal metabolism was abnormally low at all time points (P < 0.005). By contrast, thalamic metabolism was elevated at baseline (P < 0.01), but fell to subnormal levels in the p-HD subjects who developed symptoms. These findings were confirmed with an MRI-based atrophy correction for each individual PET scan. Increases in network expression and thalamic glucose metabolism may be compensatory for early neuronal losses in p-HD. Declines in these measures may herald the onset of symptoms in gene carriers.

Modeling of Brain D2 Receptor Occupancy-Plasma Concentration Relationships with a Novel Antipsychotic, YKP1358, Using Serial PET Scans in Healthy Volunteers

YKP1358 is a novel serotonin (5-HT(2A)) and dopamine (D(2)) antagonist that, in preclinical studies, fits the general profile of an atypical antipsychotic. We conducted a D(2) receptor occupancy study with YKP1358 in healthy volunteers using positron emission tomography (PET) to measure the D(2) receptor occupancy of YKP1358 and to characterize its relationship to plasma drug concentrations. A single oral dose, parallel group, dose-escalation (100, 200, and 250 mg) study was performed in 10 healthy male volunteers with the PET radiotracer [(11)C]raclopride. The D(2) receptor occupancy of striatum was measured pre-dose, and at 2, 5, and 10 h after YKP1358 administration. Serial blood samples were taken for measurement of plasma YKP1358 concentrations. D(2) receptor occupancy by YKP1358 increased to 53-83% at 2 h, and then decreased afterwards, ranging from 40-64% at 5 h to 20-51% at 10 h. The YKP1358 dose-plasma concentration relationship exhibited extensive variability, but there was a good relationship between plasma concentrations and D(2) receptor occupancy that was well predicted by a sigmoid E(max) model using nonlinear mixed effects modeling. To our knowledge, this is the first study in which the relationship between plasma concentration and the biomarker of D(2) receptor occupancy was modeled using nonlinear mixed effects modeling. It is anticipated that these results will be useful in estimating for subsequent studies the initial doses of YKP1358 required to achieve a therapeutically effective range of D(2) receptor occupancy.

Non-Hodgkin's lymphoma of the frontal sinus presenting as osteomyelitis

Objectives The aim of the study was to present a case of non-Hodgkin's lymphoma (NHL) originating in the frontal sinus that presented as osteomyelitis of the frontal bone. Methods A review of a single case including radiographic, intraoperative, and pathologic findings was done, followed by a discussion highlighting relevant literature. Results A 55-year-old man presented with pain and swelling of the forehead with 8 weeks duration. He had a history of chronic rhinosinusitis and underwent endoscopic maxillary antrostomies 4 years prior. A presumptive diagnosis of frontal sinusitis with osteomyelitis was made and prolonged oral antibiotic therapy started. The patient was referred to our center after symptoms and objective findings failed to improve. Computed tomography revealed a destructive process of the frontal bone with near total opacification of the frontal sinuses. An exploratory external frontal sinusotomy was performed revealing an infiltrative soft tissue mass filling most of the frontal sinus. Dehiscence of the posterior table was noted without dural involvement. Pathology of this mass revealed diffuse large B-cell lymphoma of intermediate grade. The patient underwent 6 cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone; radiotherapy to the frontal bone; and central nervous system prophylaxis via intrathecal methotrexate. Clinically, he fell into the Ann Arbor Stage II EA NHL category because of an isolated axillary lymph node. Now, 18 months after completion of therapy he is without evidence of disease based on serial positron emission tomography and computed tomography scanning. Conclusions We describe a case of NHL of the frontal sinus, which presented as osteomyelitis. We highlight important features of this patient's clinical presentation that can help differentiate an inflammatory process from a neoplastic process in the frontal bone. Timely diagnosis is critical, and neoplasms of the frontal sinus can be easily misdiagnosed as inflammatory.

Does coronary vasodilation after adenosine override endothelin-1-induced coronary vasoconstriction?

Endothelin-1 is a powerful coronary vasoconstrictor that is overexpressed in coronary artery disease. Adenosine is a powerful coronary vasodilator used for myocardial perfusion imaging to identify flow-limiting coronary artery stenosis. Therefore, in an animal model we tested the hypothesis that intracoronary endothelin-1 may cause myocardial perfusion abnormalities by positron emission tomography (PET) at resting conditions that may persist or only partially improve after intravenous adenosine stress in the absence of myocardial scar and flow-limiting stenosis. Fourteen dogs underwent serial PET perfusion imaging with rubidium-82 before and after subselective intracoronary infusion of endothelin-1, followed by intravenous and then intracoronary adenosine. Small physiological doses of endothelin-1 infused into the mid-left circumflex coronary artery caused quantitatively significant resting perfusion abnormalities that normalized after intracoronary adenosine but not consistently after intravenous adenosine used for diagnostic imaging. After effects of adenosine abated, resting perfusion defects returned, lasting up to 5 h in some animals. Cumulative doses of endothelin-1 caused perfusion defects that did not normalize after intravenous adenosine. In an animal model without myocardial scar or flow-limiting stenosis, intracoronary endothelin-1 causes visually apparent, quantitatively significant, long-lasting myocardial perfusion defects at resting conditions that may persist or only partially improve after intravenous adenosine used for diagnostic imaging. These results may potentially explain resting perfusion abnormalities or heterogeneity by clinical PET that may persist or only partially improve after adenosine stress perfusion imaging in the absence of myocardial scar and flow-limiting stenosis.

Self-Organized Patchiness in Asthma as a Prelude to Catastrophic Shifts

Purpose of the Study. To reveal self-organized small airway constriction contributing to large ventilation defects in asthmatics. Study Population. Mild and moderate asthmatics. Methods. Ventilation defects in asthmatics were studied during methacholine bronchoprovocation by using serial dynamic positron emission tomography with a positron-emitter nitrogen-13 tracer and a single terminal-airway model. Results. Heterogeneity of ventilation defects in asthmatics was demonstrated. In this model, constriction of terminal bronchioles was the main feature of bronchoconstriction, contributing to nonuniform ventilation defects. Consequently, on the basis of the mechanical interdependence in expansion between airways and surrounding parenchyma, clusters of constricted terminal bronchioles fed by a common tree branch developed and led to large ventilation defects. Conclusion. Clustered groups of self-organized terminal bronchiolar constriction, not large airways obstruction, contribute to large ventilation defects in acute asthma. Reviewer Comments. The nature of functional changes of both small and large airways affecting ventilation during acute asthma attacks has been unclear. Previously, MRIs of asthmatic lungs during bronchoprovocation suggested large-airway obstruction as a major cause of large ventilation defects (eg, J Allergy Clin Immunol. 2003;111:1205–1211). In this study, Venegas et al demonstrated the role of clustered terminal bronchiolar constriction resulting in ventilation defects in acute asthma. On the basis of this model, inhaled bronchodilators could be ineffective because the inhaled form might reach only well-ventilated regions and could further impede lung expansion of problematic regions and exacerbate regional ventilation defects. The concept of catastrophic shifts might account for sudden, unexplained, and severe asthma attacks in some patients. Systemic bronchodilators may be needed in some asthmatics to bypass this problem. This line of investigation is further elucidated elsewhere (J Appl Physiol. 2005;99:2388–2397).

Usefulness of 18F-Fluorodeoxyglucose PET for Radiosurgery Planning and Response Monitoring in Patients with Recurrent Spinal Metastasis

With the advancement and successful treatment of metastatic spinal cord disease, newer treatments are needed for the long-term survivors of recurrent disease. The lack of a standardized re-treatment regimen and the difficulty in delineating the tumor margins among patients who have received the treatment with metallic spinal fixation and conventional radiation are two of the challenges to be faced in recurrent metastatic spinal cord disease. In these patients, we applied hypofractionated stereotactic radiosurgery by defining the tumor margin with (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Three consecutive recurrent spinal metastasis patients underwent the CyberKnife treatment (Accuray, Inc., Sunnyvale, CA) from March 2004 to July 2004. A three-fraction schedule was applied at approximately 24 hour intervals. One patient had sarcoma and the other two patients had breast cancer. All patients had received previous conventional radiotherapy after operation ranging from 30 Gy to 45 Gy. CT-based planning was corrected by the FDG-PET hyperuptake area with the help of nuclear medicine. The mass responses were followed not only by MRI but also by FDG-PET, which was taken prior to treatment, and at one and six months after the treatment. The changes in standard uptake value (SUV) of serial PET were taken as a measure of response. To evaluate the relative SUV changes from different pretreatment values, we set a reduction index (RI), which represents the ratio of SUV change to pretreatment SUV. No significant complications were noted during treatment with a mean follow-up of 13.3 months. The tumor volume on CT-based planning was 2.2 times larger than that of the CT-PET combined planning in case 1 of paraspinal muscle invasion. But the tumor volumes showed minimal changes in the other cases, in which the metastatic tumors were confined to the vertebral bodies. The SUV one month after treatment showed variable decreases and the RI ranged from 0.07 to 0.7. However, the SUVs at 6 months were well correlated with the clinical results. One patient showed marginal failure and the other two patients showed local control of the tumor, as their RI values were 0.65 and 0.87, respectively. To our knowledge, this is the first report using FDG-PET with radiosurgery in patients with recurrent spinal metastases hidden under metallic artifacts. The mass responses measured by SUV changes in FDG-PET correlated with the clinical results.

Effect of monoamine oxidase inhibition on amphetamine-evoked changes in dopamine receptor availability in the living pig: A dual tracer PET study with [11C]harmine and [11C]raclopride

The activity of both isozymes of monoamine oxidase (MAO) is reduced by 50% in the brain of human smokers. We hypothesized that this is not an epiphenomenon, but should bring about potentiation of the action of psychostimulant drugs. To test this hypothesis, we carried out serial positron emission tomography (PET) studies in Göttingen miniature pigs to measure the binding of the MAO-A ligand [11C]harmine and to measure the changes in [11C]raclopride binding evoked by a low dose of amphetamine (0.7 mg/kg as free base, i.v.), first in a baseline condition, and, one month later, after acute treatment with pargyline (2 x 3 mg/kg as free base, i.m.). In the baseline, the distribution volume of [11C]harmine relative to the arterial input (V(d), ml g(-1)) ranged from 74 ml g(-1) in cerebellum to 139 ml g(-1) in the medial hypothalamus. Pargyline treatment reduced the magnitude of V(d) globally to 34-54 ml g(-1). Nearly complete displacement of [11C]harmine binding was detected in neocortex and striatum, but there was evidence for pargyline-resistant binding in the pituitary gland and diencephalon. In the baseline condition, the low dose of amphetamine evoked a 14% decline in the binding potential (BP) (pB) of [11C]raclopride in striatum (P = 0.026). After pargyline treatment, the amphetamine effect was of similar magnitude (-11%), although not statistically significant (P = 0.054). However, the second amphetamine challenge evoked a 24% reduction in [11C]raclopride pB relative to the original baseline condition (P = 0.018). Present results do not strongly support our hypothesis that MAO inhibition should potentiate the amphetamine-evoked dopamine release as measured in the [11C]raclopride competition paradigm.

In Vivo Evaluation of P-glycoprotein Function at the Blood-Brain Barrier in Nonhuman Primates Using [11C]Verapamil

P-glycoprotein (P-gp) is a major efflux transporter contributing to the efflux of a range of xenobiotic compounds at the blood-brain barrier (BBB). In the present study, we evaluated the P-gp function at the BBB using positron emission tomography (PET) in nonhuman primates. Serial brain PET scans were obtained in three rhesus monkeys after intravenous administration of [(11)C]verapamil under control and P-gp inhibition conditions ([PSC833 ([3'-keto-Me-Bmt(1)]-[Val(2)]-cyclosporin) 20 mg/kg/2 h]). The parent [(11)C]verapamil and its metabolites in plasma were determined by HPLC with a positron detector. The initial brain uptake clearance calculated from the integration plot was used for the quantitative analysis. After intravenous administration, [(11)C]verapamil was taken up rapidly into the brain (time to reach the peak, 0.58 min). The blood level of [(11)C]verapamil decreased rapidly, and it underwent metabolism with time. The inhibition of P-gp by PSC833 increased the brain uptake of [(11)C]verapamil 4.61-fold (0.141 versus 0.651 ml/g brain/min, p < 0.05). These results suggest that PET measurement with [(11)C]verapamil can be used for the evaluation of P-gp function at the BBB in the living brain.

Modulation of intratumoral hypoxia by the epidermal growth factor receptor inhibitor gefitinib detected using small animal PET imaging

Blockade of signaling through the epidermal growth factor receptor (EGFR) tyrosine kinase by inhibitors such as gefitinib (Iressa) can inhibit tumor angiogenesis and enhance responses to ionizing radiation. In this study, the ability of gefitinib to modulate intratumoral oxygenation was evaluated in human EGFR-expressing A431 squamous cell carcinoma xenografts using in vivo small animal positron emission tomography (PET) imaging with the hypoxia marker [(18)F]fluoroazomycin arabinoside (FAZA) and by the immunohistochemical detection of hypoxia-induced adducts of the 2-nitroimidazole, pimonidazole. Serial noninvasive PET imaging of A431 xenografts showed a significant reduction in FAZA uptake following treatment with 75 mg/kg/d of gefitinib [tumor to background ratio, 6.1 +/- 1.0 (pretreatment) versus 2.3 +/- 0.6 (posttreatment); P = 0.0004]. Similarly, ex vivo quantitation of FAZA uptake showed significantly reduced FAZA uptake in established A431 xenografts treated with gefitinib compared with vehicle control (tumor to blood ratio for controls versus gefitinib, 8.0 +/- 3.0 versus 2.7 +/- 0.8; P = 0.007; or tumor to muscle ratio controls versus gefitinib, 8.6 +/- 2.8 versus 2.6 +/- 1.0; P = 0.002). The effect of gefitinib treatment seemed to be independent of tumor size. In addition, gefitinib treatment reduced pimonidazole-binding in A431 xenografts measured after 5 and 8 days of gefitinib treatment compared with baseline and with tumors treated with vehicle alone. A strong correlation was observed between pimonidazole binding and FAZA uptake. Together, these findings show that gefitinib reduces intratumoral hypoxia.

Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

Schizophrenia may be related to dysfunctional glutamatergic activity, specifically hypofunction of the N-methyl-D-aspartate receptor (NMDAR). In addition, it has been proposed that NMDAR hypofunction may paradoxically cause an increase in glutamate release and hypermetabolism in corticolimbic regions. If a state of partial, chronic NMDAR blockade underlies schizophrenia, then schizophrenic volunteers (SV) may have greater glutamate release and associated elevations in regional cerebral blood flow (rCBF) than normal volunteers (NV), following drug-induced NMDAR antagonism. Therefore, we have given acute ketamine, a noncompetitive NMDAR antagonist, to NV (n=13) and medicated volunteers with schizophrenia (n=10) in conjunction with serial positron emission tomography blood flow studies. Drug administration caused marked rCBF elevations in frontal and cingulate regions in both groups. Contrasts between NV and SV ketamine groups showed that SV had greater relative blood flow increases in the anterior cingulate than NV. Maximum blood flow, and the area under the curve for blood flow in the anterior cingulate cortex, significantly correlated with changes in psychosis ratings in SV and NV (maximum rCBF only). These changes are consistent with a relatively hypoactive thalamic NMDAR and increased cortical glutamate neurotransmission at non-NMDARs in schizophrenia. We hypothesize that ketamine antagonizes an NMDAR-dependent inhibitory system that is partially compromised in subjects with schizophrenia. The ketamine-induced reduction of inhibition leads to a marked increase in glutamate release and hypermetabolism (elevated rCBF) in frontal and cingulate cortical regions. The loss of inhibition and increased glutamate release may cause the distorted thoughts and diminished cognitive abilities elicited by NMDAR blockade.

Etanercept therapy for immune-mediated cochleovestibular disorders: A multi-center, open-label, pilot study

Immune-mediated cochleovestibular disorders (IMCVDs) continue to present a diagnostic and therapeutic challenge. Antirheumatic agents, commonly employed for IMCVDs, are associated with variable efficacy and sometimes with serious side effects. The objective of the current study was to preliminarily evaluate the efficacy of etanercept therapy for IMCVD. In this open-label prospective pilot study, 23 patients with bilateral IMCVDs or symptoms of bilateral Meniere's disease were treated with etanercept (25 mg twice weekly, by subcutaneous injection) for 24 weeks. All participants showed progressive hearing loss within 3 months prior to the study and responded to prednisone therapy. Hearing improvement was defined as an improvement of sensorineural hearing from baseline, in at least one ear, of 15 dB or more in the pure-tone air conduction thresholds, or an increase of more than 12% in word identification score. When present, vertigo and tinnitus were assessed by frequency and severity of attack and a functional level scale. Limited serial positron emission tomography (PET) of the inner ear region was performed in 5 patients to assess disease activity. There were 12 female (52%) and 11 male patients with a mean age of 48 years. Hearing improved in 7 (30%) patients, was unchanged in 13 (57%), and worsened in 3 (13%). Of 21 patients with tinnitus, this symptom improved in 7 (33%), was unchanged in 10 (48%), and worsened in 3 (13%). Of 16 patients with vertigo, 8 (50%) were improved, 7 (47%) unchanged, and 1 (3%) worse at the end of the study. Etanercept was generally well tolerated. PET was positive on one ear of 2 of 5 patients, remained positive with treatment on 1 of these, and was initially positive in 1 deaf ear, becoming negative at followup. These prospective pilot data suggest that etanercept therapy is safe among patients with IMCVDs. However, these data do not suggest substantial efficacy of etanercept among patients with IMCVDs in improving hearing loss. There appeared to be stabilization or improvement of hearing in 87% in this group of patients with pretreatment intractable progressive hearing loss. However, the study endpoint of improvement in 70% of patients was not attained. This short-term effect of possible stabilization requires further study. PET scanning was not useful as a tool to evaluate hearing loss in a limited subset of patients.

Outcome of acutely ischemic brain tissue in prolonged middle cerebral artery occlusion: a serial positron emission tomography investigation in the baboon.

Thrombolysis within 3 to 6 hours of symptom onset is recommended therapy for acute middle cerebral artery (MCA) stroke, but recent imaging studies in humans suggest that the penumbra may last much longer in some patients. It is therefore important to study the events that take place with occlusions that last longer than 6 hours. Based upon positron emission tomography (PET), the tissue with high oxygen extraction fraction (OEF) is at risk of infarction. In a previous sequential PET study in anesthetized baboons, we documented that when reperfusion was initiated at 6 hours after MCA occlusion, the region with the acutely highest OEF was not incorporated within the final magnetic resonance imaging (MRI)-defined infarct, suggesting reperfusion prevented such demise. In agreement with this hypothesis, we report here using the same sequential PET paradigm with final chronic-stage volume MRI that a 20-hour MCA occlusion resulted in, on average, 36% of the highest OEF area being recruited into the final infarct. We also found that the portion of the highest OEF area that went on to infarct had at the earliest time-point significantly lower cerebral blood flow and cerebral oxygen metabolism (mean reductions relative to unoccluded side, 56% and 32%, respectively) than the portion that did not (41% and 11%, respectively) and that some reperfusion occurred in the latter at second time-point, that is, before recanalization. Thus, apart from duration of occlusion, the fate of the at-risk tissue is predicated by the initial severity of the ischemia as well as by early secondary events such as partial spontaneous reperfusion.