The first probe of a FLASH proton beam by PET.

The recently observed FLASH effect related to high doses delivered with high rates has the potential to revolutionize radiation cancer therapy if promising results are confirmed and an underlying mechanism understood. Comprehensive measurements are essential to elucidate the phenomenon. We report the first-ever demonstration of measurements of successive in-spill and post-spill emissions of gammas arising from irradiations by a FLASH proton beam. A small positron emission tomography (PET) system was exposed in an ocular beam of the Proton Therapy Center at MD Anderson Cancer Center to view phantoms irradiated by 3.5 × 1010protons with a kinetic energy of 75.8 MeV delivered in 101.5 ms-long spills yielding a dose rate of 164 Gy s-1. Most in-spill events were due to prompt gammas. Reconstructed post-spill tomographic events, recorded for up to 20 min, yielded quantitative imaging and dosimetric information. These findings open a new and novel modality for imaging and monitoring of FLASH proton therapy exploiting in-spill prompt gamma imaging followed by post-spill PET imaging.

The first PET glimpse of a proton FLASH beam.

We demonstrate the first ever recorded positron-emission tomography (PET) imaging and dosimetry of a FLASH proton beam at the Proton Center of the MD Anderson Cancer Center. Two scintillating LYSO crystal arrays, read out by silicon photomultipliers, were configured with a partial field of view of a cylindrical poly-methyl methacrylate (PMMA) phantom irradiated by a FLASH proton beam. The proton beam had a kinetic energy of 75.8 MeV and an intensity of about 3.5 × 1010protons that were extracted over 101.5 ms-long spills. The radiation environment was characterized by cadmium-zinc-telluride and plastic scintillator counters. Preliminary results indicate that the PET technology used in our tests can efficiently record FLASH beam events. The instrument yielded informative and quantitative imaging and dosimetry of beam-activated isotopes in a PMMA phantom, as supported by Monte Carlo simulations. These studies open a new PET modality that can lead to improved imaging and monitoring of FLASH proton therapy.

Systematic and random errors of PET-based 90 Y 3D dose quantification.

PURPOSE: The objective was to characterize both systematic and random errors in Positron Emission Tomography (PET)-based 90 Y three-dimensional (3D) dose quantification. METHODS: A modified NEMA-IEC phantom was used to emulate 90 Y-microsphere PET imaging conditions: sphere activity concentrations of 1.6 and 4.8 MBq/cc, sphere-to-background ratios of 4 and 13, and sphere diameters of 13, 17, and 37 mm. PET data were acquired using a GE D690 PET/CT scanner for 300 min on days 0-11. The data were downsampled to 60-5 min for multiple realizations to evaluate the count starvation effect. The image reconstruction algorithm was 3D-OSEM with PSF + TOF modeling; the parameters were optimized for dose-volume histogram (DVH), as a 90 Y 3D dose quantification. 90 Y-PET images were converted to dose maps using the local deposition method, then the sphere DVHs were calculated. The ground truth for the DVH was calculated using convolution method. Dose linearity was evaluated in decaying 90 Y activity (reduced count rate and total count) and decreasing acquisition durations (reduced total count only). Finally, the impacts of the low 32-ppm positron yield on PET-based 3D 90 Y-dose quantification were evaluated; the bias and variability of resulting DVHs were characterized. RESULTS: We observed nonlinear errors that depended on the 90 Y activity (count rate) and not on the total true prompt counts. These nonlinear errors in mean dose underestimated the measured mean dose by> 20% for a measured dose range of 40-230 Gy; although the shapes of the DVH were not altered. Compensation based on empirical models reduced the nonlinearity errors to be within 5% for measured dose range of 40-230 Gy. In contrast, the errors due to nonuniformity introduced by image noise dominated the systematic errors in the DVH and stretched the DVH on both tails. For the 37-mm sphere, the magnitude of errors in D80 increased from -25% to -36% when acquisition duration was decreased from 300 to 10 min. The effect of image noise on DVH was more extensive in smaller spheres; for the 17-mm sphere, the magnitude of errors in D80 increased from -29% to -45% acquisition duration was decreased from 300 to 10 min. For the 37-mm sphere, the errors in D20 increased from +3.5% to only +10.5% when the acquisition duration was decreased from 300 to 10 min; in the 17-mm sphere, the errors in D20 were 6.5% for both 300- and 10-min sphere images. CONCLUSIONS: Count-starved 90 Y-PET data introduce both systematic and random errors. The systematic error increases the apparent nonuniformity of the DVH, while the random error increases the uncertainty in the DVH. The systematic errors were larger than the random errors. Lower count rate of 90 Y-PET also introduces systematic bias, which is scanner specific. The errors of bias-compensated mean tumor dose were <10% when 90 Y-PET scan time was >15 min/bed for tumors >37 mm. Dmedian and Dmean were the most stable dose metrics. An acquisition duration of 30 min is recommended to keep the random errors < 10% for a typical tumor with sphere equivalent diameter >17 mm and average tumor dose >40 Gy.

Effects of image noise, respiratory motion, and motion compensation on 3D activity quantification in count-limited PET images.

The aims of this study were to evaluate the effects of noise, motion blur, and motion compensation using quiescent-period gating (QPG) on the activity concentration (AC) distribution-quantified using the cumulative AC volume histogram (ACVH)-in count-limited studies such as 90Y-PET/CT. An International Electrotechnical Commission phantom filled with low 18F activity was used to simulate clinical 90Y-PET images. PET data were acquired using a GE-D690 when the phantom was static and subject to 1-4 cm periodic 1D motion. The static data were down-sampled into shorter durations to determine the effect of noise on ACVH. Motion-degraded PET data were sorted into multiple gates to assess the effect of motion and QPG on ACVH. Errors in ACVH at AC90 (minimum AC that covers 90% of the volume of interest (VOI)), AC80, and ACmean (average AC in the VOI) were characterized as a function of noise and amplitude before and after QPG. Scan-time reduction increased the apparent non-uniformity of sphere doses and the dispersion of ACVH. These effects were more pronounced in smaller spheres. Noise-related errors in ACVH at AC20 to AC70 were smaller (<15%) compared to the errors between AC80 to AC90 (>15%). The accuracy of ACmean was largely independent of the total count. Motion decreased the observed AC and skewed the ACVH toward lower values; the severity of this effect depended on motion amplitude and tumor diameter. The errors in AC20 to AC80 for the 17 mm sphere were -25% and -55% for motion amplitudes of 2 cm and 4 cm, respectively. With QPG, the errors in AC20 to AC80 of the 17 mm sphere were reduced to -15% for motion amplitudes <4 cm. For spheres with motion amplitude to diameter ratio >0.5, QPG was effective at reducing errors in ACVH despite increases in image non-uniformity due to increased noise. ACVH is believed to be more relevant than mean or maximum AC to calculate tumor control and normal tissue complication probability. However, caution needs to be exercised when using ACVH in post-therapy 90Y imaging because of its susceptibility to image degradation from both image noise and respiratory motion.

Incidental primary breast cancer detected on PET-CT.

The purpose of this study is to determine the incidence of primary breast cancer (PBC) detected on (18) F-fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) in patients with a known diagnosis of non-mammary malignancies. A database search was performed to identify patients with non-mammary malignancies who had undergone staging with FDG PET-CT at a single institution between September 2005 and September 2011 and with the word "breast" reported in the PET-CT dictation. Additional breast imaging studies, clinical data, and the final histopathology of the breast lesions were correlated with the PET-CT images. Of 1951 patients who underwent PET/CT, 440 incidental breast lesions were identified in 438 patients. Of these 440 lesions, 195 (45 %) were benign, 160 (37 %) malignant, and 85 (19 %) missing data. A total of 25 PBCs were diagnosed; with a median size of 1.8 cm (range 0.8-10.7 cm); and a median SUVmax of 4.4 (range 1.7-17.6). There were 19 invasive ductal cancers, 1 invasive lobular cancer, 2 papillary cancers, 1 tubular cancer, 1 sarcomatoid cancer, and 1 ductal carcinoma in situ. Eight patients had regional nodal disease. Mammography revealed the PBC in 19 of 23 tumors (83 %), sonography in 22 of 23 (96 %). Six percent (25 of 440) of incidental breast lesions identified on FDG PET-CT represent PBCs; more than half were at an early stage and potentially curable.

New era of radiotherapy: an update in radiation-induced lung disease.

Over the last few decades, advances in radiotherapy (RT) technology have improved delivery of radiation therapy dramatically. Advances in treatment planning with the development of image-guided radiotherapy and in techniques such as proton therapy, allows the radiation therapist to direct high doses of radiation to the tumour. These advancements result in improved local regional control while reducing potentially damaging dosage to surrounding normal tissues. It is important for radiologists to be aware of the radiological findings from these advances in order to differentiate expected radiation-induced lung injury (RILD) from recurrence, infection, and other lung diseases. In order to understand these changes and correlate them with imaging, the radiologist should have access to the radiation therapy treatment plans.

TU-E-218-01: PET/CT QA/QC and Acceptance Testing.

Combined PET/CT imaging has become a routine imaging technique in diagnostic radiology and nuclear medicine alike. In this regard a thorough understanding of this modality's quality assurance and control procedures including acceptance testing is a necessary pre-requisite to ensure the optimal performance of this imaging modality. This session is designed to explain the QA and QC procedures for a PET/CT scanner with examples from two different manufacturers. The session will also cover the frequency of these tests and the elements to implement a QA/QC program for PET/CT imaging. Finally the session will cover the NEMA standard for acceptance testing of PET scanners and their meanings as well as additional recommended tests for hybrid (PET/CT) systems. LEARNING OBJECTIVES: 1. Summarize the signal processing steps for coincidence detection 2. Understand the components of a daily QA procedure 3. Identify and trouble shoot possible sources of failure in daily QA 4. List the recommended frequency of QA/QC tests 5. Describe the process of scanner calibration 6. Name the different components of the NEMA test used for PET acceptance testing 7. Understand the meaning of the results of the NEMA tests.

WE-C-217BCD-09: Compressed Sensing in PET Imaging with Partial Detector Rings.

PURPOSE: Investigate the possibility of reducing the number of PET detector elements per ring (introduce gaps) while maintaining image quality by employing compressed sensing techniques. METHODS: A uniform Ge-68 phantom was imaged on a D-RX PET/CT scanner twice; once with all detectors operational (baseline) and once with 8 equidistant detector blocks turned off (partially sampled [PS], 11% detectors off. The resulting PS sinogram was then decomposed in two different components, each sparsely represented in a specific transform domain. An iterative optimization technique was then used to recover the PS sinogram based on the solution of a combination of underdetermined system of equations and block- coordinated relaxations. In addition, the total variation is minimized for the first component to direct it into a piece-wise smooth model. Finally the two components were summed to obtain the sinogram which was used to compare with the original PS sinogram. Comparison was done only for existing sinogram pixel values. This process was repeated iteratively until a RMS error of 5% or a total of 100 iterations were reached. For each iteration update, the values of the pixels corresponding to the missing detectors were obtained from the previous iteration while the remaining pixel values were extracted from the baseline sinogram. The resultant corrected sinograms where then reconstructed using OSEM and FBP and the corresponding images for full and PS sinograms were compared using mean and max activity concentration in a ROI placed centrally over the phantom. RESULTS: For OSEM (FBP) reconstruction, the mean and max activity concentration difference were -0.06% (-0.02%) and 3.7% (5.5%) respectively when compared to baseline. CONCLUSIONS: Compressed sensing seems to have the ability to recover PS PET data. Such an approach can potentially be used to generate PET images with accurate quantitation while reducing number of detectors/ring.

SU-E-I-84: A Novel Approach for the Attenuation Correction of PET Data in PET/MR Systems.

PURPOSE: To evaluate the use of non-attenuated PET images (PET-NAC) as a means for the attenuation correction (AC) of PET images in PET/MR systems. METHODS: A 3 step iterative segmentation process is proposed. The first step is used to segment the body contour from the NAC PET images using an active contour algorithm (Kass et al., Int J Comput Vision, 321-331 (1988)). The second step was to segment the lung region from the resultant image using an optimal thresholding approach (Xu et al., IEEE T Nucl Sci, 43, 331-336 (1996)). The purpose of the third step was to delineate parts of the heart and liver from the lung contour using a region growing approach since these parts were unavoidably included in the lung contour of the second step. Finally the attenuation coefficients of the bed were included based on CT images to eliminate the impact of the couch on the accuracy of AC. The final attenuation map was then used to AC the raw PET data and Result in a final PET image (PET-IAC). To assess the proposed segmentation approach, a phantom and six patients were scanned on a GE Discovery-RX PET/CT scanner. PET-IAC was then generated from PET- NAC using the proposed approach and compared to those of CT-AC PET (PET-CTAC). Visual inspection and SUV measurements between PET-IAC and the PET-CTAC for phantom and patient studies were performed to assess the accuracy of image quantification. RESULTS: Visual inspection showed a small difference between the PET-IAC and PET-CTAC. PET-IAC tumor SUVs were on average equal to 103±9% compared to the SUVs from the PET-CTAC in the phantom study, and 110±7% in the patient studies. CONCLUSIONS: Preliminary results suggest that PET-NAC for the AC of PET images is feasible in the clinic. Such an approach can potentially be an alternative method of MR-based AC in PET/MR imaging.

Occupancy of dopamine D2 receptors by the atypical antipsychotic drugs risperidone and olanzapine: theoretical implications.

RATIONALE: To examine the D2 occupancy of two commonly used antipsychotic medications and relate this to the D2 occupancy by endogenous dopamine in schizophrenia. OBJECTIVES: The aim of this study is to compare the occupancy of striatal D2 receptors by the atypical antipsychotic medications risperidone and olanzapine at fixed dosages and to estimate the effect on D2 occupancy by dopamine as a result of these treatments. METHODS: Seven patients with schizophrenia taking risperidone 6 mg/day and nine patients with schizophrenia taking olanzapine 10 mg/day underwent an [123I]IBZM SPECT scan after 3 weeks of treatment. The specific to non-specific equilibrium partition coefficient (V3") after bolus plus constant infusion of the tracer was calculated as [(striatal activity)/(cerebellar activity)]-1. D2 receptor occupancy was calculated by comparing V3" measured in treated patients to an age-corrected V3" value derived from a group of untreated patients with schizophrenia, previously published, according to the following formula: OCC=1-(V3" treated/V3" drug free). RESULTS: V3" was significantly lower in risperidone treated patients compared with olanzapine treated patients (0.23+/-0.06 versus 0.34+/-0.08, P=-0.01), which translated to a significantly larger occupancy in schizophrenic patients treated with risperidone compared to olanzapine (69+/-8% versus 55 +/-11%, P=0.01). Data from our previous study were used to calculate the occupancy of striatal D2 receptors by antipsychotic medications required to reduce the occupancy of these receptors by endogenous dopamine to control values. In medication-free patients with schizophrenia, the occupancy of striatal D2 receptors by endogenous dopamine is estimated at 15.8%. In healthy controls, the occupancy of striatal D2 receptors by dopamine is estimated at 8.8%. In order to reduce the dopamine occupancy of striatal D2 receptors in patients with schizophrenia to control values, 48% receptor occupancy by antipsychotic medications is required. CONCLUSIONS: These data indicate that the dosage of these medications, found to be effective in the treatment of schizophrenia, reduces DA stimulation of D2 receptors to levels slightly lower than those found in unmedicated healthy subjects.

Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum.

Dopamine transmission in the ventral striatum (VST), a structure which includes the nucleus accumbens, ventral caudate, and ventral putamen, plays a critical role in the pathophysiology of psychotic states and in the reinforcing effects of virtually all drugs of abuse. The aim of this study was to assess the accuracy and precision of measurements of D(2) receptor availability in the VST obtained with positron emission tomography on the high-resolution ECAT EXACT HR+ scanner (Siemens Medical Systems, Knoxville, TN, U.S.A.). A method was developed for identification of the boundaries of the VST on coregistered high-resolution magnetic resonance imaging scans. Specific-to-nonspecific partition coefficient (V(3)") and binding potential (BP) of [(11)C]raclopride were measured twice in 10 subjects, using the bolus plus constant infusion method. [(11)C]Raclopride V(3)" in the VST (1.86 +/- 0.29) was significantly lower than in the dorsal caudate (DCA, 2.33 +/- 0.28) and dorsal putamen (DPU, 2.99 +/- 0.26), an observation consistent with postmortem studies. The reproducibility of V(3)" and BP were appropriate and similar in VST (V(3)" test-retest variability of 8.2% +/- 6.2%, intraclass correlation coefficient = 0.83), DCA (7.7% +/- 5.1%, 0.77), DPU (6.0% +/- 4.1%, 0.71), and striatum as a whole (6.3% +/- 4.1%, 0.78). Partial volume effects analysis revealed that activities in the VST were significantly contaminated by counts spilling over from the adjacent DCA and DPU: 70% +/- 5% of the specific binding measured in the VST originated from D(2) receptors located in the VST, whereas 12% +/- 3% and 18% +/- 3% were contributed by D(2) receptors in the DCA and DPU, respectively. Thus, accuracy of D(2) receptor measurement is improved by correction for partial voluming effects. The demonstration of an appropriate accuracy and precision of D(2) receptor measurement with [(11)C]raclopride in the VST is the first critical step toward the use of this ligand in the study of synaptic dopamine transmission at D(2) receptors in the VST using endogenous competition techniques.

Differential occupancy of somatodendritic and postsynaptic 5HT(1A) receptors by pindolol: a dose-occupancy study with [11C]WAY 100635 and positron emission tomography in humans.

Augmentation of selective serotonin reuptake inhibitors (SSRIs) therapy by the 5-HT(1A) receptor agent pindolol may reduce the delay between initiation of antidepressant treatment and clinical response. This hypothesis is based on the ability of pindolol to block 5-HT(1A) autoreceptors in the dorsal raphe nuclei (DRN) and to potentiate the increase in 5-HT transmission induced by SSRIs. However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT(1A) receptors during treatment with pindolol controlled release (CR) in nine healthy volunteers with Positron Emission Tomography and [11C]WAY 100635. Subjects were studied four times: at baseline, following one week of pindolol CR 7.5 mg/day (4 and 10 hrs post dose), and following one dose of pindolol CR 30 mg(4 hrs post dose). Occupancy of the DRN was 40 +/- 29% on scan 2, 38 +/- 26% on scan 3, and 64 +/- 15% on scan 4. The average occupancy in all other regions was significantly lower at each doses (18 +/- 5% on scan 2, 12 +/- 3% on scan 3, and 42 +/- 4% on scan 4). These results suggest that the blockade in the DRN reached in clinical studies (7.5 mg/day) might be too low and variable to consistently augment the therapeutic effect of SSRIs. However, these data indicate that pindolol exhibits in vivo selectivity for the DRN 5-HT(1A) autoreceptors. As DRN selectivity is desirable for potentiation of 5-HT function, this observation represents an important proof of concept for the development of 5-HT(1A) agents in this application.

In vivo quantification of brain serotonin transporters in humans using [11C]McN 5652.

UNLABELLED: Abnormal brain regional densities of serotonin (5-hydroxytryptamine [5-HT]) transporters have been reported in postmortem studies in several neuropsychiatric conditions, such as major depression and schizophrenia. trans-1,2,3,5,6,10-beta-Hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]-isoquinoline ([11C]McN 5652) is the first PET radioligand successfully developed to label 5-HT transporters in the living human brain. The purpose of this study was to develop an imaging protocol and analytic method to measure regional 5-HT transporter binding potential (BP) with [11C]McN 5652 in humans. METHODS: The arterial input function and brain uptake of (+)-[11C]McN 5652 and (-)-[11C]McN 5652, the active and inactive enantiomers, respectively, were measured in 6 healthy volunteers. RESULTS: (+)-[11C]McN 5652 concentrated in brain regions rich in 5-HT transporters (midbrain, thalamus, basal ganglia, and medial temporal lobe structures), whereas the uptake of (-)-[11C]McN 5652 was more uniformly distributed. Total distribution volumes (V(T)) were derived using kinetic 2-compartment analysis and graphic analysis. V(T) derived by both methods were highly correlated. (+)-[11C]McN 5652 regional V(T) ranged from 18 +/- 2 mL/g in the cerebellum to 46 +/- 13 mL/g in the midbrain. (-)-[11C]McN 5652 regional VT ranged from 10 +/- 2 mL/g in the cerebellum to 14 +/- 3 mL/g in the thalamus. (+)-[11C]McN 5652 V(T) were higher than (-)-[11C]McN 5652 V(T) in all regions, including the cerebellum, a region devoid of 5-HT transporters. Blocking experiments were also performed in baboons with saturating doses of citalopram and in humans with nonsaturating doses of paroxetine. Cerebellar and neocortical (+)-[11C]McN 5652 V(T) were unaffected by pretreatment with 5-HT transporter blockers. In areas of high receptor concentration (midbrain, caudate, and thalamus) 5-HT transporter blockers decreased (+)-[11C]McN 5652 V(T) to the level of cerebellum (+)-[11C]McN 5652 V(T). CONCLUSION: These experiments indicate that the use of the difference between (+)- and (-)-[11C]McN 5652 V(T) to define specific binding to 5-HT transporters leads to an overestimation of specific binding. 5-HT transporter BP was derived as the difference between the regional and cerebellar (+)-[11C]McN 5652 V(T). BP values were in good agreement with the distribution of 5-HT transporters in the human brain, except for regions of relatively low 5-HT transporter concentration, such as the prefrontal cortex, where no specific binding was detected using (+)-[11C]McN 5652. (+)-[11C]McN 5652 is an appropriate radiotracer to quantify 5-HT transporters in regions with relatively high concentration of 5-HT transporters, such as the midbrain, thalamus, and basal ganglia, and should prove useful in elucidating abnormalities of 5-HT transmission in neuropsychiatric conditions.

Positron emission tomography study of pindolol occupancy of 5-HT(1A) receptors in humans: preliminary analyses.

Preclinical studies in rodents suggest that augmentation of serotonin reuptake inhibitors (SSRIs) therapy by the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agent pindolol might reduce the delay between initiation of treatment and antidepressant response. This hypothesis is based on the ability of pindolol to potentiate the increase in serotonin (5-HT) transmission induced by SSRIs, an effect achieved by blockade of the 5-HT(1A) autoreceptors in the dorsal raphe nuclei (DRN). However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT(1A) receptors following treatment with controlled release pindolol in nine healthy volunteers with positron-emission tomography (PET). Each subject was studied four times: at baseline (scan 1), following 1 week of oral administration of pindolol CR (7.5 mg/day) at peak level, 4 h after the dose (scan 2), and at 10 h following the dose (scan 3), and following one dose of pindolol CR (30 mg) (at peak level, 4 h) (scan 4). Pindolol occupancy of 5-HT(1A) receptors was evaluated in the DRN and cortical regions as the decrease in binding potential (BP) of the radiolabelled selective 5-HT(1A) antagonist [carbonyl-(11)C]WAY-100635 or [carbonyl-(11)C] N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)cyclohexa necarboxamide abbreviated as [(11)C]WAY-100635. Pindolol dose-dependently decreased [(11)C]WAY-100635 BP. Combining all the regions, occupancy was 20 +/- 8% at scan 2, 14 +/- 8% at scan 3, and 44 +/- 8% at scan 4. The results of this study suggest that at doses used in clinical studies of augmentation of the SSRI effect by pindolol (2.5 mg t.i.d.), the occupancy of 5-HT(1A) receptors is moderate and highly variable between subjects. This factor might explain the variable results obtained in clinical studies. On the other hand, at each dose tested, pindolol occupancy of 5-HT(1A) receptors was higher in the DRN compared to cortical regions, demonstrating a significant in vivo selectivity for DRN 5-HT(1A) autoreceptors relative to cortico-limbic postsynaptic receptors. This selectivity is necessary for the potentiation of 5-HT transmission, and this finding represents an important proof of concept in the development of 5-HT(1A) agents for this application. Early evaluation of new drugs with PET imaging will enable rapid screening of compounds based on DRN selectivity and more appropriate determination of doses for clinical trials.

Validation and reproducibility of measurement of 5-HT1A receptor parameters with [carbonyl-11C]WAY-100635 in humans: comparison of arterial and reference tisssue input functions.

Serotonin 5-HT(1A) receptors are implicated in the pathophysiology of neuropsychiatric conditions. The goal of this study was to evaluate methods to derive 5-HT(1A) receptor parameters in the human brain with positron emission tomography (PET) and [carbonyl-(11)C]WAY 100635. Five healthy volunteer subjects were studied twice. Three methods of analysis were used to derive the binding potential (BP), and the specific to nonspecific equilibrium partition coefficient (k3/k4). Two methods, kinetic analysis based on a three compartment model and graphical analysis, used the arterial plasma time-activity curves as the input function to derive BP and k3/k4. A third method, the simplified reference tissue model (SRTM), derived the input function from uptake data of a region of reference, the cerebellum, and provided only k3/k4. All methods provided estimates of regional 5-HT(1A) receptor parameters that were highly correlated. Results were consistent with the known distribution of 5-HT(1A) receptors in the human brain. Compared with kinetic BP, graphical analysis slightly underestimated BP, and this phenomenon was mostly apparent in small size-high noise regions. Compared with kinetic k3/k4, the reference tissue method underestimated k3/k4 and the underestimation was apparent primarily in regions with high receptor density. Derivation of BP by both kinetic and graphical analysis was highly reliable, with an intraclass correlation coefficient (ICC) of 0.84 +/- 0.14 (mean +/- SD of 15 regions) and 0.84 +/- 0.19, respectively. In contrast, the reliability of k3/k4 was lower, with ICC of 0.53 +/- 0.28, 0.47 +/- 0.28, and 0.55 +/- 0.29 for kinetic, graphical, and reference tissue methods, respectively. In conclusion, derivation of BP by kinetic analysis using the arterial plasma input function appeared as the method of choice because of its higher test-retest reproducibility, lower vulnerability to experimental noise, and absence of bias.

Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans: validation and reproducibility.

To evaluate the postulated role of extrastriatal D1 receptors in human cognition and psychopathology requires an accurate and reliable method for quantification of these receptors in the living human brain. [11C]NNC 112 is a promising novel radiotracer for positron emission tomography imaging of the D1 receptor. The goal of this study was to develop and evaluate methods to derive D1 receptor parameters in striatal and extrastriatal regions of the human brain with [11C]NNC 112. Six healthy volunteers were studied twice. Two methods of analysis (kinetic and graphical) were applied to 12 regions (neocortical, limbic, and subcortical regions) to derive four outcome measures: total distribution volume, distribution volume ratio, binding potential (BP), and specific-to-nonspecific equilibrium partition coefficient (k3/k4). Both kinetic and graphic analyses provided BP and k3/k4 values in good agreement with the known distribution of D1 receptors (striatum > limbic regions = neocortical regions > thalamus). The identifiability of outcome measures derived by kinetic analysis was excellent. Time-stability analysis indicated that 90 minutes of data collection generated stable outcome measures. Derivation of BP and k3/k4 by kinetic analysis was highly reliable, with intraclass correlation coefficients (ICCs) of 0.90+/-0.06 (mean +/- SD of 12 regions) and 0.84+/-0.11, respectively. The reliability of these parameters derived by graphical analysis was lower, with ICCs of 0.72+/-0.17 and 0.58+/-0.21, respectively. Noise analysis revealed a noise-dependent bias in the graphical but not the kinetic analysis. In conclusion, kinetic analysis of [11C]NNC 112 uptake provides an appropriate method with which to derive D1 receptor parameters in regions with both high (striatal) and low (extrastriatal) D1 receptor density.

No evidence of altered in vivo benzodiazepine receptor binding in schizophrenia.

Deficits in gamma-amino-butyric acid (GABA) neurotransmitter systems have been implicated in the pathophysiology of schizophrenia for more than two decades. Previous postmortem and in vivo studies of benzodiazepine (BDZ) receptor density have reported alterations in several brain regions of schizophrenic patients. The goal of this study was to better characterize possible alterations of the in vivo regional distribution volume (VT) of BDZ receptors in schizoprenia, using the selective BDZ antagonist [123I]iomazenil and single photon emission computerized tomography (SPECT). Regional BDZ VT was measured under sustained radiotracer equilibrium conditions. The reproducibility and reliability of this measurement was established in four healthy volunteers. No differences in regional BDZ VT were observed between 16 male schizophrenic patients and 16 matched controls. No relationships were observed between BDZ VT and severity of psychotic symptoms in any of the regions examined. In conclusion, this study failed to identify alterations of BDZ receptors density in schizoprenia. If this illness is associated with deficits in GABA transmission, these deficits do not substantially involve BDZ receptor expression or regulation.

A new parameter for measuring metastatic bone involvement by prostate cancer: the Bone Scan Index.

In this report, we describe a method for quantitative bone scan interpretation (the Bone Scan Index or BSI) in advanced prostate cancer. The BSI estimates the fraction of the skeleton that is involved by tumor, as well as the regional distribution of the metastases in the bones. The purpose of this report is to describe the development and validation of this method in terms of reproducibility and the application of BSI for determining extent of disease and monitoring disease progression. We analyzed 263 bone scans from 90 patients being studied under four protocols at Memorial Sloan-Kettering Cancer Center for progressive, androgen-independent prostate cancer (AIPC), who had bone scans as a part of their work-up. We determined: (a) the intraobserver and interobserver variability of the BSI; (b) the comparison between a change in BSI and prostate-specific antigen (PSA); (c) the regional distribution of bony metastases in early stage D prostate cancer (<3% skeletal involvement); and (d) the rate of growth of bony metastases from prostate cancer. A cube root transformation of the percentage of involvement of the entire skeleton was used to stabilize the variance over the entire span of values (0-60% tumor involvement). The range of interobserver variability between readers was 0.2-0.5 times the cube root of the BSI (69 scans, 18 patients). Intraobserver variability was minimal when the same reader read the same scans after a 2-year interval, showing a correlation coefficient of 0.97 (reader 1) and 0.99 (reader 2), P < 0.001. There was a parallel rise in the BSI and the PSA in 24 patients (105 scans) treated for AIPC with hydrocortisone followed by suramin at PSA relapse (Pearson's moment correlation, 0.71). In a group of 27 patients with limited bone involvement by AIPC (i.e., <3% BSI), the distribution of early metastases was not random within the skeleton but was distributed in the central skeleton in a manner that matched the distribution of the normal adult bone marrow. Also, in a group of 21 patients (62 scans), the change in BSI as a function of time after diagnosis was explored graphically. The progression of bone scan changes in AIPC, from early involvement (<3%) to late involvement, was fitted to a Gompertzian equation. It showed a rapid exponential growth phase, with an estimated tumor doubling time of 43 days when the BSI was 3.3%. The change in BSI rapidly approached a more gradual slope as the percentage of skeletal involvement increased. The BSI provides a reproducible new parameter for quantitative assessment of bone involvement by AIPC. These results suggest that the BSI will be useful for stratifying patients entering treatment protocols for extent of tumor involvement of bone. Although further study is necessary, serial bone scan BSI appears capable of quantifying both the progression of bony involvement by tumor as well as the response to treatment.

Segmentation of lung lesion volume by adaptive positron emission tomography image thresholding.

BACKGROUND: It is common protocol in radionuclide therapies to administer a tracer dose of a radiopharmaceutical, determine its lesion uptake and biodistribution by gamma imaging, and then use this information to determine the most effective therapeutic dose. This treatment planning approach can be used to quantitate accurately the activity and volume of lesions and organs with positron emission tomography (PET). In this article, the authors focus on the specification of appropriate volumes of interest (VoI) using PET in association with computed tomography (CT). METHODS: The authors have developed an automatic image segmentation schema to determine the VoI of metastases to the lung from PET images, under conditions of variable background activity. An elliptical Jaszczak phantom containing a set of spheres with volumes ranging from 0.4 to 5.5 mL was filled with F-18 activity (2-3 microCi/mL) corresponding to activities clinically observed in lung lesions. Images were acquired with a cold background and then with variable source-to-background (S/B) ratios of: 7.4, 5.5, 3.1, and 2.8. Lesion VoI analysis was performed on 10 patients with 17 primary or metastatic lung lesions, applying the optimum threshold values derived from the phantom experiments. Initial volume estimates for lung lesions were determined from CT images. Approximate S/B ratios were obtained for the corresponding lesions on F-18-fluoro-2-deoxy-D-glucose (18FDG)-PET images. From the CT estimate of the lesion size and the PET estimate of the S/B ratio, the appropriate optimum threshold could be chosen. The threshold was applied to the PET images to obtain lesion activity and a final estimate of the lesion volume. RESULTS: Phantom data analysis showed that image segmentation converged to a fixed threshold value (from 36% to 44%) for sphere volumes larger than 4 mL, with the exact value depending on the S/B ratios. For patients, the use of optimum threshold schema demonstrated a good correlation (r = 0.999) between the initial volume from CT and the final volume derived from the 18FDG-PET scan (P < 0.02). The mean difference for those volumes was 8.4%. CONCLUSIONS: The adaptive thresholding method applied to PET scans enables the definition of tumor VoI, which hopefully leads to accurate tumor dosimetry. This method can also be applied to small lesions (<4 mL). It should enable physicians to track objectively changes in disease status that could otherwise be obscured by the uncertainties in the region-of-interest drawing, even when the scans are delineated by the same physician.

Midazolam changes cerebral blood flow in discrete brain regions: an H2(15)O positron emission tomography study.

BACKGROUND: Changes in regional cerebral blood flow (rCBF) determined with H2(15)O positron emission tomographic imaging can identify neural circuits affected by centrally acting drugs. METHODS: Fourteen volunteers received one of two midazolam infusions adjusted according to electroencephalographic response. Low or high midazolam effects were identified using post-hoc spectral analysis of the electroencephalographic response obtained during positron emission tomographic imaging based on the absence or presence of 14-Hz spindle activity. The absolute change in global CBF was calculated, and relative changes in rCBF were determined using statistical parametric mapping with localization to standard stereotactic coordinates. RESULTS: The low-effect group received 7.5 +/- 1.7 mg midazolam (serum concentrations, 74 +/- 24 ng/ml), and the high-effect group received 9.7 +/- 1.3 mg midazolam (serum concentrations, 129 +/- 48 ng/ml). Midazolam decreased global CBF by 12% from 39.2 +/- 4.1 to 34.4 +/- 6.1 ml x 100 g(-1) x min(-1) (P < 0.02 at a partial pressure of carbon dioxide of 40 mmHg). The rCBF changes in the low-effect group were a subset of the high-effect group. Decreased rCBF (P < 0.001) occurred in the insula, the cingulate gyrus, multiple areas in the prefrontal cortex, the thalamus, and parietal and temporal association areas. Asymmetric changes occurred, particularly in the low-effect group, and were more significant in the left frontal cortex and thalamus and the right insula. Relative rCBF was increased in the occipital areas. CONCLUSION: Midazolam causes dose-related changes in rCBF in brain regions associated with the normal functioning of arousal, attention, and memory.