Terry Jones

Assessment of Pharmacodynamic Vascular Response in a Phase I Trial of Combretastatin A4 Phosphate

PURPOSEnClinical evaluation of novel agents that target tumor blood vessels requires pharmacodynamic end points that measure vascular damage. Positron emission tomography (PET) was used to measure the effects of the vascular targeting agent combretastatin A4 phosphate (CA4P) on tumor and normal tissue perfusion and blood volume.nnnPATIENTS AND METHODSnPatients with advanced solid tumors were enrolled onto part of a phase I, accelerated-titration, dose-escalation study. The effects of 5 to 114 mg/m2 CA4P on tumor, spleen, and kidney were investigated. Tissue perfusion was measured using oxygen-15 (15O)-labeled water and blood volume was measured using 15O-labeled carbon monoxide (C15O). Scans were performed immediately before, and 30 minutes and 24 hours after the first infusion of each dose level of CA4P. All statistical tests were two sided.nnnRESULTSnPET data were obtained for 13 patients with intrapatient dose escalation. Significant dose-dependent reductions were seen in tumor perfusion 30 minutes after CA4P administration (mean change, -49% at >or= 52 mg/m2; P =.0010). Significant reductions were also seen in tumor blood volume (mean change, -15% at >or= 52 mg/m2; P =.0070). Although by 24 hours there was tumor vascular recovery, for doses >or= 52 mg/m2 the reduction in perfusion remained significant (P =.013). Thirty minutes after CA4P administration borderline significant changes were seen in spleen perfusion (mean change, -35%; P =.018), spleen blood volume (mean change, -18%; P =.022), kidney perfusion (mean change, -6%; P =.026), and kidney blood volume (mean change, -6%; P =.014). No significant changes were seen at 24 hours in spleen or kidney.nnnCONCLUSIONnCA4P produces rapid changes in the vasculature of human tumors that can be assessed using PET measurements of tumor perfusion.

The design and implementation of a motion correction scheme for neurological PET

A method is described to monitor the motion of the head during neurological positron emission tomography (PET) acquisitions and to correct the data post acquisition for the recorded motion prior to image reconstruction. The technique uses an optical tracking system, Polaris, to accurately monitor the position of the head during the PET acquisition. The PET data are acquired in list mode where the events are written directly to disk during acquisition. The motion tracking information is aligned to the PET data using a sequence of pseudo-random numbers, which are inserted into the time tags in the list mode event stream through the gating input interface on the tomograph. The position of the head is monitored during the transmission acquisition, and it is assumed that there is minimal head motion during this measurement. Each event, prompt and delayed, in the list mode event stream is corrected for motion and transformed into the transmission space. For a given line of response, normalization, including corrections for detector efficiency, geometry and crystal interference and dead time are applied prior to motion correction and rebinning in the sinogram. A series of phantom experiments were performed to confirm the accuracy of the method: (a) a point source located in three discrete axial positions in the tomograph field of view, 0 mm, 10 mm and 20 mm from a reference point, (b) a multi-line source phantom rotated in both discrete and gradual rotations through +/- 5 degrees and +/- 15 degrees, including a vertical and horizontal movement in the plane. For both phantom experiments images were reconstructed for both the fixed and motion corrected data. Measurements for resolution, full width at half maximum (FWHM) and full width at tenth maximum (FWTM), were calculated from these images and a comparison made between the fixedand motion corrected datasets. From the point source measurements, the FWHM at each axial position was 7.1 mm in the horizontal direction, and increasing from 4.7 mm at the 0 mm position, to 4.8 mm, 20 mm offset, in the vertical direction. The results from the multi-line source phantom with +/- 5 degrees rotations showed a maximum degradation in FWHM, when compared with the stationary phantom, of 0.6 mm, in the horizontal direction, and 0.3 mm in the vertical direction. The corresponding values for the larger rotation, +/- 15 degrees, were 0.7 mm and 1.1 mm, respectively. The performance of the method was confirmed with a Hoffman brain phantom moved continuously, and a clinical acquisition using [11C]raclopride (normal volunteer). A visual comparison of both the motion and non-motion corrected images of the Hoffman brain phantom clearly demonstrated the efficacy of the method. A sample time-activity curve extracted from the clinical study showed irregularities prior to motion correction, which were removed after correction. A method has been developed to accurately monitor the motion of the head during a neurological PET acquisition, and correct for this motion prior to image reconstruction. The method has been demonstrated to be accurate and does not add significantly to either the acquisition or the subsequent data processing.

Bias in iterative reconstruction of low-statistics PET data: benefits of a resolution model.

Ordered-subset expectation maximization (OSEM) is a widely used method of reconstructing PET data. Several authors have reported bias when reconstructing frames containing few counts via OSEM, although the level of bias reported varies substantially. Such bias may lead to errors in biological parameters as derived via dynamic PET. We examine low-statistics bias in OSEM reconstruction of patient data and estimate the subsequent errors in biological parameter estimates. Patient listmode data were acquired during a [11C]-DASB scan using a brain PET scanner, the high resolution research tomograph (HRRT). These data were sub-sampled to create many independent, low-count replicates. Each replicate was reconstructed with and without the use of an image based resolution model (PSF), from which bias and variance were calculated as a function of the noise equivalent counts (NEC). Time-activity curves were subsequently generated by Monte Carlo simulation and used to study the propagation of bias from the images into the biological parameters of interest, for which noise and bias were based on the NEC. The investigation was complemented by simulation of a PET scanner. Significant bias was observed when reconstructing data of low statistical quality, for both human and simulated data. For human data, this bias was substantially reduced by including a PSF model (e.g. caudate head, 1.7 M NEC, -5.5 % bias with PSF, -13 % bias without PSF). For the observed levels of bias, Monte Carlo simulations predicted biases in the binding potential of -4 and -10 % (with/without PSF). The use of the PSF changed the variance characteristics of the images, reducing variance at the voxel level for low to moderate numbers of iterations. We conclude that OSEM reconstruction of dynamic PET data can yield parameter estimates of acceptable accuracy (for DASB), despite producing biased images at low statistics. This is however dependent upon the application. The use of a resolution model is shown to reduce bias and is thus recommended. The most likely mechanism for this reduction is the suppression of noise. The magnitude of the bias for other tracers and methods of data analysis is yet to be evaluated.

The development, past achievements, and future directions of brain PET

The early developments of brain positron emission tomography (PET), including the methodological advances that have driven progress, are outlined. The considerable past achievements of brain PET have been summarized in collaboration with contributing experts in specific clinical applications including cerebrovascular disease, movement disorders, dementia, epilepsy, schizophrenia, addiction, depression and anxiety, brain tumors, drug development, and the normal healthy brain. Despite a history of improving methodology and considerable achievements, brain PET research activity is not growing and appears to have diminished. Assessments of the reasons for decline are presented and strategies proposed for reinvigorating brain PET research. Central to this is widening the access to advanced PET procedures through the introduction of lower cost cyclotron and radiochemistry technologies. The support and expertize of the existing major PET centers, and the recruitment of new biologists, bio-mathematicians and chemists to the field would be important for such a revival. New future applications need to be identified, the scope of targets imaged broadened, and the developed expertize exploited in other areas of medical research. Such reinvigoration of the field would enable PET to continue making significant contributions to advance the understanding of the normal and diseased brain and support the development of advanced treatments.

The potential of positron-emission tomography to study anticancer-drug resistance

Positron-emission tomography (PET) is a powerful tool for imaging and quantifying cellular and molecular processes in humans. It has enormous potential to increase our understanding of the pathophysiology of human tumours and to support the development of anticancer drugs. The ability of PET to image mechanisms of anticancer-drug resistance in vivo should be exploited in proof-of-concept studies at early stages of drug development.

Acoustic parameters of snoring sound to assess the effectiveness of sleep nasendoscopy in predicting surgical outcome

Objective To assess the effectiveness of two grading systems used to predict surgical outcome in nonapneic snorers. Study Design A prospective observational study. Prior to undergoing palatal surgery, 20 patients completed a sleep nasendoscopic examination involving sequential steady-state sedation with intravenous propofol. Using a combination of acoustic parameters of snoring sound as an objective outcome measurement, and the answers to a specifically designed questionnaire as a subjective outcome measurement, the effectiveness of each grading system in predicting surgical outcome was examined. Results Depending on the outcome measurement used, sensitivity in predicting success of surgery for snoring varied from 16.7% to 50.0% and specificity from 38.5% to 62.5% for the Pringle and Croft system, while sensitivity varied from 91.7% to 100% and specificity from 30.8% to 31.5% for the Camilleri system. Conclusion Sleep nasendoscopy using these classifications cannot be recommended as a reliable predictor of surgical outcome in nonapneic snorers. EBM rating: C-4

The enabling technologies needed for PET-based molecular imaging to support drug development.

It is commonly believed that all that is required to effect PET based molecular imaging to support drug development is a cyclotron and a PET scanner. This review itemises the many additional technologies needed to enable the full exploitation of PET for pharmacodynamic and pharmacokinetic measurements of normal and diseased tissues. There are ongoing developments in each area which when integrated add up to significant advances in the quality and value of the resulting data.:

Development and validation of a variance model for dynamic PET: uses in fitting kinetic data and optimizing the injected activity.

The precision of biological parameter estimates derived from dynamic PET data can be limited by the number of acquired coincidence events (prompts and randoms). These numbers are affected by the injected activity (A(0)). The benefits of optimizing A(0) were assessed using a new model of data variance which is formulated as a function of A(0). Seven cancer patients underwent dynamic [(15)O]H(2)O PET scans (32 scans) using a Biograph PET-CT scanner (Siemens), with A(0) varied (142-839 MBq). These data were combined with simulations to (1) determine the accuracy of the new variance model, (2) estimate the improvements in parameter estimate precision gained by optimizing A(0), and (3) examine changes in precision for different size regions of interest (ROIs). The new variance model provided a good estimate of the relative variance in dynamic PET data across a wide range of A(0)s and time frames for FBP reconstruction. Patient data showed that relative changes in estimate precision with A(0) were in reasonable agreement with the changes predicted by the model: Pearsons correlation coefficients were 0.73 and 0.62 for perfusion (F) and the volume of distribution (V(T)), respectively. The between-scan variability in the parameter estimates agreed with the estimated precision for small ROIs (<5 mL). An A(0) of 500-700 MBq was near optimal for estimating F and V(T) from abdominal [(15)O]H(2)O scans on this scanner. This optimization improved the precision of parameter estimates for small ROIs (<5 mL), with an injection of 600 MBq reducing the standard error on F by a factor of 1.13 as compared to the injection of 250 MBq, but by the more modest factor of 1.03 as compared to A(0) = 400 MBq.

Bias in iterative reconstruction of low-statistics PET data: Benefits of a resolution model

Ordered-subset expectation maximization (OSEM) is a widely used method of reconstructing PET data. Several authors have reported bias when reconstructing frames containing few counts via OSEM, although the level of bias reported varies substantially. Such bias may lead to errors in biological parameters as derived via dynamic PET. We examine low-statistics bias in OSEM reconstruction of patient data and estimate the subsequent errors in biological parameter estimates. Patient listmode data were acquired during a [11C]-DASB scan using a brain PET scanner, the high resolution research tomograph (HRRT). These data were sub-sampled to create many independent, low-count replicates. Each replicate was reconstructed with and without the use of an image based resolution model (PSF), from which bias and variance were calculated as a function of the noise equivalent counts (NEC). Time-activity curves were subsequently generated by Monte Carlo simulation and used to study the propagation of bias from the images into the biological parameters of interest, for which noise and bias were based on the NEC. The investigation was complemented by simulation of a PET scanner. Significant bias was observed when reconstructing data of low statistical quality, for both human and simulated data. For human data, this bias was substantially reduced by including a PSF model (e.g. caudate head, 1.7 M NEC, -5.5 % bias with PSF, -13 % bias without PSF). For the observed levels of bias, Monte Carlo simulations predicted biases in the binding potential of -4 and -10 % (with/without PSF). The use of the PSF changed the variance characteristics of the images, reducing variance at the voxel level for low to moderate numbers of iterations. We conclude that OSEM reconstruction of dynamic PET data can yield parameter estimates of acceptable accuracy (for DASB), despite producing biased images at low statistics. This is however dependent upon the application. The use of a resolution model is shown to reduce bias and is thus recommended. The most likely mechanism for this reduction is the suppression of noise. The magnitude of the bias for other tracers and methods of data analysis is yet to be evaluated.

Patient-specific noise-equivalent-counts from repeated, dose varying [O-15]H 2 O PET scans

Scanning protocols in dynamic PET imaging can be optimised to improve the accuracy and precision of measurements of physiological parameters. For [O-15]H2O scans, one of the major factors that can be controlled is the injected dose, which affects the statistical quality of the PET data as well as its accuracy. We build upon a previous dose optimisation methodology that considers patient-specific noise-equivalent-count-rates (NECRs), extending its use to dynamic PET scanning. The accuracy of this technique is examined within 4 individual patients. Each of these patients were given a series of between 4 and 6 injections of [O-15]H2O at doses that were intentionally varied between 140 and 740 MBq. Patient-specific NECR-dose curves were extrapolated from each injection. These data are used to qualify the performance of NECR-dose curve predictions in a dynamic PET setting, as found on a modern LSO PET/CT scanner. The optimal dose was defined as the dose required to give 95 % maximisation of the integral NEC within a specified time interval post administration. We find good agreement between the extrapolated NECR curves within an individual. On average, the variability between injections produced a standard deviation of 3 % in the optimal dose calculated for the specific patient. The optimal doses ranged from 264 to 640 MBq between subjects, for maximising the NECR during the times most critical to the measurement of blood flow. We also find that although administration of the tracer at the back of the wrist in a pelvic scan produces a higher global NECR, the signal-to-noise ratio in the image is reduced compared to a similar injected dose at the elbow. We conclude that patient-specific NECR methods can provide useful guidance in dose optimisation.