Julian C. Matthews

Tumor Survivin Is Downregulated by the Antisense Oligonucleotide LY2181308: A Proof-of-Concept, First-in-Human Dose Study

Purpose: Enhanced tumor cell survival through expression of inhibitors of apoptosis (IAP) is a hallmark of cancer. Survivin, an IAP absent from most normal tissues, is overexpressed in many malignancies and associated with a poorer prognosis. We report the first-in-human dose study of LY2181308, a second-generation antisense oligonucleotide (ASO) directed against survivin mRNA. Patients and Methods: A dose-escalation study evaluating the safety, pharmacokinetics, and pharmacodynamics of LY2181308 administered intravenously for 3 hours as a loading dose on 3 consecutive days and followed by weekly maintenance doses. Patients were eligible after signing informed consent, had exhausted approved anticancer therapies and agreed to undergo pre- and posttreatment tumor biopsies to evaluate reduction of survivin protein and gene expression. Results: A total of 40 patients were treated with LY2181308 at doses of 100 to 1,000 mg. Twenty-six patients were evaluated at the recommended phase 2 dose of 750 mg, at which level serial tumor sampling and [11C]LY2183108 PET (positron emission tomography) imaging demonstrated that ASO accumulated within tumor tissue, reduced survivin gene and protein expression by 20% and restored apoptotic signaling in tumor cells in vivo. Pharmacokinetics were consistent with preclinical modeling, exhibiting rapid tissue distribution, and terminal half-life of 31 days. Conclusions: The tumor-specific, molecularly targeted effects demonstrated by this ASO in man underpin confirmatory studies evaluating its therapeutic efficacy in cancer.

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.

Pharmacokinetic Evaluation of N-[2-(Dimethylamino)Ethyl]Acridine-4-Carboxamide in Patients by Positron Emission Tomography

PURPOSE To evaluate tumor, normal tissue, and plasma pharmacokinetics of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA). The study aimed to determine the pharmacokinetics of carbon-11-labeled DACA ([11C]DACA) and evaluate the effect of pharmacologic doses of DACA on radiotracer kinetics. PATIENTS AND METHODS [11C]DACA (at 1/1,000 phase I starting dose) was administered to 24 patients with advanced cancer (pre-phase I) or during a phase I trial of DACA in five patients. Positron emission tomography (PET) was performed to assess pharmacokinetics and tumor blood flow. Plasma samples were analyzed for metabolite profile of [11C]DACA. RESULTS There was rapid systemic clearance of [11C]DACA over 60 minutes (1.57 and 1.46 L x min(-1) x m(-2) in pre-phase I and phase I studies, respectively) with the production of several radiolabeled plasma metabolites. Tumor, brain, myocardium, vertebra, spleen, liver, lung, and kidneys showed appreciable uptake of 11C radioactivity. The area under the time-versus-radioactivity curves (AUC) showed the highest variability in tumors. Of interest to potential toxicity, maximum radiotracer concentrations (Cmax) in brain and vertebra were low (0.67 and 0.54 m(2) x mL(-1), respectively) compared with other tissues. A moderate but significant correlation was observed for tumor blood flow with AUC (r = 0.76; P =.02) and standardized uptake value (SUV) at 55 minutes (r = 0.79; P =.01). A decrease in myocardial AUC ( P =.03) and splenic and myocardial SUV ( P =.01 and.004, respectively) was seen in phase I studies. Significantly higher AUC, SUV, and Cmax were observed in tumors in phase I studies. CONCLUSION The distribution of [11C]DACA and its radiolabeled metabolites was observed in a variety of tumors and normal tissues. In the presence of unlabeled DACA, pharmacokinetics were altered in myocardium, spleen, and tumors. These data have implications for predicting activity and toxicity of DACA and support the use of PET early in drug development.

Pharmacokinetic assessment of novel anti-cancer drugs using spectral analysis and positron emission tomography: A feasibility study

Purpose: The aim of this study was to investigate the feasibility of evaluating the pharmacokinetics of radiolabeled anti-cancer drugs using spectral analysis, a non-compartmental tracer kinetic modeling technique, and positron emission tomography (PET). Methods: Dynamic PET studies were performed on patients receiving tracer doses of 5-fluorouracil (5-[18F]-FU) and two developmental drugs – [11C]-temozolomide and [11C]-acridine carboxamide. Spectral analysis was then used to (a) determine individual and group average pharmacokinetics, (b) predict tumour handling in response to different drug administration regimens, and (c) produce functional parametric images describing regional pharmacokinetics. Results: Spectral analysis could distinguish tumour kinetics from normal tissue kinetics in an individual [11C]-temozolomide study and demonstrated a markedly greater volume of distribution (VD) in glioma than in normal brain, although there was no appreciable difference in mean residence time. Analysis of pooled acridine carboxamide data (n=22) revealed a relatively large VD (and prolonged retention) in the liver and spleen and a markedly lower VD (and initial uptake) in the brain. Continuous infusion of 5-[18F]-FU was predicted to achieve a concentration in colorectal metastases in liver approximately 10 times that achieved in plasma at 10 h after commencement of the infusion. Conclusions: We conclude that spectral analysis provides important pharmacokinetic information about radiolabeled anti-cancer drugs with relatively few model assumptions.

A Multi-Center Randomized Proof-of-Concept Clinical Trial Applying [18F]FDG-PET for Evaluation of Metabolic Therapy with Rosiglitazone XR in Mild to Moderate Alzheimer's Disease

Here we report the first multi-center clinical trial in Alzheimers disease (AD) using fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) measures of brain glucose metabolism as the primary outcome. We contrasted effects of 12 months treatment with the PPARγ agonist Rosiglitazone XR versus placebo in 80 mild to moderate AD patients. Secondary objectives included testing for reduction in the progression of brain atrophy and improvement in cognition. Active treatment was associated with a sustained but not statistically significant trend from the first month for higher mean values in Kiindex and CMRgluindex, novel quantitative indices related to the combined forward rate constant for [18F]FDG uptake and to the rate of cerebral glucose utilization, respectively. However, neither these nor another analytical approach recently validated using data from the Alzheimers Disease Neuroimaging Initiative indicated that active treatment decreased the progression of decline in brain glucose metabolism. Rates of brain atrophy were similar between active and placebo groups and measures of cognition also did not suggest clear group differences. Our study demonstrates the feasibility of using [18F]FDG-PET as part of a multi-center therapeutics trial. It suggests that Rosiglitazone is associated with an early increase in whole brain glucose metabolism, but not with any biological or clinical evidence for slowing progression over a 1 year follow up in the symptomatic stages of AD.

Tumor, Normal Tissue, and Plasma Pharmacokinetic Studies of Fluorouracil Biomodulation With N-Phosphonacetyl-l-aspartate, Folinic Acid, and Interferon Alfa

PURPOSE To evaluate the effect of N-phosphonacetyl-L-aspartate (PALA), folinic acid (FA), and interferon alfa (IFN-alpha) biomodulation on plasma fluorouracil (5FU) pharmacokinetics and tumor and liver radioactivity uptake and retention after [18F]-fluorouracil (5-[18F]-FU) administration. PATIENTS AND METHODS Twenty-one paired pharmacokinetic studies were completed on patients with colorectal, gastric, and hepatocellular cancer, utilizing positron emission tomography (PET), which allowed the acquisition of tumor, normal tissue, and plasma pharmacokinetic data and tumor blood flow (TBF) measurements. The first PET study was completed when the patient was biomodulator-naive and was repeated on day 8 after the patient had been treated with either PALA, FA, or IFN-alpha in recognized schedules. RESULTS TBF was an important determinant of tumor radioactivity uptake (r = .90; P < .001) and retention (r = .96; P < .001), for which radioactivity represents a composite signal of 5-[18F]-FU and [18F]-labeled metabolites and catabolites. After treatment with PALA, TBF decreased (four of four patients; P = .043), as did tumor radioactivity exposure (five of five patients; P = .0437), with no change in plasma 5FU clearance. With FA treatment, there were no differences observed in whole-body metabolism, plasma 5FU clearance, or tumor and liver pharmacokinetics. IFN-alpha had measurable effects on TBF and 5-[18F]-FU metabolism but had no apparent affect on liver blood flow. CONCLUSION The administration of PALA and IFN-alpha produced measurable changes in plasma, tumor, and liver pharmacokinetics after 5-[18F]-FU administration. No changes were observed after FA administration. In vivo effects may negate the anticipated therapeutic advantage of 5FU biomodulation with some agents.

Fully 4D image reconstruction by estimation of an input function and spectral coefficients

A new dynamic image reconstruction method for PET is proposed. First, a set of exponential temporal basis functions is predefined, covering the entire range of kinetics (from static through to a delta function). Just as in spectral analysis, such a selection is designed to be able to handle all possible tissue responses for multi-compartmental tissue models. Second, an initial estimate of an input function is defined. The time-dependent PET radiotracer concentration is then modeled (through the system matrix in the reconstruction algorithm) as a superposition of the exponential temporal basis functions, convolved with the input function. The reconstruction method uses an expectation maximization (EM) algorithm to operate directly on the measured PET data in order to i. estimate the coefficients of the exponential functions, and ii. improve the estimate of the input function. The coefficients and the input function are estimated only as a means of regularizing the model of the time-dependent image: the final reconstruction is used with conventional post-reconstruction kinetic analysis, with a different input function if need be (as the estimated input function may not correspond to the true input function). Results from tests on simulated data reveal a simultaneous benefit of noise reduction and improved kinetic parameter estimates when compared to conventional methodology. The method is also demonstrated on measured HRRT PET data for an FDG study.

Single scan parameterization of space-variant point spread functions in image space via a printed array: the impact for two PET/CT scanners

Incorporation of a resolution model during statistical image reconstruction often produces images of improved resolution and signal-to-noise ratio. A novel and practical methodology to rapidly and accurately determine the overall emission and detection blurring component of the system matrix using a printed point source array within a custom-made Perspex phantom is presented. The array was scanned at different positions and orientations within the field of view (FOV) to examine the feasibility of extrapolating the measured point source blurring to other locations in the FOV and the robustness of measurements from a single point source array scan. We measured the spatially-variant image-based blurring on two PET/CT scanners, the B-Hi-Rez and the TruePoint TrueV. These measured spatially-variant kernels and the spatially-invariant kernel at the FOV centre were then incorporated within an ordinary Poisson ordered subset expectation maximization (OP-OSEM) algorithm and compared to the manufacturers implementation using projection space resolution modelling (RM). Comparisons were based on a point source array, the NEMA IEC image quality phantom, the Cologne resolution phantom and two clinical studies (carbon-11 labelled anti-sense oligonucleotide [(11)C]-ASO and fluorine-18 labelled fluoro-l-thymidine [(18)F]-FLT). Robust and accurate measurements of spatially-variant image blurring were successfully obtained from a single scan. Spatially-variant resolution modelling resulted in notable resolution improvements away from the centre of the FOV. Comparison between spatially-variant image-space methods and the projection-space approach (the first such report, using a range of studies) demonstrated very similar performance with our image-based implementation producing slightly better contrast recovery (CR) for the same level of image roughness (IR). These results demonstrate that image-based resolution modelling within reconstruction is a valid alternative to projection-based modelling, and that, when using the proposed practical methodology, the necessary resolution measurements can be obtained from a single scan. This approach avoids the relatively time-consuming and involved procedures previously proposed in the literature.

Robustness of multivariate image analysis assessed by resampling techniques and applied to FDG-PET scans of patients with Alzheimer's disease.

For finite and noisy samples extraction of robust features or patterns which are representative of the population is a formidable task in which over-interpretation is not uncommon. In this work, resampling techniques have been applied to a sample of 42 FDG PET brain images of 19 healthy volunteers (HVs) and 23 Alzheimers disease (AD) patients to assess the robustness of image features extracted through principal component analysis (PCA) and Fisher discriminant analysis (FDA). The objective of this work is to: 1) determine the relative variance described by the PCA to the population variance; 2) assess the robustness of the PCA to the population sample using the largest principal angle between PCA subspaces; 3) assess the robustness and accuracy of the FDA. Since the sample does not have histopathological data the impact of possible clinical misdiagnosis on the discrimination analysis is investigated. The PCA can describe up to 40% of the total population variability. Not more than the first three or four PCs can be regarded as robust on which a robust FDA can be build. Standard error images showed that regions close to the falx and around ventricles are less stable. Using the first three PCs, sensitivity and specificity were 90.5% and 96.9% respectively. The use of resampling techniques in the evaluation of the robustness of many multivariate image analysis methods enables researchers to avoid over-analysis when using these methods applied to many different neuroimaging studies often with small sample sizes.

Iterative Kinetic Parameter Estimation within Fully 4D PET Image Reconstruction

4D PET imaging seeks to estimate kinetic parameters of physiological significance through the generation of a time series of 3D images. Conventionally the time series is reconstructed one frame at a time, and then the kinetic modeling is applied as a post-reconstruction step to estimate the desired parameters. Such a separated approach does not account for the task of kinetic parameter estimation within the reconstruction itself. This work indicates that conventional frame-by-frame maximum likelihood reconstruction in high noise situations is sub-optimal if post-reconstruction kinetic parameter estimation is to be performed. As an alternative, a simple to implement, EM-based iterative reconstruction method is proposed which uses all of the acquired data in every iteration and includes the image-space kinetic parameter estimation process within the reconstruction. The method can accommodate kinetic models of any chosen complexity with relative ease, and can deliver more accurate kinetic parameter estimates than the conventional approach for low-statistics data.