Jye Smith

Increasing feasibility and utility of 18F-FDOPA PET for the management of glioma

INTRODUCTION Despite radical treatment therapies, glioma continues to carry with it a uniformly poor prognosis. Patients diagnosed with WHO Grade IV glioma (glioblastomas; GBM) generally succumb within two years, even those with WHO Grade III anaplastic gliomas and WHO Grade II gliomas carry prognoses of 2-5 and 2 years, respectively. PET imaging with (18)F-FDOPA allows in vivo assessment of the metabolism of glioma relative to surrounding tissues. The high sensitivity of (18)F-DOPA imaging grants utility for a number of clinical applications. METHODS A collection of published work about (18)F-FDOPA PET was made and a critical review was discussed and written. RESULTS A number of research papers have been published demonstrating that in conjunction with MRI, (18)F-FDOPA PET provides greater sensitivity and specificity than these modalities in detection, grading, prognosis and validation of treatment success in both primary and recurrent gliomas. In further comparisons with (11)C-MET, (18)F-FLT, (18)F-FET and MRI, (18)F-FDOPA has shown similar or better efficacy. Recently synthesis cassettes have become available, making (18)F-FDOPA more accessible. CONCLUSIONS According to the available data, (18)F-FDOPA PET is a viable radiotracer for imaging and treatment planning of gliomas. ADVANCES IN KNOWLEDGE AND IMPLICATION FOR PATIENT CARE (18)F-FDOPA PET appears to be a viable radiopharmaceutical for the diagnosis and treatment planning of gliomas cases, improving on that of MRI and (18)F-FDG PET.

Early prediction of treatment response in advanced gliomas with 18F-DOPA positron-emission tomography

The Editor Current Oncology August 27, 2013 Imaging markers that enable prediction of survival are of interest for aiding clinical decision-making for patients with advanced glioma. However, current imaging methods based on the use of contrast-enhanced magnetic resonance imaging (mri) and 18F-fludeoxyglucose positron-emission tomography (pet) applied in the early stages after treatment are not strongly correlated with patient outcome. In conjunction with mri, amino-acid pet tracers have shown promise for this application, including variations in l-[methyl-11C]-methionine uptake1 and 3′-dexoy-3′-[18F] fluorothymidine (flt)2 uptake, and volume variations of regions with high flt and 6-[18F] fluoro-l-dopa (18F-dopa)3 uptake. Uptake of flt is predictive of survival in recurrent advanced glioma, even when chemotherapy renders mri unreliable2. However, previous serial assessments have typically considered global uptake within the tumour1,2,4, even though treatment failure frequently occurs locally within areas of existing abnormality5. The hypothesis explored here is that poor patient survival is directly related to the extent of the most treatment-resistant cluster of malignant cells exhibiting persistent metabolic activity. Apart from the use of 18F-dopa as an early surrogate marker, a key difference between this study and previous work is the longitudinal comparison of metabolic activity within focal peritumoural regions. The study enrolled 9 patients (7 men; age range: 52–71 years), summarized in Table i, with histopathologically confirmed high-grade brain tumour (World Health Organization grade iv). The institutional ethics review board approved the study, and patients provided informed written consent. Patients received mri and 18F-dopa pet scans at two time points: a baseline immediately before tumour resection, and a follow-up at 12 weeks after resection. The post-resection interval consisted of 2 weeks’ recovery, a 6-week course of chemoradiotherapy (external-beam radiotherapy of 60 Gy in 30 fractions or 40 Gy in 15 fractions, with concurrent temozolomide), and 4 weeks’ recovery to minimize potential treatment-induced variations in metabolism. (Figure 1 provides a schematic outline.) The pet intensities were normalized to the ipsilateral cerebellum and reported as standardized uptake value ratios. One patient did not receive chemoradiotherapy. Table I Values extracted from each dataset Figure 1 Timing of magnetic resonance imaging (mri) and 18F-dopa positron-emission tomography (fdopa). Both modalities were used at two time points: once before surgery and once 12 weeks after surgery. Chemo-rt = chemoradiation therapy. After rigid registration, the most metabolically active voxel in each post-treatment tumour was selected from the pet image. Using nearby anatomic features from the fused mri, the corresponding location was selected on the pre-surgery image under the guidance of experienced specialists (PT, MF, RLJ, CW, AC) blinded to the pre-treatment pet image and patient outcome. The mean 18F-dopa uptake within a 1-cm radius sphere centred on each landmark was calculated before computing the difference between baseline and follow-up. The 1-cm radius traded off the typical statistical variation in pet intensities and potential inaccuracies in spatial correspondences with the size of metabolically active regions. A Cox proportional hazards analysis model was used to evaluate the relationship between variations in 18Fdopa uptake and survival. Survival times, plotted in Figure 2 as a function of change in 18F-dopa uptake, ranged from less than 30 weeks to more than 110 weeks. At last report, 3 patients remained alive. Variations in 18F-dopa uptake ranged from less than −50% to more than +20%. The results, summarized in Table ii, demonstrate that a decrease in 18F-dopa uptake is a predictor of extended survival. For interest, the selected regions in each patient are shown in Figures 3–5. A Cox proportional hazards model fitted the data closely (r = 0.65), and showed that the hazard to the patient declined by 10.3% with each 1% decrease in local 18F-dopa uptake. The null hypothesis—that changes in 18F-dopa are not related to survival—was rejected with some significance (p < 0.032). Figure 2 Plot of survival versus local change in the spherical region centred on the point of greatest metabolism after treatment. A value of 0% (dotted line) indicates no change in 18F-dopa uptake. Chemo-rt = chemoradiation therapy. aPatient was alive at last ... Table II Statistics extracted from all patients Figure 3 The spherical region of interest (green circles) superimposed on the 18F-dopa positron-emission tomography (pet) and contrast-enhanced magnetic resonance imaging (mri) images for patients 1–3 at baseline and follow-up. Baseline images were acquired ... Figure 5 The spherical region of interest (green circles) superimposed on the 18F-dopa positron-emission tomography (pet) and contrast-enhanced magnetic resonance (mr) images for patients 7–9 at baseline and follow-up. Baseline images were acquired before ... Figure 4 The spherical region of interest (green circles) superimposed on the 18F-dopa positron-emission tomography (pet) and contrast-enhanced magnetic resonance (mr) images for patients 4–6 at baseline and follow-up. Baseline images were acquired before ... A second model, incorporating age and sex, was compared with the first using analysis of variance (Table iii). The comparison showed that the models largely overlapped (p > 0.7), and consecutive increases for log likelihood (4.74 for change in local 18F-dopa, 0.24 for age, and 0.23 for sex) indicated that age and sex had a more limited influence on the results. Finally, global 18F-dopa uptake (mean over the entire tumour) was compared with survival. Compared with local 18F-dopa, global 18F-dopa was less correlated with survival (5.2% decline in hazard for 1% decrease in uptake), had a poorer fit (r = 0.33), and was less significant (p < 0.1). Table III Crudea analysis of variance that considers additional effects of age and sex The more significant correlation between 18F-dopa variations locally within tumours (rather than globally), supports the hypothesis that patient survival might be linked to focal points of treatment failure within peritumoural colonies of malignant cells that exhibit enhanced amino-acid uptake after therapy. Hence, variations in 18F-dopa are potentially indicative of a genetic predisposition in certain tumours toward treatment sensitivity, with the resulting delay before disease progression leading to extended survival. These results motivate for the use of 18F-dopa–based response criteria as endpoint markers and extend the concept of using 18F-dopa–based response criteria to as early as 12 weeks after surgery. Earlier prediction of response could potentially enable early transfer to palliative care if appropriate, early enrolment of patients into therapeutic trials for recurrent tumour, and rapid screening of new therapeutic agents.

Joint factor and kinetic analysis of dynamic FDOPA PET scans of brain cancer patients

Kinetic analysis is an essential tool of Positron Emission Tomography image analysis. However it requires a pure tissue time activity curve (TAC) in order to calculate the system parameters. Pure tissue TACs are particularly difficult to obtain in the brain as the low resolution of PET means almost all voxels are a mixture of tissues. Factor analysis explicitly accounts for mixing but is an underdetermined problem that can give arbitrary results. A joint factor and kinetic analysis is proposed whereby factor analysis explicitly accounts for mixing of tissues. Hence, more meaningful parameters are obtained by the kinetic models, which also ensure a less ambiguous solution to the factor analysis. The method was tested using a cylindrical phantom and the 18F-DOPA data of a brain cancer patient.

Design and utilisation of protocols to characterise dynamic PET uptake of two tracers using basis pursuit

Imaging using more than one biological process using PET could be of great utility, but despite previously proposed approaches to dual-tracer imaging, it is seldom performed. The alternative of performing multiple scans is often infeasible for clinical practice or even in research studies. Dual-tracer PET scanning allows for multiple PET radiotracers to be imaged within the same imaging session. In this paper we describe our approach to utilise the basis pursuit method to aid in the design of dual-tracer PET imaging experiments, and later in separation of the signals. The advantage of this approach is that it does not require a compartment model architecture to be specified or even that both signals are distinguishable in all cases. This means the method for separating dual-tracer signals can be used for many feasible and useful combinations of biology or radiotracer, once an appropriate scanning protocol has been decided upon. Following a demonstration in separating the signals from two consecutively injected radionuclides in a controlled experiment, phantom and list-mode mouse experiments demonstrated the ability to test the feasibility of dual-tracer imaging protocols for multiple injection delays. Increases in variances predicted for kinetic macro-parameters V D and K I in brain and tumoral tissue were obtained when separating the synthetically combined data. These experiments confirmed previous work using other approaches that injections delays of 10-20 min ensured increases in variance were kept minimal for the test tracers used. On this basis, an actual dual-tracer experiment using a 20 min delay was performed using these radio tracers, with the kinetic parameters (V D and K I) extracted for each tracer in agreement with the literature. This study supports previous work that dual-tracer PET imaging can be accomplished provided certain constraints are adhered to. The utilisation of basis pursuit techniques, with its removed need to specify a model architecture, allows the feasibility of a range of imaging protocols to be investigated via simulation in a straight-forward manner for a wide range of possible scenarios. The hope is that the ease of utilising this approach during feasibility studies and in practice removes any perceived technical barrier to performing dual-tracer imaging.

PET motion correction in context of integrated PET/MR: Current techniques, limitations, and future projections

&NA; Patient motion is an important consideration in modern PET image reconstruction. Advances in PET technology mean motion has an increasingly important influence on resulting image quality. Motion‐induced artifacts can have adverse effects on clinical outcomes, including missed diagnoses and oversized radiotherapy treatment volumes. This review aims to summarize the wide variety of motion correction techniques available in PET and combined PET/CT and PET/MR, with a focus on the latter. A general framework for the motion correction of PET images is presented, consisting of acquisition, modeling, and correction stages. Methods for measuring, modeling, and correcting motion and associated artifacts, both in literature and commercially available, are presented, and their relative merits are contrasted. Identified limitations of current methods include modeling of aperiodic and/or unpredictable motion, attaining adequate temporal resolution for motion correction in dynamic kinetic modeling acquisitions, and maintaining availability of the MR in PET/MR scans for diagnostic acquisitions. Finally, avenues for future investigation are discussed, with a focus on improvements that could improve PET image quality, and that are practical in the clinical environment.

Federated optimisation of kinetic analysis problems

&NA; Positron Emission Tomography (PET) data is intrinsically dynamic, and kinetic analysis of dynamic PET data can substantially augment the information provided by static PET reconstructions. Yet despite the insights into disease that kinetic analysis offers, it is not used clinically and seldom used in research beyond the preclinical stage. The utility of PET kinetic analysis is hampered by several factors including spatial inconsistency within regions of homogeneous tissue and relative computational expense when fitting complex models to individual voxels. Even with sophisticated algorithms inconsistencies can arise because local optima frequently have narrow basins of convergence, are surrounded by relatively flat (uninformative) regions, have relatively low‐gradient valley floors, or combinations thereof. Based on the observation that cost functions for individual voxels frequently bear some resemblance to each‐other, this paper proposes the federated optimisation of the individual kinetic analysis problems within a given image. This approach shares parameters proposed during optimisation with other, similar voxels. Federated optimisation exploits the redundancy typical of large medical images to improve the optimisation residuals, computational efficiency and, to a limited extent, image consistency. This is achieved without restricting the formulation of the kinetic model, resorting to an explicit regularisation parameter, or limiting the resolution at which parameters are computed. HighlightsFederated optimisation is a new method for kinetic analysis of dynamic medical images.It exploits inherent redundancy in images to efficiently improve time activity curve fits.Visual consistency is sometimes slightly improved, without explicit regularisation.The method is agnostic to model formulation. Graphical abstract Figure. No caption available.

Large Scale Simplex Optimisation to Accelerate Kinetic Analysis

Although Positron Emission Tomography images are implicitly dynamic and the temporal variation of tracers often holds relevant information, kinetic analysis of the data is seldom performed due to its computational expense, especially when flexible ODE-based formulations are used. Kinetic analysis at the voxel scale remains expensive even with recent formulations relying on the closed form summation of convolution of exponentials. This work proposes a scheme to accelerate the kinetic analysis of large populations of time activity curves, by selectively sharing tailored simplex optimisations between them. Experiments on synthetic and real data demonstrate that the approach not only accelerates kinetic analysis, but maintains equivalent or better fitting accuracy than existing approaches that optimise time activity curves individually.

Optimising the detection of colorectal cancer liver metastases with dynamic Fdg pet acquisitions

53 year old man with human immunodeficiency virus (HIV) developed 3–4 weeks of severe crampy abdominal pain and nausea. The patient had been started on anti-retroviral therapy only 6 months prior. Computed tomography (CT) scan of the abdomen and pelvis demonstrated lymphadenopathy which was considered suspicious for lymphoma. Fluorodeoxy-glucose Positron Emission Tomography (FDG PET/CT) was performed which demonstrated FDG avid disease above and below the diaphragms. The low dose CT also demonstrated the presence of ‘fat in bowel sign’ with an associated nearby FDG avid mass suggesting a small bowel intussusception. Subsequent Diagnostic CT was co-registered better demonstrating the intussusception without vascular compromise. The patient subsequently underwent a laparotomy. At laparotomy the intussusception was identified and manually reduced. The involved segment of small bowel was resected and sent for surgical pathology. The macroscopic pathological specimen demonstrated an endoluminal mass measuring up to 3.5 cm with a yellow/ fleshy dimpled surface. Histologically the lesion was Classical Mixed Cellularity Hodgkin lymphoma. On immmuno-histochemistry the tumour showed diffuse/strong nuclear positive Ebstein Barr Virus-encoded RNA staining. This is the first case we have identified in the literature of a FDGPET-CT diagnosed small bowel intussusception due to lead point of a Classical Hodgkins lymphoma tumour mass in an adult. P56 A V/Q SCAN LEADING TO THE DIAGNOSIS OF A BRONCHIAL NEUROENDOCRINE (ATYPICAL CARCINOID) TUMOUR R Garzan1, A Aminazad1, M Jost1, F Thien1 1Eastern Health, Melbourne, Australia Background: Apart from the diagnosis of Pulmonary Embolism, V/Q scans can be helpful in establishing alternative diagnoses. Aims: We describe a 59-year-old man whose abnormal V/Q scan led to the final diagnosis of a bronchial Neuroendocrine tumour. Methods: A 59-year old man (life-long non-smoker) presented to the emergency department with several weeks of dyspnea and chest infection Poster Presentations

Assessing local outcomes in heterogeneous gliomas

Tumours are known to be heterogeneous, yet typical treatment plans consider them as a single unit. This may influence treatment outcomes. However, treatment cannot be customised to intra-tumour variation without a method to establish outcomes at an intra-tumour scale. This work proposes a method to both assess and measure outcomes locally within tumours. Methods: Four patients were scanned at two post-surgery time points using contrast enhanced MRI and 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) PET. The shell of active tumour tissue is divided into a set of small subregions at both time points. Local outcome is measured from changes in subregion volume over time. The utility of the proposed approach is evaluated by measuring the correlation between PET uptake and documented growth. Correlation with overall survival time was also examined. Results: Local outcomes were heterogeneous and evidence of a positive correlation between local 18F-DOPA uptake and local progression was observed. Conclusions: Given that intra-tumour outcomes are heterogeneous the consistently positive correlation between FDOPA uptake and progression, local analysis of tumours could prove useful for treatment planning.

Contribution of FDOPA PET to radiotherapy planning for advanced glioma

Despite radical treatment with surgery, radiotherapy and chemotherapy, advanced gliomas recur within months. Geographic misses in radiotherapy planning may play a role in this seemingly ineluctable recurrence. Planning is typically performed on post-contrast MRIs, which are known to underreport tumour volume relative to FDOPA PET scans. FDOPA PET fused with contrast enhanced MRI has demonstrated greater sensitivity and specificity than MRI alone. One sign of potential misses would be differences between gross target volumes (GTVs) defined using MRI alone and when fused with PET. This work examined whether such a discrepancy may occur. Materials and Methods: For six patients, a 75 minute PET scan using 3,4-dihydroxy-6-18F-fluoro-L-phynel-alanine (18F-FDOPA) was taken within 2 days of gadolinium enhanced MRI scans. In addition to standard radiotherapy planning by an experienced radiotherapy oncologist, a second gross target volume (GTV) was defined by an experienced nuclear medicine specialist for fused PET and MRI, while blinded to the radiotherapy plans. The volumes from standard radiotherapy planning were compared to the PET defined GTV. Results: The comparison indicated radiotherapy planning would change in several cases if FDOPA PET data was available. PET-defined contours were external to 95% prescribed dose for several patients. However, due to the radiotherapy margins, the discrepancies were relatively small in size and all received a dose of 50 Gray or more. Conclusions: Given the limited size of the discrepancies it is uncertain that geographic misses played a major role in patient outcome. Even so, the existence of discrepancies indicates that FDOPA PET could assist in better defining margins when planning radiotherapy for advanced glioma, which could be important for highly conformal radiotherapy plans.