Quantitative PET in the 2020s: a roadmap.

Positron emission tomography (PET) plays an increasingly important role in research and clinical applications, catalysed by remarkable technical advances and a growing appreciation of the need for reliable, sensitive biomarkers of human function in health and disease. Over the last 30 years, a large amount of the physics and engineering effort in PET has been motivated by the dominant clinical application during that period, oncology. This has led to important developments such as PET/CT, whole-body PET, 3D PET, accelerated statistical image reconstruction, and time-of-flight PET. Despite impressive improvements in image quality as a result of these advances, the emphasis on static, semi-quantitative 'hot spot' imaging for oncologic applications has meant that the capability of PET to quantify biologically relevant parameters based on tracer kinetics has not been fully exploited. More recent advances, such as PET/MR and total-body PET, have opened up the ability to address a vast range of new research questions, from which a future expansion of applications and radiotracers appears highly likely. Many of these new applications and tracers will, at least initially, require quantitative analyses that more fully exploit the exquisite sensitivity of PET and the tracer principle on which it is based. It is also expected that they will require more sophisticated quantitative analysis methods than those that are currently available. At the same time, artificial intelligence is revolutionizing data analysis and impacting the relationship between the statistical quality of the acquired data and the information we can extract from the data. In this roadmap, leaders of the key sub-disciplines of the field identify the challenges and opportunities to be addressed over the next ten years that will enable PET to realise its full quantitative potential, initially in research laboratories and, ultimately, in clinical practice.

Markerless motion estimation for motion-compensated clinical brain imaging.

Motion-compensated brain imaging can dramatically reduce the artifacts and quantitative degradation associated with voluntary and involuntary subject head motion during positron emission tomography (PET), single photon emission computed tomography (SPECT) and computed tomography (CT). However, motion-compensated imaging protocols are not in widespread clinical use for these modalities. A key reason for this seems to be the lack of a practical motion tracking technology that allows for smooth and reliable integration of motion-compensated imaging protocols in the clinical setting. We seek to address this problem by investigating the feasibility of a highly versatile optical motion tracking method for PET, SPECT and CT geometries. The method requires no attached markers, relying exclusively on the detection and matching of distinctive facial features. We studied the accuracy of this method in 16 volunteers in a mock imaging scenario by comparing the estimated motion with an accurate marker-based method used in applications such as image guided surgery. A range of techniques to optimize performance of the method were also studied. Our results show that the markerless motion tracking method is highly accurate (<2 mm discrepancy against a benchmarking system) on an ethnically diverse range of subjects and, moreover, exhibits lower jitter and estimation of motion over a greater range than some marker-based methods. Our optimization tests indicate that the basic pose estimation algorithm is very robust but generally benefits from rudimentary background masking. Further marginal gains in accuracy can be achieved by accounting for non-rigid motion of features. Efficiency gains can be achieved by capping the number of features used for pose estimation provided that these features adequately sample the range of head motion encountered in the study. These proof-of-principle data suggest that markerless motion tracking is amenable to motion-compensated brain imaging and holds good promise for a practical implementation in clinical PET, SPECT and CT systems.

Anti-angiogenic potential of VEGF blocker dendron loaded on to gellan gum hydrogels for tissue engineering applications.

Damage of non-vascularised tissues such as cartilage and cornea can result in healing processes accompanied by a non-physiological angiogenesis. Peptidic aptamers have recently been reported to block the vascular endothelial growth factor (VEGF). However, the therapeutic applications of these aptamers are limited due to their short half-life in vivo. In this work, an enhanced stability and bioavailability of a known VEGF blocker aptamer sequence (WHLPFKC) was pursued through its tethering of molecular scaffolds based on hyperbranched peptides, the poly(ɛ-lysine) dendrons, bearing three branching generations. The proposed design allowed simultaneous and orderly-spaced exposure of 16 aptamers per dendrimer to the surrounding biological microenvironent, as well as a relatively hydrophobic core based on di-phenylalanine aiming to promote an hydrophobic interaction with the hydrophobic moieties of ionically crosslinked methacrylated gellan gum (iGG-MA) hydrogels. The VEGF blocker dendrons were entrapped in iGG-MA hydrogels, and their capacity to prevent endothelial cell sprouting was assessed qualitatively and quantitatively using 3D in vitro models and the in vivo chick chorioallantoic membrane assay. The data demonstrate that at nanoscale concentrations, the dendronised structures were able to enhance control of the biological actvity of WHLPFKC at the material/tissue interface and hence the anti-angiogenic capacity of iGG-MA hydrogels not only preventing blood vessel invasion, but also inducing their regression at the tissue/iGG-MA interface. The in ovo study confirmed that iGG-MA functionalised with the dendron VEGF blockers do inhibit angiogenesis by controlling both size and ramifications of blood vessels in the proximity of the implanted gel surface. Copyright © 2016 John Wiley & Sons, Ltd.

Development of MPC-DPA polymeric nanoparticle systems for inhalation drug delivery applications.

Inhalation of nanoparticles for pulmonary drug delivery offers the potential to harness nanomedicine formulations of emerging therapeutics, such as curcumin, for treatment of lung cancer. Biocompatible nanoparticles composed of poly(2-methacryloyloxyethyl phosphorylcholine)-b-poly(2-(diisopropylamino)ethyl methacrylate) (MPC-DPA) have been shown to be suitable nanocarriers for drugs, whilst N-trimethyl chitosan chloride (TMC) coating of nanoparticles has been reported to further enhance their cellular delivery efficacy; the combination of the two has not been previously investigated. Development of effective systems requires the predictable, controllable, and reproducible ability to prepare nanosystems possessing particle sizes, and drug loading capacities, appropriate for successful airway travel, lung tissue penetration, and tumor suppression. Although a number of MPC-DPA based nanosystems have been described, a complete understanding of parameters controlling nanoparticle formation, size, and morphology has not been reported; in particular the effects of differing solvents phases remains unclear. In this current study a matrix of 31 solvent combinations were examined to provide novel data pertaining to the formation of MPC-DPA nanoparticles, and in doing so afforded the selection of systems with particle sizes appropriate for pulmonary delivery applications to be loaded with curcumin, and coated with TMC. This paper presents the first report of novel data detailing the successful preparation, characterisation, and optimisation of MPC-DPA nanoparticles of circa 150-180nm diameter, with low polydispersity, and a curcumin loading range of circa 2.5-115µM, tunable by preparation parameters, with and without TMC coating, and thus considered suitable candidates for inhalation drug delivery applications.

In silico investigation of factors affecting the MV imaging performance of a novel water-equivalent EPID.

PURPOSE: A Geant4 model of a novel, water-equivalent electronic portal imaging device (EPID) prototype for radiotherapy imaging and dosimetry utilising an array of plastic scintillating fibres (PSFs) has been developed. Monte Carlo (MC) simulations were performed to quantify the PSF-EPID imaging performance and to investigate design aspects affecting performance for optimisation. METHODS: Using the Geant4 model, the PSF-EPID's imaging performance for 6 MV photon beams was quantified in terms of its modulation transfer function (MTF), noise power spectrum (NPS) and detective quantum efficiency (DQE). Model parameters, including fibre dimensions, optical cladding reflectivity and scintillation yield, were varied to investigate impact on imaging performance. RESULTS: The MC-calculated DQE(0) for the reference PSF-EPID geometry employing 30mm fibres was approximately nine times greater than values reported for commercial EPIDs. When using 10mm long fibres, the PSF-EPID DQE(0) was still approximately three times greater than that of a commercial EPID. Increased fibre length, cladding reflectivity and scintillation yield produced the greatest decreases in NPS and increases in DQE. CONCLUSIONS: The potential to develop an optimised next-generation water-equivalent EPID with MV imaging performance at least comparable to commercial EPIDs has been demonstrated. Factors most important for optimising prototype design include fibre length, cladding reflectivity and scintillation yield.

Simulation-based optimisation of the PET data processing for partial saturation approach protocols.

Positron emission tomography (PET) with [(11)C]Raclopride is an important tool for studying dopamine D2 receptor expression in vivo. [(11)C]Raclopride PET binding experiments conducted using the Partial Saturation Approach (PSA) allow the estimation of receptor density (B(avail)) and the in vivo affinity appK(D). The PSA is a simple, single injection, single scan experimental protocol that does not require blood sampling, making it ideal for use in longitudinal studies. In this work, we generated a complete Monte Carlo simulated PET study involving two groups of scans, in between which a biological phenomenon was inferred (a 30% decrease of B(avail)), and used it in order to design an optimal data processing chain for the parameter estimation from PSA data. The impact of spatial smoothing, noise removal and image resolution recovery technique on the statistical detection was investigated in depth. We found that image resolution recovery using iterative deconvolution of the image with the system point spread function associated with temporal data denoising greatly improves the accuracy and the statistical reliability of detecting the imposed phenomenon. Before optimisation, the inferred B(avail) variation between the two groups was underestimated by 42% and detected in 66% of cases, while a false decrease of appK(D) by 13% was detected in more than 11% of cases. After optimisation, the calculated B(avail) variation was underestimated by only 3.7% and detected in 89% of cases, while a false slight increase of appK(D) by 3.7% was detected in only 2% of cases. We found during this investigation that it was essential to adjust a factor that accounts for difference in magnitude between the non-displaceable ligand concentrations measured in the target and in the reference regions, for different data processing pathways as this ratio was affected by different image resolutions.

Postreconstruction nonlocal means filtering of whole-body PET with an anatomical prior.

Positron emission tomography (PET) images usually suffer from poor signal-to-noise ratio (SNR) due to the high level of noise and low spatial resolution, which adversely affect its performance for lesion detection and quantification. The complementary information present in high-resolution anatomical images from multi-modality imaging systems could potentially be used to improve the ability to detect and/or quantify lesions. However, previous methods that use anatomical priors usually require matched organ/lesion boundaries. In this study, we investigated the use of anatomical information to suppress noise in PET images while preserving both quantitative accuracy and the amplitude of prominent signals that do not have corresponding boundaries on computerized tomography (CT). The proposed approach was realized through a postreconstruction filter based on the nonlocal means (NLM) filter, which reduces noise by computing the weighted average of voxels based on the similarity measurement between patches of voxels within the image. Anatomical knowledge obtained from CT was incorporated to constrain the similarity measurement within a subset of voxels. In contrast to other methods that use anatomical priors, the actual number of neighboring voxels and weights used for smoothing were determined from a robust measurement on PET images within the subset. Thus, the proposed approach can be robust to signal mismatches between PET and CT. A 3-D search scheme was also investigated for the volumetric PET/CT data. The proposed anatomically guided median nonlocal means filter (AMNLM) was first evaluated using a computer phantom and a physical phantom to simulate realistic but challenging situations where small lesions are located in homogeneous regions, which can be detected on PET but not on CT. The proposed method was further assessed with a clinical study of a patient with lung lesions. The performance of the proposed method was compared to Gaussian, edge-preserving bilateral and NLM filters, as well as median nonlocal means (MNLM) filtering without an anatomical prior. The proposed AMNLM method yielded improved lesion contrast and SNR compared with other methods even with imperfect anatomical knowledge, such as missing lesion boundaries and mismatched organ boundaries.

Exposure (mAs) optimisation of a multi-detector CT protocol for hepatic lesion detection: Are thinner slices better?

INTRODUCTION: The purpose of this work was to determine the exposure-optimised slice thickness for hepatic lesion detection with CT. METHODS: A phantom containing spheres (diameter 9.5, 4.8 and 2.4 mm) with CT density 10 HU below the background (50 HU) was scanned at 125, 100, 75 and 50 mAs. Data were reconstructed at 5-, 3- and 1-mm slice thicknesses. Noise, contrast-to-noise ratio (CNR), area under the curve (AUC) as calculated using receiver operating characteristic analysis and sensitivity representing lesion detection were calculated and compared. RESULTS: Compared with the 125 mAs/5 mm slice thickness setting, significant reductions in AUC were found for 75 mAs (P < 0.01) and 50 mAs (P < 0.05) at 1- and 3-mm thicknesses, respectively; sensitivity for the 9.5-mm sphere was significantly reduced for 75 (P < 0.05) and 50 mAs (P < 0.01) at 1-mm thickness; sensitivity for the 4.8-mm sphere was significantly lower for 100, 75 and 50 mAs at all three slice thicknesses (P < 0.05). The 2.4-mm sphere was rarely detected. At each slice thickness, noise at 100, 75 and 50 mAs exposures was approximately 10, 30 and 50% higher, respectively, than that at 125 mAs exposure. CNRs decreased in an irregular manner with reductions in exposure and slice thickness. CONCLUSION: This study demonstrated no advantage to using slices below 5 mm thickness, and consequently thinner slices are not necessarily better.

Poly(Epsilon-lysine) dendrons tethered with phosphoserine increase mesenchymal stem cell differentiation potential of calcium phosphate gels.

Calcium phosphates (CaP) are considered as biomaterials of choice for the treatment of critical-sized bone defects. Novel injectable CaP materials integrating poly(epsilon-lysine) generation 3 dendrons tethered with phosphoserine were obtained by sol-gel synthesis. This type of dendron was integrated to mimic the biochemical structure of noncollagenous proteins present in the forming osteoids during bone repair. Sol-gel synthesis was coupled with a dialysis process able to equilibrate the materials at a physiological pH value. Fourier transform infrared spectroscopy (FTIR) showed the successful retention of the dendrons after gel dialysis, whereas X-ray diffraction analysis demonstrated both the pH-tuned formation of a hydroxyapatite crystalline phase within the gel and the complete removal of ammonium nitrate deriving from the sol-gel reaction solvent. Scanning electron microscopy images confirmed the presence of crystalline domains in gels synthesized at pH 9.0. Injectability tests showed that the optimized formulations fulfilled the rheological properties required to minimally invasive surgical procedures. Cytotoxicity tests on osteoblast-like MG-63 cells as well as morphology and viability studies showed that the dendrons induced a significantly higher level of cell proliferation at early incubation time. Differentiation of the cell was also clearly enhanced at longer incubation time as demonstrated by both alkaline phosphatase activity and expression of typical markers. Altogether, the data from this work indicate the clinical potential of the osteoid-mimicking CaP cements in minimally invasive bone surgery.

Left ventricular systolic function in HER2/neu negative breast cancer patients treated with anthracycline chemotherapy: a comparative analysis of left ventricular ejection fraction and myocardial strain imaging over 12 months.

AIM: Anthracycline agents are undermined by their cardiotoxicity. As life expectancy following treatment is greatly improved, techniques that ensure early detection and timely management of cardiotoxicity are essential. The aim of the present study was to evaluate left ventricular (LV) systolic function with LV ejection fraction (LVEF) and two-dimensional myocardial strain up to 12 months after anthracycline chemotherapy, specifically in HER2/neu negative breast cancer patients. METHODS: Seventy-eight consecutive anthracycline naïve breast cancer patients were studied before and immediately after anthracycline chemotherapy. Fifty HER2/neu negative patients were studied over 12 months with serial echocardiograms at four time points. All patients were treated with standard regimens containing anthracyclines. RESULTS: Global systolic strain was significantly reduced immediately after, and 6 months after anthracyclines (-19.0 ± 2.3% to -17.5 ± 2.3% (P<0.001) and -18.2 ± 2.2% (P=0.01) respectively). A non-uniform reduction in strain was observed each time with relative sparing of the LV apex. LVEF remained largely unchanged at both time points. Global strain normalised by 12 months in the majority of patients. Persistently reduced strain was observed in 16% (n=8); these patients had a greater reduction in strain at 6 months (≤ -17.2%), and had received higher cumulative anthracycline doses. CONCLUSION: Myocardial strain imaging is more sensitive than LVEF for the early detection and intermediate term monitoring of LV systolic function following anthracycline chemotherapy in HER2/neu negative breast cancer patients, and may aid in the development of improved monitoring protocols.

Altered left ventricular longitudinal diastolic function correlates with reduced systolic function immediately after anthracycline chemotherapy.

AIMS: The benefits from anthracycline chemotherapy are undermined by potentially life-threatening cardiotoxicity. Transthoracic echocardiography is the most commonly used method for monitoring cardiotoxicity, and centres on the measurement of left ventricular systolic function. The aim of this study was to utilize two-dimensional speckle tracking echocardiography (2DSTE) at baseline and immediately after anthracycline chemotherapy to investigate whether patients with significant changes in systolic function after anthracycline therapy would also develop alterations in diastolic parameters. METHODS AND RESULTS: Fifty-two women with histologically confirmed breast cancer were prospectively recruited. Echocardiograms were performed 1 week prior to and 1 week following chemotherapy (always before adjuvant trastuzumab or thoracic radiotherapy). Conventional Doppler, tissue velocity imaging (TVI), and 2DSTE were used to measure diastolic function. 2DSTE measurements included longitudinal diastolic strain, early (E-Sr), and late (A-Sr) myocardial strain rate. 2DSTE and left ventricular ejection fraction (LVEF) were used to measure longitudinal systolic function. Altered LV diastolic function (including E-Sr) was observed in the entire cohort after chemotherapy, with a differential reduction in participants with a post therapy LVEF <55%. Pre-chemotherapy systolic strain was found to predict reduced E-Sr post therapy (P = 0.04). Univariate predictors of E-Sr were LVEF post therapy (P = 0.049) and systolic strain post-therapy (P = 0.01). In a multivariate analysis, systolic strain after chemotherapy was the strongest independent predictor (P = 0.001). CONCLUSION: Altered LV diastolic function was observed immediately after the administration of therapeutic doses of anthracycline chemotherapy. Furthermore, our analysis indicates that the changes in diastolic function are associated with reduced systolic function.

The 18 kDa translocator protein (peripheral benzodiazepine receptor) expression in the bone of normal, osteoprotegerin or low calcium diet treated mice.

The presence of the translocator protein (TSPO), previously named as the mitochondrial or peripheral benzodiazepine receptor, in bone cells was studied in vitro and in situ using RT-qPCR, and receptor autoradiography using the selective TSPO ligand PK11195.In vitro, the TSPO is highly expressed in osteoblastic and osteoclastic cells.In situ, constitutive expression of TSPO is found in bone marrow and trabecular bone, e.g., spongiosa. Mice with a reduction of bone turnover induced by a 4-day treatment of osteoprotegerin reduces [(3)H]PK11195 binding in the spongiosa (320±128 Bq x mg(-1), 499±106 Bq x mg(-1) in saline-treated controls). In contrast, mice with an increase in bone turnover caused by a 4-day low calcium diet increases [(3)H]PK11195 binding in the spongiosa (615±90 Bq x mg(-1)). Further, our study includes technical feasibility data on [(18)F]fluoride microPET imaging of rodent bone with altered turnover. Despite [(18)F]fluoride having high uptake, the in vivo signal differences were small. Using a phantom model, we describe the spillover effect and partial volume loss that affect the quantitative microPET imaging of the small bone structures in experimental mouse models. In summary, we demonstrate the expression of TSPO in small rodent bone tissues, including osteoblasts and osteoclasts. A trend increase in TSPO expression was observed in the spongiosa from low to high bone turnover conditions. However, despite the potential utility of TSPO expression as an in vivo biomarker of bone turnover in experimental rodent models, our small animal PET imaging data using [(18)F]fluoride show that even under the condition of a good biological signal-to-noise ratio and high tracer uptake, the currently achievable instrument sensitivity and spatial resolution is unlikely to be sufficient to detect subtle differences in small structures, such as mouse bone.

Synthesis, characterisation and in vitro anti-angiogenic potential of dendron VEGF blockers.

To overcome the lack of in vivo stability of certain peptides used in cancer treatment and to increase their retention time in the extracellular matrix of the target tissue, the anti-angiogenic WHLPFKC sequence is synthesised at the uppermost branching generation of a poly(ε-lysine) dendron. The root of these dendrons is designed to interact preferentially with macromolecules of the extracellular matrix, whilst the uppermost branching generation of the dendron increased the exposed density of the bioactive peptide. Bioactivity testing of the blockers is performed on HUVECs. The results show that the dendron tethered with VEGF blockers was still able to inhibit proliferation and angiogenesis. Their relatively larger structure did not prevent the interaction with VEGF.

Two-dimensional myocardial strain imaging detects changes in left ventricular systolic function immediately after anthracycline chemotherapy.

AIMS: The efficacy of anthracyclines is undermined by potential life-threatening cardiotoxicity. Cardiotoxicity is dependent upon several factors and the timing to its development is variable. Moreover, as adjuvant therapy with trastuzumab often follows, a close monitoring of cardiac function in those treated with anthracyclines is mandatory. Left ventricular ejection fraction (LVEF) by echocardiography is currently used for monitoring cardiotoxicity; however, LVEF has numerous limitations. Two-dimensional strain imaging may provide a more sensitive measure of altered LV systolic function, so the aim of the present study was to compare LVEF and LV systolic strain before and after anthracyclines. METHODS AND RESULTS: Fifty-two women with histologically confirmed breast cancer were prospectively studied. Echocardiographic LVEF (by Simpson's method), global and regional peak longitudinal, radial, and circumferential 2D systolic strain were measured 1 week before and 1 week after chemotherapy. Global and regional longitudinal LV systolic strain was significantly reduced after treatment; global longitudinal strain decreased from -17.7 to -16.3% (P < 0.01) with 48% of global measurements reduced by >10%. Global and regional radial LV systolic strain after treatment was also significantly reduced; global radial strain dropped from 40.5 to 34.5% (P < 0.01) with 59% of global measurements reduced by >10%. In contrast, no reduction in LVEF >10% after chemotherapy was observed. CONCLUSION: Reduced LV systolic strain immediately after anthracycline treatment may indicate early impairment of myocardial function before detectable change in LVEF.

Benchmarking of a motion sensing system for medical imaging and radiotherapy.

We have tested the performance of an Optotrak Certus system, which optically tracks multiple markers, in both position and time. To do this, we have developed custom code which enables a range of testing protocols, and make this code available to the community. We find that the Certus' positional accuracy is very high, around 20 microm at a distance of 2.8 m. In contrast, we find that its timing accuracy is typically no better than around 5-10% for typical data rates, whether one is using an ethernet connection or a dedicated SCSI link from the system to a host computer. However, with our code we are able to attach very accurate timestamps to the data frames, and in cases where regularly-spaced data are not an absolute requirement, this will be more than adequate.