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Implant-associated Staphylococcus aureus infections are difficult to treat because of biofilm formation. Bacteria in a biofilm are often insensitive to antibiotics and host immunity. Monoclonal antibodies (mAbs) could provide an alternative approach to improve the diagnosis and potential treatment of biofilm-related infections. Here, we show that mAbs targeting common surface components of S. aureus can recognize clinically relevant biofilm types. The mAbs were also shown to bind a collection of clinical isolates derived from different biofilm-associated infections (endocarditis, prosthetic joint, catheter). We identify two groups of antibodies: one group that uniquely binds S. aureus in biofilm state and one that recognizes S. aureus in both biofilm and planktonic state. Furthermore, we show that a mAb recognizing wall teichoic acid (clone 4497) specifically localizes to a subcutaneously implanted pre-colonized catheter in mice. In conclusion, we demonstrate the capacity of several human mAbs to detect S. aureus biofilms in vitro and in vivo.

PURPOSE: The increasing incidence of small renal tumors in an aging population with comorbidities has stimulated the development of minimally invasive treatments. This study aimed to assess the efficacy and demonstrate feasibility of multimodality imaging of intratumoral administration of holmium-166 microspheres ((166)HoAcAcMS). This new technique locally ablates renal tumors through high-energy beta particles, while the gamma rays allow for nuclear imaging and the paramagnetism of holmium allows for MRI. METHODS: (166)HoAcAcMS were administered intratumorally in orthotopic renal tumors (Balb/C mice). Post administration CT, SPECT and MRI was performed. At several time points (2 h, 1, 2, 3, 7 and 14 days) after MS administration, tumors were measured and histologically analyzed. Holmium accumulation in organs was measured using inductively coupled plasma mass spectrometry. RESULTS: (166)HoAcAcMS were successfully administered to tumor bearing mice. A striking near-complete tumor-control was observed in (166)HoAcAcMS treated mice (0.10±0.01 cm(3) vs. 4.15±0.3 cm(3) for control tumors). Focal necrosis and inflammation was present from 24 h following treatment. Renal parenchyma outside the radiated region showed no histological alterations. Post administration CT, MRI and SPECT imaging revealed clear deposits of (166)HoAcAcMS in the kidney. CONCLUSIONS: Intratumorally administered (166)HoAcAcMS has great potential as a new local treatment of renal tumors for surgically unfit patients. In addition to strong cancer control, it provides powerful multimodality imaging opportunities.

Abstract Background Three-dimensional (3D)-printed saw guides are frequently used to optimize osteotomy results and are usually designed based on computed tomography (CT), despite the radiation burden, as radiation-less alternatives like magnetic resonance imaging (MRI) have inferior bone visualization capabilities. This study investigated the usability of MR-based synthetic-CT (sCT), a novel radiation-less bone visualization technique for 3D planning and design of patient-specific saw guides. Methods Eight human cadaveric lower arms (mean age: 78y) received MRI and CT scans as well as high-resolution micro-CT. From the MRI scans, sCT were generated using a conditional generative adversarial network. Digital 3D bone surface models based on the sCT and general CT were compared to the surface model from the micro-CT that was used as ground truth for image resolution. From both the sCT and CT digital bone models saw guides were designed and 3D-printed in nylon for one proximal and one distal bone position for each radius and ulna. Six blinded observers placed these saw guides as accurately as possible on dissected bones. The position of each guide was assessed by optical 3D-scanning of each bone with positioned saw guide and compared to the preplanning. Eight placement errors were evaluated: three translational errors (along each axis), three rotational errors (around each axis), a total translation (∆T) and a total rotation error (∆R). Results Surface models derived from micro-CT were on average smaller than sCT and CT-based models with average differences of 0.27 ± 0.30 mm for sCT and 0.24 ± 0.12 mm for CT. No statistically significant positioning differences on the bones were found between sCT- and CT-based saw guides for any axis specific translational or rotational errors nor between the ∆T (p = .284) and ∆R (p = .216). On Bland-Altman plots, the ∆T and ∆R limits of agreement (LoA) were within the inter-observer variability LoA. Conclusions This research showed a similar error for sCT and CT digital surface models when comparing to ground truth micro-CT models. Additionally, the saw guide study showed equivalent CT- and sCT-based saw guide placement errors. Therefore, MRI-based synthetic CT is a promising radiation-less alternative to CT for the creation of patient-specific osteotomy surgical saw guides.

Cardiac parameters obtained from single-photon emission computed tomographic (SPECT) images can be affected by respiratory motion, image filtering, and animal positioning. We investigated the influence of these factors on ultra-high-resolution murine myocardial perfusion SPECT. Five mice were injected with 99m technetium ( 99m Tc)-tetrofosmin, and each was scanned in supine and prone positions in a U-SPECT-II scanner with respiratory and electrocardiographic (ECG) gating. ECG-gated SPECT images were created without applying respiratory motion correction or with two different respiratory motion correction strategies. The images were filtered with a range of three-dimensional gaussian kernels, after which end-diastolic volumes (EDVs), end-systolic volumes (ESVs), and left ventricular ejection fractions were calculated. No significant differences in the measured cardiac parameters were detected when any strategy to reduce or correct for respiratory motion was applied, whereas big differences (> 5%) in EDV and ESV were found with regard to different positioning of animals. A linear relationship ( p < .001) was found between the EDV or ESV and the kernel size of the gaussian filter. In short, respiratory gating did not significantly affect the cardiac parameters of mice obtained with ultra-high-resolution SPECT, whereas the position of the animals and the image filters should be the same in a comparative study with multiple scans to avoid systematic differences in measured cardiac parameters.

Limited spatial resolution of preclinical positron emission tomography (PET) and single-photon emission computed tomography (SPECT) has slowed down applications of molecular imaging in small animals. Here we present the latest-generation U-SPECT system (U-SPECT + , MILabs, Utrecht, the Netherlands) enabling radionuclide imaging of mice with quarter-millimeter resolution. The system was equipped with the newest high-resolution collimator with 0.25 mm diameter circular pinholes. It was calibrated with technetium-99 m point source measurements from which the system matrix was calculated. Images were reconstructed using pixel-based ordered subset expectation maximization (OSEM). Various phantoms and mouse SPECT scans were acquired. The reconstructed spatial resolution (the smallest visible capillary diameter in a hot-rod resolution phantom) was 0.25 mm. Knee joint images show tiny structures such as the femur epicondyle sulcus, as well as a clear separation between cortical and trabecular bone structures. In addition, time-activity curves of the lumbar spine illustrated that tracer dynamics in tiny tissue amounts could be measured. U-SPECT + allows discrimination between molecular concentrations in adjacent volumes of as small as 0.015 mL, which is significantly better than can be imaged by any existing SPECT or PET system. This increase in the level of detail makes it more and more attractive to replace ex vivo methods and allows monitoring biological processes in tiny parts of organs in vivo.

Detection of x-rays and gamma rays with high spatial resolution can be achieved with scintillators that are optically coupled to electron-multiplying charge-coupled devices (EMCCDs). These can be operated at typical frame rates of 50 Hz with low noise. In such a set-up, scintillation light within each frame is integrated after which the frame is analyzed for the presence of scintillation events. This method allows for the use of scintillator materials with relatively long decay times of a few milliseconds, not previously considered for use in photon-counting gamma cameras, opening up an unexplored range of dense scintillators. In this paper, we test CdWO4 and transparent polycrystalline ceramics of Lu2O3:Eu and (Gd,Lu)2O3:Eu as alternatives to currently used CsI:Tl in order to improve the performance of EMCCD-based gamma cameras. The tested scintillators were selected for their significantly larger cross-sections at 140 keV (99mTc) compared to CsI:Tl combined with moderate to good light yield. A performance comparison based on gamma camera spatial and energy resolution was done with all tested scintillators having equal (66%) interaction probability at 140 keV. CdWO4, Lu2O3:Eu and (Gd,Lu)2O3:Eu all result in a significantly improved spatial resolution over CsI:Tl, albeit at the cost of reduced energy resolution. Lu2O3:Eu transparent ceramic gives the best spatial resolution: 65 um full-width-at-half-maximum (FWHM) compared to 147 um FWHM for CsI:Tl. In conclusion, these 'slow' dense scintillators open up new possibilities for improving the spatial resolution of EMCCD-based scintillation cameras. [ABSTRACT FROM AUTHOR]

Detection of scattered gamma quanta degrades image contrast and quantitative accuracy of single-photon emission computed tomography (SPECT) imaging. This paper reviews methods to characterize and model scatter in SPECT and correct for its image degrading effects, both for clinical and small animal SPECT. Traditionally scatter correction methods were limited in accuracy, noise properties and/or generality and were not very widely applied. For small animal SPECT, these approximate methods of correction are often sufficient since the fraction of detected scattered photons is small. This contrasts with patient imaging where better accuracy can lead to significant improvement of image quality. As a result, over the last two decades, several new and improved scatter correction methods have been developed, although often at the cost of increased complexity and computation time. In concert with (i) the increasing number of energy windows on modern SPECT systems and (ii) excellent attenuation maps provided in SPECT/CT, some of these methods give new opportunities to remove degrading effects of scatter in both standard and complex situations and therefore are a gateway to highly quantitative single- and multi-tracer molecular imaging with improved noise properties. Widespread implementation of such scatter correction methods, however, still requires significant effort. [ABSTRACT FROM AUTHOR]

High-resolution imaging of x-ray and gamma-ray distributions can be achieved with cameras that use charge coupled devices (CCDs) for detecting scintillation light flashes. The energy and interaction position of individual gamma photons can be determined by rapid processing of CCD images of individual flashes. Here we investigate the improvement of such a gamma camera when a micro-machined retro-reflector is used to increase the light output of a continuous scintillation crystal. At 122 keV we found that retro-reflectors improve the intrinsic energy resolution (full width at half maximum (FWHM)) by 32% (from 50% to 34%) and the signal-to-noise (SNR) ratio by 18%. The spatial resolution (FWHM) was improved by about 4%, allowing us to obtain a resolution of 159 um. The full width at tenth maximum (FWTM) improvement was 13%. Therefore, this enhancement is a next step towards realizing compact high-resolution devices for imaging gamma emitters. [ABSTRACT FROM AUTHOR]

Gamma cameras based on charge-coupled devices (CCDs) and micro-columnar CsI scintillators can reach high spatial resolutions. However, the gamma interaction probability of these scintillators is low (typically <30% at 141 keV) due to the limited thickness of presently available micro-columnar scintillators. Continuous scintillators can improve the interaction probability but suffer from increased light spread compared to columnar scintillators. In addition, for both types of scintillators, gamma photons incident at an oblique angle reduce the spatial resolution due to the variable depth of interaction (DOI). To improve the spatial resolution and spectral characteristics of these detectors, we have developed a fast analytic scintillation detection algorithm that makes use of a depth-dependent light spread model and as a result is able to estimate the DOI in the scintillator. This algorithm, performing multi-scale frame analysis, was tested for an electron multiplying CCD (EM-CCD) optically coupled to CsI(Tl) scintillators of different thicknesses. For the thickest scintillator (2.6 mm) a spatial resolution of 148 µm full width half maximum (FWHM) was obtained with an energy resolution of 46% FWHM for perpendicularly incident gamma photons (interaction probability 61% at 141 keV). The multi-scale algorithm improves the spatial resolution up to 11%, the energy resolution up to 36% and the signal-to-background counts ratio up to 46% compared to a previously implemented algorithm that did not model the depth-dependent light spread. In addition, the multi-scale algorithm can accurately estimate DOI. As a result, degradation of the spatial resolution due to the variable DOI for gamma photons incident at a 45° angle was improved from 2.0 [?] 103 to 448 µm FWHM. We conclude that the multi-scale algorithm significantly improves CCD-based gamma cameras as can be applied in future SPECT systems. [ABSTRACT FROM AUTHOR]

Charge-coupled devices (CCDs) coupled to scintillation crystals can be used for high-resolution imaging with x-rays and gamma rays. When the CCD images can be read out fast enough, the energy and interaction position of individual gamma quanta can be estimated by a real-time image analysis of the scintillation light flashes ('photon-counting mode'). The electron-multiplying CCD (EMCCD) is well suited for fast read out, since even at high frame rates it has extremely low read-out noise. Back-illuminated (BI) EMCCDs have much higher quantum efficiency than front-illuminated (FI) EMCCDs. Here we compare the spatial and energy resolution of gamma cameras based on FI and BI EMCCDs. The CCDs are coupled to a 1000 µm thick columnar CsI(Tl) crystal for the purpose of Tc-99m and I-125 imaging. Intrinsic spatial resolutions of 44 µm for I-125 and 49 µm for Tc-99m were obtained when using a BI EMCCD, which is an improvement by a factor of about 1.2-2 over the FI EMCCD. Furthermore, in the energy spectrum of the BI EMCCD, the I-125 signal could be clearly separated from the background noise, which was not the case for the FI EMCCD. The energy resolution of a BI EMCCD for Tc-99m was estimated to be approximately 36 keV, full width at half maximum, at 141 keV. The excellent results for the BI EMCCD encouraged us to investigate the cooling requirements for our setup. We have found that for the BI EMCCD, the spatial and energy resolution, as well as image noise, remained stable over a range of temperatures from ?50 °C to ?15 °C. This is a significant advantage over the FI EMCCD, which suffered from loss of spatial and especially energy resolution at temperatures as low as ?40 °C. We conclude that the use of BI EMCCDs may significantly improve the imaging capabilities and the cost efficiency of CCD-based high-resolution gamma cameras. [ABSTRACT FROM AUTHOR]

Pinhole collimation is widely recognized for offering superior resolution-sensitivity trade-off in SPECT imaging of small subjects. The newly developed EXIRAD-3D autoradiography technique (MILabs B.V.) based on a highly focusing multi-pinhole collimator achieves micron-resolution SPECT for cryo-cooled tissue samples. For such high resolutions, the choice of pinhole material may have a significant impact on images. Therefore, this paper aims to compare the performance of EXIRAD-3D with lead, tungsten, gold, and depleted uranium pinhole collimators designed such that they achieve equal sensitivities. Performance in terms of resolution is characterized for several radioisotopes, namely 111In (171 keV and 245 keV), 99mTc (140 keV), 201Tl (71 keV), and 125I (27 keV). Using Monte Carlo simulation, point spread functions were generated and their profiles as well as their full-width-at-half-maximum and full-width-at-tenth-maximum were determined and evaluated for different materials and isotopes. Additionally, simulated reconstructions of a Derenzo resolution phantom, validated with experimental data, were judged by assessment of the resolvable rods as well as a contrast-to-noise ratio (CNR) analysis. Our results indicate that using materials with higher photon-stopping power yields images with better CNR for the studied isotopes with improvements ranging from 1.9% to 36.6%. Visual assessment on the reconstructed images suggests that for EXIRAD-3D, the tungsten collimator is generally a good choice for a wide range of SPECT isotopes. For relatively high-energy isotopes such as 111In, using gold inserts can be beneficial. [ABSTRACT FROM AUTHOR]

SPECT can be used to image dopamine transporter (DaT) availability in the human striatum, e.g. for diagnosis of Parkinson's disease (PD). As traditional SPECT provides limited resolution and sensitivity, we proposed a full ring focusing multi-pinhole SPECT system (G-SPECT-I (Beekman 2015 Eur. J. Nucl. Med. Mol. Imaging42 S209)) which demonstrated a 2.5 mm reconstructed resolution in phantom scans. G-SPECT-I achieves data completeness in the scan region of interest by translating the patient bed with an xyz-stage and combining projections from all bed positions into image reconstruction using a scanning focus method (SFM). This paper aims to develop dedicated SFM parameters for performing a DaTscan with high effective sensitivity and appropriate sampling. To this end, the axial scanning length was restricted and transaxial bed trajectories with a reduced number of positions based on a convex hull data-completeness model were tested. Quantitative accuracy was assessed using full G-SPECT-I simulations of an Alderson phantom based on measured system matrices. For each sampling strategy, the specific binding ratio (SBR) and asymmetry index (AI) in the left and right striatum, as well as the Localized SBR (L-SBR) and the Localized AI (L-AI) in eight striatal sub-regions were calculated and compared to those of the reference scan which performs full brain oversampling using 112 bed positions. Results show that structures essential for PD diagnosis were visually and quantitatively barely affected even when using the lowest number of bed translations (i.e. 4). The maximum deviation from the reference was only 1.5%, 1.5%, 5.5% and 7.0% for the SBR, AI, L-SBR and L-AI, respectively, when 4 positions were used. Thus, it is possible to perform an accurate DaTscan with a confined axial scan region and a limited number of focused bed positions. This enables protocols for extremely fast dynamic SPECT scans with less than half-minute time frames, which can be useful for motion correction. [ABSTRACT FROM AUTHOR]

Recently, we proposed and optimized dedicated multi-pinhole molecular breast tomosynthesis (MBT) that images a lightly compressed breast. As MBT may also be performed with other types of collimators, the aim of this paper is to optimize MBT with fan beam and slit-slat collimators and to compare its performance to that of multi-pinhole MBT to arrive at a truly optimized design. Using analytical expressions, we first optimized fan beam and slit-slat collimator parameters to reach maximum sensitivity at a series of given system resolutions. Additionally, we performed full system simulations of a breast phantom containing several tumours for the optimized designs. We found that at equal system resolution the maximum achievable sensitivity increases from pinhole to slit-slat to fan beam collimation with fan beam and slit-slat MBT having on average a 48% and 20% higher sensitivity than multi-pinhole MBT. Furthermore, by inspecting simulated images and applying a tumour-to-background contrast-to-noise (TB-CNR) analysis, we found that slit-slat collimators underperform with respect to the other collimator types. The fan beam collimators obtained a similar TB-CNR as the pinhole collimators, but the optimum was reached at different system resolutions. For fan beam collimators, a 6–8 mm system resolution was optimal in terms of TB-CNR, while with pinhole collimation highest TB-CNR was reached in the 7–10 mm range. [ABSTRACT FROM AUTHOR]

Imaging of 99mTc-labelled tracers is gaining popularity for detecting breast tumours. Recently, we proposed a novel design for molecular breast tomosynthesis (MBT) based on two sliding focusing multi-pinhole collimators that scan a modestly compressed breast. Simulation studies indicate that MBT has the potential to improve the tumour-to-background contrast-to-noise ratio significantly over state-of-the-art planar molecular breast imaging. The aim of the present paper is to optimize the collimator-detector geometry of MBT. Using analytical models, we first optimized sensitivity at different fixed system resolutions (ranging from 5 to 12 mm) by tuning the pinhole diameters and the distance between breast and detector for a whole series of automatically generated multi-pinhole designs. We evaluated both MBT with a conventional continuous crystal detector with 3.2 mm intrinsic resolution and with a pixelated detector with 1.6 mm pixels. Subsequently, full system simulations of a breast phantom containing several lesions were performed for the optimized geometry at each system resolution for both types of detector. From these simulations, we found that tumour-to-background contrast-to-noise ratio was highest for systems in the 7 mm–10 mm system resolution range over which it hardly varied. No significant differences between the two detector types were found. [ABSTRACT FROM AUTHOR]

Planar molecular breast imaging (MBI) is rapidly gaining in popularity in diagnostic oncology. To add 3D capabilities, we introduce a novel molecular breast tomosynthesis (MBT) scanner concept based on multi-pinhole collimation. In our design, the patient lies prone with the pendant breast lightly compressed between transparent plates. Integrated webcams view the breast through these plates and allow the operator to designate the scan volume (e.g. a whole breast or a suspected region). The breast is then scanned by translating focusing multi-pinhole plates and NaI(Tl) gamma detectors together in a sequence that optimizes count yield from the volume-of-interest. With simulations, we compared MBT with existing planar MBI. In a breast phantom containing different lesions, MBT improved tumour-to-background contrast-to-noise ratio (CNR) over planar MBI by 12% and 111% for 4.0 and 6.0 mm lesions respectively in case of whole breast scanning. For the same lesions, much larger CNR improvements of 92% and 241% over planar MBI were found in a scan that focused on a breast region containing several lesions. MBT resolved 3.0 mm rods in a Derenzo resolution phantom in the transverse plane compared to 2.5 mm rods distinguished by planar MBI. While planar MBI cannot provide depth information, MBT offered 4.0 mm depth resolution. Our simulations indicate that besides offering 3D localization of increased tracer uptake, multi-pinhole MBT can significantly increase tumour-to-background CNR compared to planar MBI. These properties could be promising for better estimating the position, extend and shape of lesions and distinguishing between single and multiple lesions. [ABSTRACT FROM AUTHOR]

The recently developed versatile emission computed tomography (VECTor) technology enables high-energy SPECT and simultaneous SPECT and PET of small animals at sub-mm resolutions. VECTor uses dedicated clustered pinhole collimators mounted in a scanner with three stationary large-area NaI(Tl) gamma detectors. Here, we develop and validate dedicated image reconstruction methods that compensate for image degradation by incorporating accurate models for the transport of high-energy annihilation gamma photons. Ray tracing software was used to calculate photon transport through the collimator structures and into the gamma detector. Input to this code are several geometric parameters estimated from system calibration with a scanning 99mTc point source. Effects on reconstructed images of (i) modelling variable depth-of-interaction (DOI) in the detector, (ii) incorporating photon paths that go through multiple pinholes (‘multiple-pinhole paths’ (MPP)), and (iii) including various amounts of point spread function (PSF) tail were evaluated. Imaging 18F in resolution and uniformity phantoms showed that including large parts of PSFs is essential to obtain good contrast-noise characteristics and that DOI modelling is highly effective in removing deformations of small structures, together leading to 0.75 mm resolution PET images of a hot-rod Derenzo phantom. Moreover, MPP modelling reduced the level of background noise. These improvements were also clearly visible in mouse images. Performance of VECTor can thus be significantly improved by accurately modelling annihilation gamma photon transport. [ABSTRACT FROM AUTHOR]