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Introduction The human epidermal growth factor receptor 2 (HER2) status is important for HER2 targeting therapies. T his information is obtained through immunohistochemistry (IHC) or in situ hybridisation (ISH), which necessitates tissue sampling, and may miss tumor heterogeneity as not every lesion consists of the same cells, nor expresses the same levels of HER2. To assess multiple lesions, whole-body imaging using PET/CT imaging might be a solution. A 68Ga-labeled, NOTA-coupled, single-domain antibody (sdAb) targeting the HER2 receptor has been developed (1). Methods In this phase II trial, 20 patients (pts) with locally advanced or metastatic breast carcinoma (BC) were included. Pts were injected intravenously with a typical dose of 100 ug and an activity range of 98-168 MBq 68GaNOTA-anti-HER2 sdAb, followed by PET/CT (Siemens Biograph Vision, 120 s per bed position and 40 s for the legs) at 90 min post injection (pi). A 2nd tracer injection, followed by PET/CT with identical parameters, was done within 8 days. In both image data sets, up to 5 lesions (minimal diameter 12mm, for lymph nodes in the short axis) per pt were selected with no more than 2 per organ system. Peak Standard Uptake Values (SUVpeak) of selected lesions were measured on both scans with Siemens' Syngo.via VB40 and compared with student t-test and Bland-Altman Plots for differences. Results/Discussion Out of 20 pts included with BC (6 HER2+, 14 HER2-) with a mean age of 58.6 y (37-81), three were scanned only once: one owing to the COVID-19 pandemic and two due to withdrawal of consent. An example of repeated tracer injection and subsequent imaging is shown in fig. 1. No safety concerns were identified in these 20 patients, confirming the excellent safety of this imaging tracer. For repeatability analysis, 50 lesions were delineated by a study team member on both scans in 17 pts. No significant differences between the two measurements were found (p:0.40). The repeatability coefficient (RC) was 38.2%. The mean absolute percentagedifference (MAPD), which is the mean of 1100x(SUV2- all subjects, was 13.6%, comparable to repeated values reported for 18F-FDG (2). Bland-Altman plot with the relative difference is shown in Fig. 2. Independent uptake analysis of all lesions by a central image reviewer, blinded to the HER2 status of the patient is ongoing. Conclusions This study confirms that on PET/CT imaging in patients with breast carcinoma, SUVpeak is a highly repeatable metric for quantifying 68GaNOTA-anti-HER2 sdAb uptake in subsequent scans. lts repeatability is similar to that reported for other routinely used tracers, such as FDG. Additional studies to define the potential clinical benefit of this technique are currently ongoing.

I-GMIB-anti-human epidermal growth factor receptor type 2 (HER2)-VHH1 is a targeted radionuclide theranostic agent directed at HER2-expressing cancers. VHH1 is a single-domain antibody covalently linked to therapeutic I via the linker -succinimidyl 4-guanidino-methyl-3-iodobenzoate (SGMIB). The phase I study was aimed at evaluating the safety, biodistribution, radiation dosimetry, and tumor-imaging potential of I-GMIB-anti-HER2-VHH1 in healthy volunteers and breast cancer patients. In a first cohort, 6 healthy volunteers were included. The biodistribution of I-GMIB-anti-HER2-VHH1 was assessed using whole-body (anterior and posterior) planar images obtained at 40 min and at 2, 4, 24, and 72 h after intravenously administered (38 ± 9 MBq) I-GMIB-anti-HER2-VHH1. Imaging data were analyzed using OLINDA/EXM software to determine the dosimetry. Blood and urine samples were obtained over 72 h. In the second cohort, 3 patients with metastatic HER2-positive breast cancer were included. Planar whole-body imaging was performed at 2 and 24 h after injection. Additional SPECT/CT images were obtained after the whole-body images at 2 and 24 h if there was relevant uptake in known cancer lesions. No drug-related adverse events were observed throughout the study. The biologic half-life of I-GMIB-anti-HER2-VHH1 in healthy subjects was about 8 h. After intravenous administration, the compound was eliminated from the blood with a 2.5-h half-life. The drug was eliminated primarily via the kidneys. The drug was stable in circulation, and there was no increased accumulation in the thyroid or stomach. The absorbed dose to the kidneys was 1.54 ± 0.25 mGy/MBq, and to bone marrow it was 0.03 ± 0.01 mGy/MBq. SPECT/CT imaging in patients with advanced breast cancer showed focal uptake of I-GMIB-anti-HER2-VHH1 in metastatic lesions. Because of its favorable toxicity profile and its uptake in HER2-positive lesions, this radiopharmaceutical can offer new therapeutic options to patients who have progressed on trastuzumab, pertuzumab, or trastuzmab emtansine, given its difference in mode-of-action. A dose escalation is planned in a subsequent phase I/II study to assess the therapeutic window of this compound (NCT04467515).

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High spatial resolution ?-imaging can be achieved with scintillator readout by low-noise, fast, electron-multiplying charge-coupled devices (EMCCDs). Previously we have shown that false-positive events due to EMCCD noise can be rejected by using the sum signal from silicon photomultipliers (SiPMs) mounted on the sides of the scintillator. Here we launch a next generation hybrid CCD-SiPM camera that utilizes the individual SiPM signals and maximum likelihood estimation (MLE) pre-localization of events to discriminate between true and false events in CCD frames. In addition, SiPM signals are utilized for improved energy discrimination. The performance of this hybrid detector was tested for a continuous CsI:Tl crystal at 140 keV. With a pre-localization accuracy of 1.06 mm (full-width-at-half-maximum) attained with MLE the signal-to-background ratio (SBR) was improved by a factor of 5.9, 4.0 or 2.2 compared to the EMCCD-only readout, at the cost of rejecting, respectively, 47%, 9% or 4% of the events. Combining the pre-localization and SiPM energy estimation improved the energy resolution from 50% to (19 ± 3)% while maintaining the spatial resolution at 180 µm.

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 CdWO? and transparent polycrystalline ceramics of Lu?O?:Eu and (Gd,Lu)?O?: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 ((99m)Tc) compared to CsI:Tl combined with moderate to good light yield. A performancecomparison based on gamma camera spatial and energy resolution was done with all tested scintillators having equal (66%) interaction probability at 140 keV. CdWO?, Lu?O?:Eu and (Gd,Lu)?O?:Eu all result in a significantly improved spatial resolution over CsI:Tl, albeit at the cost of reduced energy resolution. Lu?O?:Eu transparent ceramic gives the best spatial resolution: 65 µm full-width-at-half-maximum (FWHM) compared to 147 µm FWHM for CsI:Tl. In conclusion, these 'slow' dense scintillators open up new possibilities for improving the spatial resolution of EMCCD-based scintillation cameras.

Gamma cameras based on charge-coupled devices (CCDs) coupled to continuous scintillation crystals can combine a good detection efficiency with high spatial resolutions with the aid of advanced scintillation detection algorithms. A previously developed analytical multi-scale algorithm (MSA) models the depth-dependent light distribution but does not take statistics into account. Here we present and validate a novel statistical maximum-likelihood algorithm (MLA) that combines a realistic light distribution model with an experimentally validated statistical model. The MLA was tested for an electron multiplying CCD optically coupled to CsI(Tl) scintillators of different thicknesses. For (99m)Tc imaging, the spatial resolution (for perpendicular and oblique incidence), energy resolution and signal-to-background counts ratio (SBR) obtained with the MLA were compared with those of the MSA. Compared to the MSA, the MLA improves the energy resolution by more than a factor of 1.6 and the SBR is enhanced by more than a factor of 1.3. For oblique incidence (approximately 45°), the depth-of-interaction corrected spatial resolution is improved by a factor of at least 1.1, while for perpendicular incidence the MLA resolution does not consistently differ significantly from the MSA result for all tested scintillator thicknesses. For the thickest scintillator (3 mm, interaction probability 66% at 141 keV) a spatial resolution (perpendicular incidence) of 147 µm full width at half maximum (FWHM) was obtained with an energy resolution of 35.2% FWHM. These results of the MLA were achieved without prior calibration of scintillations as is needed for many statistical scintillation detection algorithms. We conclude that the MLA significantly improves the gamma camera performance compared to the MSA.

Electron-multiplying charge-coupled devices (EMCCDs) coupled to scintillation crystals can be used for high-resolution imaging of gamma rays in scintillation counting mode. However, the detection of false events as a result of EMCCD noise deteriorates the spatial and energy resolution of these gamma cameras and creates a detrimental background in the reconstructed image. In order to improve the performance of an EMCCD-based gamma camera with a monolithic scintillation crystal, arrays of silicon photon-multipliers (SiPMs) can be mounted on the sides of the crystal to detect escaping scintillation photons, which are otherwise neglected. This will provide a priori knowledge about the correct number and energies of gamma interactions that are to be detected in each CCD frame. This information can be used as an additional detection criterion, e.g. for the rejection of otherwise falsely detected events. The method was tested using a gamma camera based on a back-illuminated EMCCD, coupled to a 3 mm thick continuous CsI:Tl crystal. Twelve SiPMs have been mounted on the sides of the CsI:Tl crystal. When the information of the SiPMs is used to select scintillation events in the EMCCD image, the background level for (99m)Tc is reduced by a factor of 2. Furthermore, the SiPMs enable detection of (125)I scintillations. A hybrid SiPM-/EMCCD-based gamma camera thus offers great potential for applications such as in vivo imaging of gamma emitters.

Charge Coupled Devices (CCDs) optically coupled to scintillation crystals can be used to construct high resolution gamma cameras. Previously, several groups have reported intrinsic detector spatial resolutions below 100 microns. 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. The Electron-Multiplying CCD (EMCCD) is well-suited for fast read out, since even at high frame rates it has extremely low readout noise. However, due to the often very low light levels present in scintillation gamma cameras, further reduction of noise is desirable. Here, the EMCCD is optically coupled to a 1000-mum-thick columnar CsI(Tl) crystal for Tc-99m and 1-125 imaging. We investigate noise reduction through summing of signals in pixels before the gain register and readout circuit of the EMCCD ("pixel binning"). We compare the energy and spatial resolution, photopeak efficiency (PE) and signal-to-noise ratio (SNR) of an EMCCD-based gamma camera for the case of binning vs. non-binning. When pixels were read out simultaneously in groups of 4 the spatial resolution is slightly worse in the direction of binning, but the number of false-positive counts resulting from background noise for 1-125 was reduced by 74% compared to the no binning case. We conclude that the use of charge binning when reading out EMCCDs may significantly improve the energy spectra and noise properties of CCD-based high-resolution gamma cameras.

The performance of pinhole single photon emission computed tomography (SPECT) depends on the spatial resolution of the gamma-ray detectors used. Pinhole cameras suffer from strong resolution loss due to the varying depth-of-interaction (DOI) of gamma quanta that enter the detector material at an angle. We eliminate DOI effects in a scintillation gamma camera via a dedicated optic fiber bundle that acts as a focusing collimator for light generated in a scintillation crystal. A curved crystal is connected to a concavely shaped fiber-optic bundle such that the fibers connect perpendicularly to the crystal's convex surface and point straight at the pinhole opening. Limiting the fiber numerical apertures can be used to suppress resolution losses due to light spread. Here we demonstrate experimentally that this prototype position-sensitive gamma sensor successfully eliminates DOI effects, and has an intrinsic resolution of better than 280 microm full width at half maximum with an interaction probability of 67% for 140 keV photons. Therefore, the detector has great potential for increasing the resolution of pinhole SPECT.

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 µm. 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.

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

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.

Background Confetti fluorescence and other multi-color genetic labelling strategies are useful for observing stem cell regeneration and for other problems of cell lineage tracing. One difficulty of such strategies is segmenting the cell boundaries, which is a very different problem from segmenting color images from the real world. This paper addresses the difficulties and presents a superpixel-based framework for segmentation of regenerated muscle fibers in mice. Results We propose to integrate an edge detector into a superpixel algorithm and customize the method for multi-channel images. The enhanced superpixel method outperforms the original and another advanced superpixel algorithm in terms of both boundary recall and under-segmentation error. Our framework was applied to cross-section and lateral section images of regenerated muscle fibers from confetti-fluorescent mice. Compared with “ground-truth” segmentations, our framework yielded median Dice similarity coefficients of 0.92 and higher. Conclusion Our segmentation framework is flexible and provides very good segmentations of multi-color muscle fibers. We anticipate our methods will be useful for segmenting a variety of tissues in confetti fluorecent mice and in mice with similar multi-color labels., National University of Singapore (Duke-NUS SRP Phase 2 Research Block Grant), Singapore. National Research Foundation (CREATE programme), Singapore-MIT Alliance for Research and Technology (SMART)