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Background: Microspheres loaded with radioactive 166 Ho ( 166 Ho-MS) are novel particles for radioembolisation and intratumoural treatment. Because of the limited penetration of β radiation, quantitative imaging of microsphere distribution is crucial for optimal intratumoural treatment. Computed tomography (CT) may provide high-resolution and fast imaging of the distribution of these microspheres, with lower costs and widespread availability in comparison with current standard single-photon emission tomography (SPECT) and magnetic resonance imaging. This phantom study investigated the feasibility of CT quantification of 166 Ho-MS., Methods: CT quantification was performed on a phantom with various concentrations of HoCl and Ho-MS to investigate the CT sensitivity and calibrate the CT recovery. 166 Ho-MS were injected into ex vivo tissues, in VX-2 cancer-bearing rabbits, and in patients with head-neck cancer, to demonstrate sensitivity and clinical visibility. The amount of Ho-MS was determined by CT scanning, using a density-based threshold method and compared with a validated 166 Ho SPECT quantification method., Results: In the phantom, a near perfect linearity (least squares R 2 > 0.99) between HU values and concentration of 166 Ho was found. Ex vivo tissue experiments showed an excellent correlation (r = 0.99, p < 0.01) between the dose calibrator, SPECT, and CT imaging. CT recovery was on average 86.4% ex vivo, 76.0% in rabbits, and 99.1% in humans., Conclusion: This study showed that CT-based quantification of Ho microspheres is feasible and is a high-resolution alternative to SPECT-based determination of their local distribution.

Purpose: As an alternative to technetium-99m-macroaggregated albumin ( 99m Tc-MAA), a scout dose of holmium-166 ( 166 Ho) microspheres can be used prior to 166 Ho-radioembolization. The use of identical particles for pre-treatment and treatment procedures may improve the predictive value of pre-treatment analysis of distribution. The aim of this study was to analyze the agreement between 166 Ho-scout and 166 Ho-therapeutic dose in comparison with the agreement between 99m Tc-MAA and 166 Ho-therapeutic dose., Methods: Two separate scout dose procedures were performed ( 99m Tc-MAA and 166 Ho-scout) before treatment in 53 patients. First, qualitative assessment was performed by two blinded nuclear medicine physicians who visually rated the agreement between the 99m Tc-MAA, 166 Ho-scout, and 166 Ho-therapeutic dose SPECT-scans (i.e., all performed in the same patient) on a 5-point scale. Second, agreement was measured quantitatively by delineating lesions and normal liver on FDG-PET/CT. These volumes of interest (VOIs) were co-registered to the SPECT/CT images. The predicted absorbed doses (based on 99m Tc-MAA and 166 Ho-scout) were compared with the actual absorbed dose on post-treatment SPECT., Results: A total of 23 procedures (71 lesions, 22 patients) were included for analysis. In the qualitative analysis, 166 Ho-scout was superior with a median score of 4 vs. 2.5 for 99m Tc-MAA (p < 0.001). The quantitative analysis showed significantly narrower 95%-limits of agreement for 166 Ho-scout in comparison with 99m Tc-MAA when evaluating lesion absorbed dose (- 90.3 and 105.3 Gy vs. - 164.1 and 197.0 Gy, respectively). Evaluation of normal liver absorbed dose did not show difference in agreement between both scout doses and 166 Ho-therapeutic dose (- 2.9 and 5.5 Gy vs - 3.6 and 4.1 Gy for 99m Tc-MAA and 166 Ho-scout, respectively)., Conclusions: In this study, 166 Ho-scout was shown to have a superior predictive value for intrahepatic distribution in comparison with 99m Tc-MAA.

Background: In patients with metastatic neuroendocrine neoplasms, the liver is the most commonly affected organ and a crucial factor for prognosis and survival. Peptide receptor radionuclide therapy can prolong progression-free survival in these patients. Additional treatment of liver disease might further improve outcomes. We aimed to investigate the safety and efficacy of additional holmium-166 ( 166 Ho) radioembolisation after peptide receptor radionuclide therapy in patients with metastatic liver neuroendocrine neoplasms., Methods: The Holmium Embolization Particles for Arterial Radiotherapy Plus 177 Lu-Dotatate in Salvage Neuroendocrine Tumour Patients (HEPAR PLuS) study was a single-centre, phase 2 study done at the University Medical Center Utrecht (Utrecht, Netherlands). Patients, aged at least 18 years, with histologically proven grade 1 or 2 neuroendocrine neoplasms of all origins, an Eastern Cooperative Oncology Group performance status of 0-2, and three or more measurable liver metastases according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 criteria received 166 Ho-radioembolisation within 20 weeks after four cycles of peptide receptor radionuclide therapy (lutetium-177-dotatate [ 177 Lu-dotatate]). The primary endpoint was objective liver tumour response in the treated liver volume, defined as complete response (disappearance of all lesions) or partial response (≥30% decrease in the sum of the longest diameters of the target lesions, compared with baseline measurements), according to RECIST 1.1, analysed per protocol at 3 months. Safety was assessed in all patients who received treatment. This study is registered with ClinicalTrials.gov, NCT02067988. Recruitment is completed and long-term follow-up is ongoing., Findings: From Oct 15, 2014, to Sept 12, 2018, 34 patients were assessed for eligibility. 31 patients received treatment and 30 (97%) patients were available for primary endpoint assessment and completed 6 months of follow-up. Three (9%) patients were excluded at screening and one (3%) patient was treated and died before the primary endpoint and was replaced. According to the per-protocol analysis 13 (43%; 95% CI 26-63) of 30 patients achieved an objective response in the treated volume. The most frequently reported Common Terminology Criteria for Adverse Events (CTCAE) grade 3-4 clinical and laboratory toxicities within 6 months included abdominal pain (three [10%] of 31 patients), increased γ-glutamyl transpeptidase (16 [54%]), and lymphocytopenia (seven [23%]). One (3%) fatal treatment-related serious adverse event occurred (radioembolisation-induced liver disease). Two (6%) patients had serious adverse events deemed to be unrelated to treatment (gastric ulcer and perforated cholecystitis)., Interpretation: 166 Ho-radioembolisation, as an adjunct to peptide receptor radionuclide therapy in patients with neuroendocrine neoplasm liver metastases, is safe and efficacious. Radioembolisation can be considered in patients with bulky liver disease, including after peptide receptor radionuclide therapy. A future randomised, controlled study should investigate the added benefit of this treatment on progression-free survival., Funding: None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

166 Ho-microspheres have recently been approved for clinical use for hepatic radioembolization in the European Union. The aim of this study was to investigate the absorbed dose-response relationship and its association with overall survival for 166 Ho radioembolization in patients with liver metastases. Methods: Patients treated in the HEPAR I and II studies who underwent an 18 F-FDG PET/CT scan at baseline, a posttreatment 166 Ho SPECT/CT scan, and another 18 F-FDG PET/CT scan at the 3-mo follow-up were included for analysis. The posttreatment 166 Ho-microsphere activity distributions were estimated with quantitative SPECT/CT reconstructions using a quantitative Monte Carlo-based method. The response of each tumor was based on the change in total lesion glycolysis (TLG) between baseline and follow-up and was placed into 1 of 4 categories, according to the PERCIST criteria, ranging from complete response to progressive disease. Patient-level response was grouped according to the average change in TLG per patient. The absorbed dose-response relationship was assessed using a linear mixed model to account for correlation of tumors within patients. Median overall survival was compared between patients with and without a metabolic liver response, using a log-rank test. Results: Thirty-six patients with a total of 98 tumors were included. The relation between tumor-absorbed dose and both tumor-level and patient-level response was explored. At a tumor level, a significant difference in geometric mean absorbed dose was found between complete response (232 Gy; 95% confidence interval [CI], 178-303 Gy; n = 32) and stable disease (147 Gy; 95% CI, 113-191 Gy; n = 28) ( P = 0.01) and between complete response and progressive disease (117 Gy; 95% CI, 87-159 Gy; n = 21) ( P = 0.0008). This constitutes a robust absorbed dose-response relationship. At a patient level, a significant difference was found between patients with complete or partial response (210 Gy; 95% CI, 161-274 Gy; n = 13) and patients with progressive disease (116 Gy; 95% CI, 81-165 Gy; n = 9) ( P = 0.01). Patients were subsequently grouped according to their average change in TLG. Patients with an objective response (complete or partial) exhibited a significantly higher overall survival than nonresponding patients (stable or progressive disease) (median, 19 mo vs. 7.5 mo; log-rank, P = 0.01). Conclusion: These results confirm a significant absorbed dose-response relationship in 166 Ho radioembolization. Treatment response is associated with a higher overall survival., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Intrahepatic dosimetry is paramount to optimize radioembolization treatment accuracy using radioactive holmium-166 microspheres ( 166 Ho). This requires a practical protocol that combines quantitative imaging of microsphere distribution with automated and robust delineation of the volumes of interest. To this end, we propose a dual isotope single photon emission computed tomography (SPECT) protocol based on 166 Ho therapeutic microspheres and technetium-99 m ( 99m Tc) stannous phytate, which accumulates in healthy liver tissue. This protocol may allow accurate and automatic estimation of tumor-absorbed dose and healthy liver-absorbed dose. The current study focuses on a Monte Carlo-based reconstruction framework that inherently corrects for scatter crosstalk between the 166 Ho and 99m Tc imaging. To demonstrate the feasibility of the method, it is evaluated with realistic phantom experiments and patient data., Methods: The Utrecht Monte Carlo System (UMCS) was extended to include detailed modeling of crosstalk interactions between 99m Tc and 166 Ho. First, 99m Tc images were reconstructed including energy window-based corrections for 166 Ho downscatter. Next, 99m Tc downscatter in the 81-keV 166 Ho window was Monte Carlo simulated to allow quantitative reconstruction of the 166 Ho images. The accuracy of the 99m Tc-downscatter modeling was evaluated by comparing measurements with simulations. In addition, the ratio between 99m Tc and 166 Ho yielding the best 166 Ho dose estimates was established and the quantitative accuracy was reported., Results: Given the same level of activity, 99m Tc contributes twice as many counts to the 81-keV window than 166 Ho, and four times as many counts to the 140-keV window, applying a 166 Ho/ 99m Tc ratio of 5:1 yielded a high accuracy in both 166 Ho and 99m Tc reconstruction. Phantom experiments revealed that the accuracy of quantitative 166 Ho activity recovery was reduced by 10% due to the presence of 99m Tc. Twenty iterations (8 subsets) of the SPECT/CT reconstructions were considered feasible for clinical practice. Applicability of the proposed protocol was shown in a proof-of-concept case., Conclusion: A novel 166 Ho/ 99m Tc dual-isotope protocol for automatic dosimetry compensates accurately for downscatter and allows for the addition of 99m Tc without compromising 166 Ho SPECT image quality.

Background: New digital PET scanners with improved time of flight timing and extended axial field of view such as the Siemens Biograph Vision have come on the market and are expected to replace current generation photomultiplier tube (PMT)-based systems such as the Siemens Biograph mCT. These replacements warrant a direct comparison between the systems, so that a smooth transition in clinical practice and research is guaranteed, especially when quantitative values are used for dosimetry-based treatment guidance. The new generation digital PET scanners offer increased sensitivity. This could particularly benefit 90 Y imaging, which tends to be very noisy owing to the small positron branching ratio and high random fraction of 90 Y. This study aims to determine the ideal reconstruction settings for the digital Vision for quantitative 90 Y imaging and to evaluate the image quality and quantification of the digital Vision in comparison with its predecessor, the PMT-based mCT, for 90 Y imaging in radioembolisation procedures., Methods: The NEMA image quality phantom was scanned to determine the ideal reconstruction settings for the Vision. In addition, an anthropomorphic phantom was scanned with both the Vision and the mCT, mimicking a radioembolisation patient with lung, liver, tumour, and extrahepatic deposition inserts. Image quantification of the anthropomorphic phantom was assessed by the lung shunt fraction, the tumour to non-tumour ratio, the parenchymal dose, and the contrast to noise ratio of extrahepatic depositions., Results: For the Vision, a reconstruction with 3 iterations, 5 subsets, and no post-reconstruction filter is recommended for quantitative 90 Y imaging, based on the convergence of the recovery coefficient. Comparing both systems showed that the noise level of the Vision is significantly lower than that of the mCT (background variability of 14% for the Vision and 25% for the mCT at 2.5·10 3  MBq for the 37 mm sphere size). For quantitative 90 Y measures, such as needed in radioembolisation, both systems perform similarly., Conclusions: We recommend to reconstruct 90 Y images acquired on the Vision with 3 iterations, 5 subsets, and no post-reconstruction filter for quantitative imaging. The Vision provides a reduced noise level, but similar quantitative accuracy as compared with its predecessor the mCT.

Purpose: Prior to 90 Y hepatic radioembolization, a dosage of 99m Tc-macroaggregated albumin ( 99m Tc-MAA) is administered to simulate the distribution of the 90 Y-loaded microspheres. This pretreatment procedure enables lung shunt estimation, detection of potential extrahepatic depositions, and estimation of the intrahepatic dose distribution. However, the predictive accuracy of the MAA particle distribution is often limited. Ideally, 90 Y microspheres would also be used for the pretreatment procedure. Based on previous research, the pretreatment activity should be limited to the estimated safety threshold of 100 MBq, making imaging challenging. The purpose of this study was to evaluate the quality of intra- and extrahepatic imaging of 90 Y-based pretreatment positron emission tomography/computed tomography (PET/CT) and quantitative single photon emission computed tomography (SPECT)/CT scans, by means of phantom experiments and a patient study., Methods: An anthropomorphic phantom with three extrahepatic depositions was filled with 90 Y chloride to simulate a lung shunt fraction (LSF) of 5.3% and a tumor to nontumor ratio (T/N) of 7.9. PET /CT (Siemens Biograph mCT) and Bremsstrahlung SPECT/CT (Siemens Symbia T16) images were acquired at activities ranging from 1999 MBq down to 24 MBq, representing post- and pretreatment activities. PET/CT images were reconstructed with the clinical protocol and SPECT/CT images were reconstructed with a quantitative Monte Carlo-based reconstruction protocol. Estimated LSF, T/N, contrast to noise ratio of all extrahepatic depositions, and liver parenchymal and tumor dose were compared with the phantom ground truth. A clinically reconstructed SPECT/CT of 150 MBq 99m Tc represented the current clinical standard. In addition, a 90 Y pretreatment scan was simulated for a patient by acquiring posttreatment PET/CT and SPECT/CT data with shortened acquisition times., Results: At an activity of 100 MBq 90 Y, PET/CT overestimated LSF [+10 percentage point (pp)], underestimated liver parenchymal dose (-3 Gy/GBq), and could not detect the extrahepatic depositions. SPECT/CT more accurately estimated LSF (-0.7 pp), parenchymal dose (-0.3 Gy/GBq) and could detect all three extrahepatic depositions. 99m Tc SPECT/CT showed similar accuracy as 90 Y SPECT/CT (LSF: +0.2 pp, parenchymal dose: +0.4 Gy/GBq, all extrahepatic depositions visible), although the noise level in the liver compartment was considerably lower for 99m Tc SPECT/CT compared to 90 Y SPECT/CT. The patient's SPECT/CT simulating a pretreatment 90 Y procedure accurately represented the posttreatment 90 Y microsphere distribution., Conclusions: Quantitative SPECT/CT of 100 MBq 90 Y could accurately estimate LSF, T/N, parenchymal and tumor dose, and visualize extrahepatic depositions., (© 2019 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Background: Quantitative SPECT imaging in targeted radionuclide therapy with lutetium-177 holds great potential for individualized treatment based on dose assessment. The establishment of dose-effect relations requires a standardized method for SPECT quantification. The purpose of this multi-center study is to evaluate quantitative accuracy and inter-system variations of different SPECT/CT systems with corresponding commercially available quantitative reconstruction algorithms. This is an important step towards a vendor-independent standard for quantitative lutetium-177 SPECT., Methods: Four state-of-the-art SPECT/CT systems were included: Discovery™ NM/CT 670Pro (GE Healthcare), Symbia Intevo™, and two Symbia™ T16 (Siemens Healthineers). Quantitative accuracy and inter-system variations were evaluated by repeatedly scanning a cylindrical phantom with 6 spherical inserts (0.5 - 113 ml). A sphere-to-background activity concentration ratio of 10:1 was used. Acquisition settings were standardized: medium energy collimator, body contour trajectory, photon energy window of 208 keV (± 10%), adjacent 20% lower scatter window, 2 × 64 projections, 128 × 128 matrix size, and 40 s projection time. Reconstructions were performed using GE Evolution with Q.Metrix™, Siemens xSPECT Quant™, Siemens Broad Quantification™ or Siemens Flash3D™ algorithms using vendor recommended settings. In addition, projection data were reconstructed using Hermes SUV SPECT™ with standardized reconstruction settings to obtain a vendor-neutral quantitative reconstruction for all systems. Volumes of interest (VOI) for the spheres were obtained by applying a 50% threshold of the sphere maximum voxel value corrected for background activity. For each sphere, the mean and maximum recovery coefficient (RC mean and RC max ) of three repeated measurements was calculated, defined as the imaged activity concentration divided by the actual activity concentration. Inter-system variations were defined as the range of RC over all systems., Results: RC decreased with decreasing sphere volume. Inter-system variations with vendor-specific reconstructions were between 0.06 and 0.41 for RC mean depending on sphere size (maximum 118% quantification difference), and improved to 0.02-0.19 with vendor-neutral reconstructions (maximum 38% quantification difference)., Conclusion: This study shows that eliminating sources of possible variation drastically reduces inter-system variation in quantification. This means that absolute SPECT quantification for 177 Lu is feasible in a multi-center and multi-vendor setting; however, close agreement between vendors and sites is key for multi-center dosimetry and quantitative biomarker studies.

Background: Post-haemorrhagic ventricular dilatation can be measured accurately by MRI. However, two-dimensional (2-D) cranial US can be used at the bedside on a daily basis., Objective: To assess whether the ventricular volume can be determined accurately using US., Materials and Methods: We included 31 preterm infants with germinal matrix intraventricular haemorrhage. Two-dimensional cranial US images were acquired and the ventricular index, anterior horn width and thalamo-occipital distance were measured. In addition, cranial MRI was performed. The ventricular volume on MRI was determined using a previously validated automatic segmentation algorithm. We obtained the correlation and created a linear model between MRI-derived ventricular volume and 2-D cranial US measurements., Results: The ventricular index, anterior horn width and thalamo-occipital distance as measured on 2-D cranial US were significantly associated with the volume of the ventricles as determined with MRI. A general linear model fitted the data best: ∛ventricular volume (ml) = 1.096 + 0.094 × anterior horn width (mm) + 0.020 × thalamo-occipital distance (mm) with R 2  = 0.831., Conclusion: The volume of the lateral ventricles of infants with germinal matrix intraventricular haemorrhage can be estimated using 2-D cranial US images by application of a model.

Computed tomography perfusion (CTP) is increasingly used to determine treatment eligibility for acute ischemic stroke patients. Automated postprocessing of raw CTP data is routinely used, but it can fail. In reviewing 176 consecutive acute ischemic stroke patients, failures occurred in 20 patients (11%) during automated postprocessing by the RAPID software. Failures were caused by motion (n = 11, 73%), streak artifacts (n = 2, 13%), and poor contrast bolus arrival (n = 2, 13%). Stroke physicians should review CTP results with care before they are being integrated in their decision-making process.

Radioembolization treatment is preceded by a 99m Tc-MAA safety procedure, which is used to estimate the lung shunt fraction (LSF). Normally, the LSF is estimated by using the geometric mean of planar scintigraphy (PS-GM). However, concern has been raised about the potential overestimation of the LSF by PS-GM. Alternatively, SPECT/CT may be used for LSF estimation, but requires lengthy acquisitions, 3D segmentation, and has a limited field of view, which calls for extrapolation of the reconstructed lung counts, which introduces another source of error. We have developed a simplified SPECT/CT protocol for LSF estimation, called the quantitative orthogonal planar (QOP) method that requires only four projections to quantitatively reconstruct liver and lung activity. This mitigates the problems associated with LSF estimations from SPECT/CT. The purpose of this study was to introduce and evaluate QOP by comparing its performance to PS-GM and SPECT/CT in a retrospective patient study, and by supporting simulation experiments. Patients who received at least one 99m Tc-MAA safety procedure in our center were included in this study. QOP and PS-GM were compared to SPECT/CT in Bland-Altman analyses. Supporting digital phantom experiments with a known ground-truth were performed to evaluate the performance of this method. Analysis of PS-GM versus SPECT/CT LSF estimates revealed both a larger imprecision and significant bias by PS-GM (limits of agreement: 8.1 percentage points (pp); bias: 2.7 pp). The QOP method agreed better with the SPECT/CT-based estimation (limits of agreement: 2.07 pp; bias: 0.52 pp). This observation was consistent with the digital phantom experiments. We have proposed and evaluated a novel method called QOP for LSF estimation that performs almost as accurate as SPECT/CT, but without the need for lung mass extrapolation, long scan duration, or extensive manual segmentation, making it as fast as current PS-GM.

Recent research into the efficacy of radioembolization has brought this field to an interesting position, in which fluorodeoxyglucose (FDG)-PET/CT is being used extensively for prognosis and response assessment, as well as a tool to define viable tumor volumes for the use in dosimetry. As such, there is an overlap with existing techniques used in radiotherapy; however, many are very specific to the radioembolization paradigm. This article describes the current state-of-the-art of the use of FDG-PET/CT for patient selection, prognosis, treatment evaluation, and as a research tool into absorbed dose-response relationships in radioembolization., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Radioembolization is increasingly used as a bridge to resection (i.e., radiation lobectomy). It combines ipsilateral tumor control with the induction of contralateral hypertrophy to facilitate lobar resection. The aim of this pilot study was to investigate the complementary value of hepatobiliary scintigraphy (HBS) before and after radioembolization in the assessment of the future remnant liver. Methods: Consecutive patients with liver tumors who underwent HBS before and after 90 Y radioembolization were included. Regional (treated/nontreated) and whole liver function and volume were determined on HBS and CT. Changes in regional liver function and volume were correlated with the functional liver absorbed doses, determined on 90 Y PET/CT. In addition, the correlation between liver volume and function change was evaluated. Results: Thirteen patients (10 hepatocellular carcinoma, 3 metastatic colorectal carcinoma) were included. Liver function of the treated part declined after radioembolization (HBS-pre, 4.0%/min/m 2 ; HBS-post, 1.9%/min/m 2 ; P = 0.001), whereas the function of the nontreated part increased (HBS-pre, 1.4%/min/m 2 ; HBS-post, 2.8%/min/m 2 ; P = 0.009). Likewise, treated volume decreased (pretreatment, 1,118.7 cm 3 ; posttreatment, 870.7 cm 3 ; P = 0.003), whereas the nontreated volume increased (pretreatment, 412.7 cm 3 ; posttreatment, 577.6 cm 3 ; P = 0.005). Bland-Altman analysis revealed a large bias (29%) between volume decrease and function decrease in the treated part and wide limits of agreement (-7.7%-65.6%). The bias between volume and function change was smaller (±6.0%) in the nontreated part of the liver, but limits of agreement were still wide (-117.9%-106.7%). Conclusion: Radioembolization induces regional changes in liver function that are accurately detected by HBS. Limits of agreement between function and volume changes were wide, showing large individual differences. This finding indicates that HBS may have a complementary role in the management of patients for radiation lobectomy., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Quantitative accuracy of the single photon emission computed tomography (SPECT) reconstruction of the pretreatment procedure of liver radioembolization is crucial for dosimetry; visual quality is important for detecting doses deposited outside the planned treatment volume. Quantitative accuracy is limited by respiratory motion. Conventional gating eliminates motion by count rejection but increases noise, which degrades the visual reconstruction quality. Motion compensation using all counts can be performed if the motion signal and motion vector field over time are known. The measurement of the motion signal of a patient currently requires a device (such as a respiratory belt) attached to the patient, which complicates the acquisition. The motion vector field is generally extracted from a previously acquired four-dimensional scan and can differ from the motion in the scan performed during the intervention. The simultaneous acquisition of fluoroscopic and nuclear projections can be used to obtain both the motion vector field and the projections of the corresponding (moving) activity distribution. This eliminates the need for devices attached to the patient and provides an accurate motion vector field for SPECT reconstruction. Our approach to motion compensation would primarily be beneficial for interventional SPECT because the time-critical setting requires fast scans and no inconvenience of an external apparatus. The purpose of this work is to evaluate the performance of the motion compensation approach for interventional liver SPECT by means of simulations., Methods: Nuclear and fluoroscopic projections of a realistic digital human phantom with respiratory motion were generated using fast Monte Carlo simulators. Fluoroscopic projections were sampled at 1-5 Hz. Nuclear data were acquired continuously in list mode. The motion signal was extracted from the fluoroscopic projections by calculating the center-of-mass, which was then used to assign each photon to a corresponding motion bin. The fluoroscopic projections were reconstructed per bin and coregistered, resulting in a motion vector field that was used in the SPECT reconstruction. The influence of breathing patterns, fluoroscopic imaging dose, sampling rate, number of bins, and scanning time was studied. In addition, the motion compensation method was compared with conventional gating to evaluate the detectability of spheres with varying uptake ratios., Results: The liver motion signal was accurately extracted from the fluoroscopic projections, provided the motion was stable in amplitude and the sampling rate was greater than 2 Hz. The minimum total fluoroscopic dose for the proposed method to function in a 5-min scan was 10 µGy. Although conventional gating improved the quantitative reconstruction accuracy, substantial background noise was observed in the short scans because of the limited counts available. The proposed method similarly improved the quantitative accuracy, but generated reconstructions with higher visual quality. The proposed method provided better visualization of low-contrast features than when using gating., Conclusion: The proposed motion compensation method has the potential to improve SPECT reconstruction quality. The method eliminates the need for external devices to measure the motion signal and generates an accurate motion vector field for reconstruction. A minimal increase in the fluoroscopic dose is required to substantially improve the results, paving the way for clinical use., (© 2019 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Background: Monte Carlo-based iterative reconstruction to correct for photon scatter and collimator effects has been proven to be superior over analytical correction schemes in single-photon emission computed tomography (SPECT/CT), but it is currently not commonly used in daily clinical practice due to the long associated reconstruction times. We propose to use a convolutional neural network (CNN) to upgrade fast filtered back projection (FBP) image quality so that reconstructions comparable in quality to the Monte Carlo-based reconstruction can be obtained within seconds., Results: A total of 128 technetium-99m macroaggregated albumin pre-treatment SPECT/CT scans used to guide hepatic radioembolization were available. Four reconstruction methods were compared: FBP, clinical reconstruction, Monte Carlo-based reconstruction, and the neural network approach. The CNN generated reconstructions in 5 sec, whereas clinical reconstruction took 5 min and the Monte Carlo-based reconstruction took 19 min. The mean squared error of the neural network approach in the validation set was between that of the Monte Carlo-based and clinical reconstruction, and the lung shunting fraction difference was lower than 2 percent point. A phantom experiment showed that quantitative measures required in radioembolization were accurately retrieved from the CNN-generated reconstructions., Conclusions: FBP with an image enhancement neural network provides SPECT reconstructions with quality close to that obtained with Monte Carlo-based reconstruction within seconds.

Simultaneous acquisition of nuclear and fluoroscopic projections could be of benefit for image-guided radionuclide administration. A gamma camera positioned behind an x-ray flat panel detector can accomplish such simultaneous acquisition, but the gamma camera performance suffers from the intense x-ray dose. A regular NaI(Tl)-based camera has nominal performance up to 0.02 nGy dose per pulse, whereas 10 nGy dose is expected for our foreseen applications. We evaluated the performance of CeBr 3 - and CZT-based detectors and investigated a cost-effective improvement of a regular NaI(Tl)-based camera by the introduction of a high-pass filter and shorting circuit. A CeBr 3 -based detector was exposed to 5 mGy x-ray dose and the resulting light emission was measured over time to quantify the crystal afterglow, allowing comparison with a previously measured NaI(Tl)-based detector. The NaI(Tl)-, CeBr 3 - and CZT-based detectors were exposed to x-ray pulse sequences with dose from 0.06 to 60 nGy, while being irradiated with a gamma source. The mean gamma energy and energy resolution in between the x-ray pulses were measured as a reference of the detector performance. The afterglow signal after 3 ms was 14.1% for the NaI(Tl)-based detector, whereas for the CeBr 3 -based detector it was only 0.1%. The limits for a proper functioning detectors are 0.32 nGy for the NaI(Tl)-based detector with high-pass filter and shorting circuit and 18.94 nGy for the one with CeBr 3 . No energy degradation was observed for the CZT module in the studied dose range. The performance of regular NaI(Tl)-based gamma cameras deteriorates when exposed to high x-ray doses. CeBr 3 and CZT are much better suited for introduction into a dual-layer detector but have high associated costs. Addition of a high-pass filter and shorting circuit into the PMT of a NaI(Tl)-based detector is a cost-effective solution that works well for low dose levels.

Introduction: The limited axial coverage of many computed tomography (CT) scanners poses a high risk on false negative findings in cerebral CT-perfusion (CTP) imaging. Axial coverage may be increased by moving the table back and forth during image acquisition. However, this method often increases the acquisition interval between CT frames, which may influence the CTP analysis. In this study, we evaluated the influence of different acquisition intervals on quantitative perfusion maps and infarct volumes by analyzing patient data with three CTP analysis methods., Methods: CT-perfusion data from 25 patients with ischemic stroke were used for this study. The acquisition interval was synthetically reduced from 1 to 5 s before calculating perfusion values, which included cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). The color scaling of the perfusion was scaled such that the mean perfusion value had the same color-coding as the mean perfusion in the 1 s reference. Also, infarct core and penumbra volumes (summary map) were calculated using default thresholds of CBV and relative MTT (rMTT). The original, 1 s acquisition interval scan served as the reference standard. A commercial block-circulant singular value decomposition (bSVD) based method (ISP; Philips Healthcare), a non-commercial bSVD method, and a non-linear regression (NLR) model-based method were evaluated., Results: Cerebral blood volume values generated with bSVD and NLR were not significantly different from the reference standard, while ISP showed significant differences for acquisition intervals of 3 and 4 s. MTT and CBF values generated with bSVD and ISP were significantly different for all acquisition intervals, whereas NLR did not show any significant differences. Calibrated perfusion maps were able to distinguish healthy from infarcted tissue up to an acquisition interval of 5 s for all methods. The infarct core volumes were significantly different for acquisition intervals of 2 (NLR) and 3 s (bSVD and ISP) or greater. For the penumbra volumes, NLR showed no significant differences, while bSVD and ISP showed significant differences for the 5 s interval and for all intervals, respectively. Visual inspection of the summary maps indicated minor differences between the reference standard and acquisition intervals of 4 s or less (ISP) and 5 s or less (bSVD and NLR)., Conclusion: Altering the acquisition interval may introduce a bias in the perfusion parameters. Calibration of the visualization of the perfusion maps with increasing acquisition intervals allowed distinction between healthy and infarcted tissue. Infarct volumes based on relative MTT can be influenced by the acquisition interval, but visual inspection of the summary maps indicated minor differences between the reference standard and acquisition intervals up to 4 (ISP) and 5 s (bSVD and NLR). Taken together, axial coverage can be increased by prolonging the acquisition interval up to 5 s depending on the perfusion analysis., (© 2019 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Background and Purpose- Predicting malignant middle cerebral artery (MCA) infarction can help to identify patients who may benefit from preventive decompressive surgery. We aimed to investigate the association between the ratio of intracranial cerebrospinal fluid (CSF) volume to intracranial volume (ICV) and malignant MCA infarction. Methods- Patients with an occlusion proximal to the M3 segment of the MCA were selected from the DUST (Dutch Acute Stroke Study). Admission imaging included noncontrast computed tomography (CT), CT perfusion, and CT angiography. Patient characteristics and CT findings were collected. The ratio of intracranial CSF volume to ICV (CSF/ICV) was quantified on admission thin-slice noncontrast CT. Malignant MCA infarction was defined as a midline shift of >5 mm on follow-up noncontrast CT, which was performed 3 days after the stroke or in case of clinical deterioration. To test the association between CSF/ICV and malignant MCA infarction, odds ratios and 95% CIs were calculated for 3 multivariable models by using binary logistic regression. Model performances were compared by using the likelihood ratio test. Results- Of the 286 included patients, 35 (12%) developed malignant MCA infarction. CSF/ICV was independently associated with malignant MCA infarction in 3 multivariable models: (1) with age and admission National Institutes of Health Stroke Scale (odds ratio, 3.3; 95% CI, 1.1-11.1), (2) with admission National Institutes of Health Stroke Scale and poor collateral score (odds ratio, 7.0; 95% CI, 2.6-21.3), and (3) with terminal internal carotid artery or proximal M1 occlusion and poor collateral score (odds ratio, 7.7; 95% CI, 2.8-23.9). The performance of model 1 (areas under the receiver operating characteristic curves, 0.795 versus 0.824; P =0.033), model 2 (areas under the receiver operating characteristic curves, 0.813 versus 0.850; P <0.001), and model 3 (areas under the receiver operating characteristic curves, 0.811 versus 0.856; P <0.001) improved significantly after adding CSF/ICV. Conclusions- The CSF/ICV ratio is associated with malignant MCA infarction and has added value to clinical and imaging prediction models in limited numbers of patients.

Fluoroscopic procedures involving radionuclides would benefit from interventional nuclear imaging by obtaining real-time feedback on the activity distribution. We have previously proposed a dual-layer detector that offers such procedural guidance by simultaneous fluoroscopic and nuclear planar imaging. Acquisition of single photon computed tomography (SPECT) and cone beam computed tomography (CBCT) could provide additional information on the activity distribution. This study investigates the feasibility and the image quality of simultaneous SPECT/CBCT, by means of phantom experiments and simulations. Simulations were performed to study the obtained reconstruction quality for (i) clinical SPECT/CT, (ii) a dual-layer scanner configured with optimized hardware, and (iii) our (non-optimized) dual-layer prototype. Experiments on an image quality phantom and an anthropomorphic phantom (including extrahepatic depositions with volumes and activities close to the median values encountered in hepatic radioembolization) were performed with a clinical SPECT/CT scanner and with our dual-layer prototype. Nuclear images were visually and quantitatively evaluated by measuring the tumor/non-tumor (T/N) ratio and contrast-to-noise ratio (CNR). The simulations showed that the maximum obtained CNR was 38.8  ±  0.8 for the clinical scanner, 30.2  ±  0.9 for the optimized dual-layer scanner, and 20.8  ±  0.4 for the prototype scanner. T/N ratio showed a similar decline. The phantom experiments showed that performing simultaneous SPECT/CBCT is feasible. The CNR obtained from the SPECT reconstruction of largest sphere in the image quality phantom was 43.1 for the clinical scanner and 28.6 for the developed prototype scanner. The anthropomorphic phantom showed that the extrahepatic depositions were detected with both scanners. A dual-layer detector is able to simultaneously acquire SPECT and CBCT. Both CNR and T/N ratio are worse than that of a clinical system, but the phantom experiments showed that extrahepatic depositions with volumes and activities close to the median values encountered in hepatic radioembolization could be distinguished.

Purpose: To assess the radiation dose associated with always-on dual-energy acquisitions in clinical practice over a broad range of clinical protocols using a dual-layer detector CT (DLCT; IQon spectral CT, Philips Healthcare) as compared to an otherwise technically equivalent single-layer detector CT (SLCT; Brilliance iCT, Philips healthcare)., Materials and Methods: Dose-length-product data for consecutive examinations over a six-month period acquired with DLCT were retrospectively collected and compared to consecutive examinations from an SLCT. Imaging protocols were optimized for diagnostic image quality for each system prior to data collection. Dose reports of CT protocols that were used at least 50 times on both systems were collected. After exclusion of statistical outliers, protocols were evaluated with regard to reported dose levels., Results: In total, 4536 dose reports for DLCT and 5783 reports for SLCT were collected. All DLCT examinations were acquired at 120 kVp, enabling dual-energy analysis. With SLCT, 79% of examinations were acquired at 120 kVp, and 21% at 100/80 kVp. Protocols for 15 indications were used more than 50 times on both scanners. For seven protocols there was no significant difference between the two scanners (p > 0.05), whereas seven protocols were acquired with higher dose levels on SLCT compared to the DLCT (p < 0.03). For one protocol, the DLCT dose was significantly higher (p < 0.005) compared to the SLCT., Conclusion: Dual-layer detector CT enables acquisition of dual-energy information over a broad range of clinical indications without increasing radiation dose when compared to a conventional single-layer detector CT., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose To develop and evaluate a dual-layer detector capable of acquiring intrinsically registered real-time fluoroscopic and nuclear images in the interventional radiology suite. Materials and Methods The dual-layer detector consists of an x-ray flat panel detector placed in front of a γ camera with cone beam collimator focused at the x-ray focal spot. This design relies on the x-ray detector absorbing the majority of the x-rays while it is more transparent to the higher energy γ photons. A prototype was built and dynamic phantom images were acquired. In addition, spatial resolution and system sensitivity (evaluated as counts detected within the energy window per second per megabecquerel) were measured with the prototype. Monte Carlo simulations for an improved system with varying flat panel compositions were performed to assess potential spatial resolution and system sensitivity. Results Experiments with the dual-layer detector prototype showed that spatial resolution of the nuclear images was unaffected by the addition of the flat panel (full width at half maximum, 13.6 mm at 15 cm from the collimator surface). However, addition of the flat panel lowered system sensitivity by 45%-60% because of the nonoptimized transmission of the flat panel. Simulations showed that an attenuation of 27%-35% of the γ rays in the flat panel could be achieved by decreasing the crystal thickness and housing attenuation of the flat panel. Conclusion A dual-layer detector was capable of acquiring real-time intrinsically registered hybrid images, which could aid interventional procedures involving radionuclides. Published under a CC BY-NC-ND 4.0 license. Online supplemental material is available for this article.

Purpose: The efficiency of radioembolization procedures could be greatly enhanced if results of the 99m Tc-MAA pretreatment procedure were immediately available in the interventional suite, enabling 1-day procedures as a result of direct estimation of the hepatic radiation dose and lung shunt fraction. This would, however, require a relatively fast, but still quantitative, SPECT procedure, which might be achieved with acquisition protocols using nonuniform durations of the projection images., Methods: SPECT liver images of the 150-MBq 99m Tc-MAA pretreatment procedure were simulated for eight different lesion locations and two different lesion sizes using the digital XCAT phantom for both single- and dual-head scanning geometries with respective total acquisition times of 1, 2, 5, 10, and 30 min. Three nonuniform projection-time acquisition protocols ("half-circle SPECT (HCS)," "nonuniform SPECT (NUS) I," and "NUS II") for fast quantitative SPECT of the liver were designed and compared with the standard uniform projection-time protocol. Images were evaluated in terms of contrast-to-noise ratio (CNR), activity recovery coefficient (ARC), tumor/non-tumor (T/N) activity concentration ratio, and lung shunt fraction (LSF) estimation. In addition, image quality was verified with a physical phantom experiment, reconstructed with both clinical and Monte Carlo-based reconstruction software., Results: Simulations showed no substantial change in image quality and dosimetry by usage of a nonuniform projection-time acquisition protocol. Upon shortening acquisition times, CNR dropped, but ARC, T/N ratio, and LSF estimates were stable across all simulated acquisition times. Results of the physical phantom were in agreement with those of the simulations., Conclusion: Both uniform and nonuniform projection-time acquisition liver SPECT protocols yield accurate dosimetric metrics for radioembolization treatment planning in the interventional suite within 10 min, without compromising image quality. Consequently, fast quantitative SPECT of the liver in the interventional suite is feasible., (© 2018 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Background: Generation of a SPECT scan during procedure may aid in the optimization of treatments as liver radioembolization by offering image-guided dosimetry. This, however, requires both shortened acquisition times and fast quantitative reconstruction. Focusing collimators increase sensitivity and thus may speed up imaging. Monte Carlo-based iterative reconstruction has shown to provide quantitative results for parallel hole collimators but may be slow. The purpose of this work is to develop fast Monte Carlo-based reconstruction for focusing collimators and to evaluate the impact of reconstruction and collimator choice on quantitative accuracy of liver dosimetry by means of simulations., Results: The developed fast Monte Carlo simulator was found to accurately generate projections compared to a full Monte Carlo simulation, providing projections in several seconds instead of several days. Monte Carlo-based scatter correction was superior to other scatter correction methods in describing recovered activity and reached similar noise levels as dual-energy window scatter correction. Although truncation artifacts were present in the cone beam collimator (50 cm), the region inside the field of view (FOV) could be reconstructed without loss of accuracy. Provided the object to image is inside the FOV, the focusing collimator with 50 cm focal distance could retrieve the same noise levels as a parallel hole collimator in 68% of the total scanning time, the multifocal collimator in 73% of the time, and the 100-cm focal distance collimator in 84% of the time., Conclusion: Focusing collimators combined with Monte Carlo-based reconstruction have the ability to enable quantitative imaging of the FOV in a significantly shorter timeframe. The proposed approach to the forward projector will additionally make it possible to reconstruct within minutes. These are crucial steps in moving toward real-time dosimetry during interventions.

Radioembolization is an established treatment for chemoresistant and unresectable liver cancers. Currently, treatment planning is often based on semi-empirical methods, which yield acceptable toxicity profiles and have enabled the large-scale application in a palliative setting. However, recently, five large randomized controlled trials using resin microspheres failed to demonstrate a significant improvement in either progression-free survival or overall survival in both hepatocellular carcinoma and metastatic colorectal cancer. One reason for this might be that the activity prescription methods used in these studies are suboptimal for many patients.In this review, the current dosimetric methods and their caveats are evaluated. Furthermore, the current state-of-the-art of image-guided dosimetry and advanced radiobiological modeling is reviewed from a physics' perspective. The current literature is explored for the observation of robust dose-response relationships followed by an overview of recent advancements in quantitative image reconstruction in relation to image-guided dosimetry.This review is concluded with a discussion on areas where further research is necessary in order to arrive at a personalized treatment method that provides optimal tumor control and is clinically feasible.

Purpose: Prior to 90 Y radioembolization, a pretreatment procedure is performed, in which 99m Tc-macroaggerated albumin ( 99m Tc-MAA) is administered to estimate the amount of activity shunting to the lungs. A high lung shunt fraction (LSF) may impose lower prescribed treatment activity or even impede treatment. Accurate LSF measurement is therefore important, but is hampered by the use of MAA particles, which differ from 90 Y microspheres. Ideally, 90 Y microspheres would also be used for the pretreatment procedure, but this would require the activity to be lower than an estimated safety threshold of about 100 MBq to avoid unintended radiation damage. However, 90 Y is very challenging to image, especially at low activities (<100 MBq). The purpose of this study was to evaluate the performance of three nuclear imaging techniques in estimating the LSF in a low activity 90 Y pretreatment scan, using an anthropomorphic phantom: (a) positron emission tomography/computed tomography (PET/CT), (b) Bremsstrahlung single photon emission tomography/computed tomography (SPECT/CT), and (c) planar imaging., Methods: The lungs and liver of an anthropomorphic phantom were filled with 90 Y chloride to acquire an LSF of 15%. Several PET/CT (Siemens Biograph mCT), Bremsstrahlung SPECT/CT (Siemens Symbia T16) and planar images (Siemens Symbia T16) were acquired at a range of 90 Y activities (1586 MBq down to 25 MBq). PET images were reconstructed using a clinical protocol (attenuation correction, TOF, scatter and random correction, OP-OSEM), SPECT images were reconstructed using both a clinical protocol (attenuation correction, OSEM) and a Monte Carlo (MC)-based reconstruction method (MC-based detector, scatter, and attenuation modeling, OSEM), for planar images the geometric mean was calculated. In addition, in all cases except clinical SPECT, background correction was included. The LSF was calculated by assessing the reconstructed activity in the lungs and in the liver, as delineated on the CT images. In addition to the 15% LSF, an extra "cold" region was included to simulate an LSF of 0%., Results: PET reconstructions accurately estimated the LSF (absolute difference <2 percent point (pp)) when total activity was over 200 MBq, but greatly overestimated the LSF (up to 25pp) when activity decreased. Bremsstrahlung SPECT clinical reconstructions overestimated the LSF (up to 13pp) when activity was both high and low. Similarly, planar images overestimated the LSF (up to 23pp). MC-based SPECT reconstructions accurately estimated the LSF with an absolute difference of less than 1.3pp for activities as low as 70 MBq., Conclusions: Bremsstrahlung SPECT/CT can accurately estimate the LSF for a 90 Y pretreatment procedure using a theoretically safe 90 Y activity as low as 70 MBq, when reconstructed with an MC-based model., (© 2018 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Purpose: Spectral CT using a dual layer detector offers the possibility of retrospectively introducing spectral information to conventional CT images. In theory, the dual-layer technology should not come with a dose or image quality penalty for conventional images. In this study, we evaluate the influence of a dual-layer detector (IQon Spectral CT, Philips Healthcare) on the image quality of conventional CT images, by comparing these images with those of a conventional but otherwise technically comparable single-layer CT scanner (Brilliance iCT, Philips Healthcare), by means of phantom experiments., Methods: For both CT scanners, conventional CT images were acquired using four adult scanning protocols: (a) body helical, (b) body axial, (c) head helical, and (d) head axial. A CATPHAN 600 phantom was scanned to conduct an assessment of image quality metrics at equivalent (CTDI) dose levels. Noise was characterized by means of noise power spectra (NPS) and standard deviation (SD) of a uniform region, and spatial resolution was evaluated with modulation transfer functions (MTF) of a tungsten wire. In addition, contrast-to-noise ratio (CNR), image uniformity, CT number linearity, slice thickness, slice spacing, and spatial linearity were measured and evaluated. Additional measurements of CNR, resolution and noise were performed in two larger phantoms., Results: The resolution levels at 50%, 10%, and 5% MTF of the iCT and IQon showed small, but significant differences up to 0.25 lp/cm for body scans, and up to 0.2 lp/cm for head scans in favor of the IQon. The iCT and IQon showed perfect CT linearity for body scans, but for head scans both scanners showed an underestimation of the CT numbers of materials with a high opacity. Slice thickness was slightly overestimated for both scanners. Slice spacing was comparable and reconstructed correctly. In addition, spatial linearity was excellent for both scanners, with a maximum error of 0.11 mm. CNR was higher on the IQon compared to the iCT for both normal and larger phantoms with differences up to 0.51. Spatial resolution did not change with phantom size, but noise levels increased significantly. For head scans, IQon had a noise level that was significantly lower than the iCT, on the other hand IQon showed noise levels significantly higher than the iCT for body scans. Still, these differences were well within the specified range of performance of iCT scanners., Conclusions: At equivalent dose levels, this study showed similar quality of conventional images acquired on iCT and IQon for medium-sized phantoms and slightly degraded image quality for (very) large phantoms at lower tube voltages on the IQon. Accordingly, it may be concluded that the introduction of a dual-layer detector neither compromises image quality of conventional images nor increases radiation dose for normal-sized patients, and slightly degrades dose efficiency for large patients at 120 kVp and lower tube voltages., (© 2018 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Background: Neuroendocrine tumours (NET) consist of a heterogeneous group of neoplasms with various organs of origin. At diagnosis 21% of the patients with a Grade 1 NET and 30% with a Grade 2 NET have distant metastases. Treatment with peptide receptor radionuclide therapy (PRRT) shows a high objective response rate and long median survival after treatment. However, complete remission is almost never achieved. The liver is the most commonly affected organ in metastatic disease and is the most incriminating factor for patient survival. Additional treatment of liver disease after PRRT may improve outcome in NET patients. Radioembolization is an established therapy for liver metastasis. To investigate this hypothesis, a phase 2 study was initiated to assess effectiveness and toxicity of holmium-166 radioembolization ( 166 Ho-RE) after PRRT with lutetium-177 ( 177 Lu)-DOTATATE., Methods: The HEPAR PLUS trial ("Holmium Embolization Particles for Arterial Radiotherapy Plus 177 Lu-DOTATATE in Salvage NET patients") is a single centre, interventional, non-randomized, non-comparative, open label study. In this phase 2 study 30-48 patients with > 3 measurable liver metastases according to RECIST 1.1 will receive additional 166 Ho-RE within 20 weeks after the 4th and last cycle of PRRT with 7.4 GBq 177 Lu-DOTATATE. Primary objectives are to assess tumour response, complete and partial response according to RECIST 1.1, and toxicity, based on CTCAE v4.03, 3 months after 166 Ho-RE. Secondary endpoints include biochemical response, quality of life, biodistribution and dosimetry., Discussion: This is the first prospective study to combine PRRT with 177 Lu-DOTATATE and additional 166 Ho-RE in metastatic NET. A radiation boost on intrahepatic disease using 166 Ho-RE may lead to an improved response rate without significant additional side-effects., Trial Registration: Clinicaltrials.gov NCT02067988 , 13 February 2014. Protocol version: 6, 30 november 2016.

Purpose: In intra-arterial hepatic radioembolization using Holmium-166 ( 166 Ho) microspheres, a predicted lung-absorbed dose of more than 30 Gy is a contraindication for therapy. Therefore, scout imaging by means of quantitative SPECT of the lungs after a low-dose pretreatment session is essential. Earlier we showed the superiority of Monte Carlo-based iterative SPECT reconstructions over conventional reconstructions due to its quantitative nature, required for dosimetry, at the cost of substantial computation times. In clinical routine, however, the limited available time between scout imaging and therapy constrains its application. To reduce computation times, we investigated the minimum number of iterations required to guarantee a clinical acceptable accuracy in lung dose estimation using patient and phantom data., Methods: 166 Ho scout SPECT data (range: 222-283 MBq) were used from 10 patients. SPECT images were Monte Carlo-based OSEM reconstructed (effective iterations: 240). Additionally, the 4D XCAT anthropomorphic phantom was used to mimic studies with an injected scout activity of 250 MBq and with varying lung-absorbed doses ranging from 0.9 to 225 Gy for a therapeutic dosage of 15 GBq. These studies were reconstructed in the same way as the patient data, and were also reconstructed using a clinically available, standard OSEM algorithm for comparison. Lung-absorbed dose was determined using VOI analysis as a function of iterations., Results: The estimated lung-absorbed dose in nine patients ranged upon MC-based OSEM convergence from 0 to 0.26 Gy for a therapeutic dosage. One patient had an estimated lung absorbed-dose for a therapeutic dosage of 20.3 Gy upon MC-based OSEM convergence, or 18.4 Gy after 40 iterations (-9%). The phantom data showed that the lung-absorbed dose upon OSEM convergence was underestimated by 15% as compared to the actual simulated lung dose, and the dose after 40 iterations was underestimated by 9% as compared to the dose upon convergence. Both underestimations were irrespective of the magnitude of the lung-absorbed dose (0.9 to 225 Gy) and thus can be easily corrected for. The quantitative accuracy of the MC-based OSEM reconstructions (40 iterations, before convergence) outperformed the clinical OSEM reconstruction while estimating the lung dose., Conclusions: The number of effective iterations necessary for quantitative estimation of the lung dose using MC-based OSEM can be reduced from 240 to 40. The resulting sixfold reduction in calculation time enables processing of the scout images before therapy administration., (© 2018 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

This case report describes a patient who experienced a recurrent ischemic stroke within 24 h. Dual-energy computed tomography (DECT) angiography on admission showed 2 intracardiac thrombi, 1 in the left ventricle and 1 in the left atrial appendage. Following the second ischemic event, repeated DECT angiography showed that the ventricular thrombus had considerably diminished, suggesting that the recurrent brain infarction was caused by cardioembolism. This case emphasizes (1) the potential benefit of cardiac evaluation through CT angiography in the acute stroke setting, and (2) the use of DECT angiography for the detection of thrombus and the differentiation between thrombus, the myocardial wall, and a slow flow of contrast.

Purpose: In breast-conserving surgery (BCS), the cancer is sometimes incompletely excised, leading to reduced patient survival. To pursue complete excisions, radioactive seed localization (RSL) may be used to insert an iodine-125 seed into the tumor. The seed is used as a marker for the location of the tumor during surgery. RSL does not, however, show the extent of the tumor. Based on RSL, we pursue to visualize the seed location together with the extent from diagnostic images., Methods: A system with two gamma-camera heads and two parallel-hole collimators was recently proposed to triangulate the location of an iodine-125 seed during BCS. In the present study, this system was extended with a range camera to visualize a sphere centered on the seed in relation to the breast. This sphere contains the entire tumor and thus defines the target volume for BCS. Physical experiments with acrylic block phantoms (thickness ranging from 3.5 to 6.5 cm) were performed to assess the absolute bias and the precision with which this sphere can be visualized., Results: When a 6.5 cm thick phantom was used, along the horizontal plane, the target volume was visualized with an absolute bias and a precision of 2.1 and 0.8 mm, respectively. Along the vertical axis (i.e., z-axis), these values were 4.2 and 2.8 mm, respectively., Conclusions: The proposed system visualizes the target volume with an absolute bias that may be acceptable for BCS., (© 2018 American Association of Physicists in Medicine.)

In SPECT/CT systems x-ray and γ-ray imaging is performed sequentially. Simultaneous acquisition may have advantages, for instance in interventional settings. However, this may expose a gamma camera to relatively high x-ray doses and deteriorate its functioning. We studied the NaI(Tl) response to x-ray pulses with a photodiode, PMT and gamma camera, respectively. First, we exposed a NaI(Tl)-photodiode assembly to x-ray pulses to investigate potential crystal afterglow. Next, we exposed a NaI(Tl)-PMT assembly to 10 ms LED pulses (mimicking x-ray pulses) and measured the response to flashing LED probe-pulses (mimicking γ-pulses). We then exposed the assembly to x-ray pulses, with detector entrance doses of up to 9 nGy/pulse, and analysed the response for γ-pulse variations. Finally, we studied the response of a Siemens Diacam gamma camera to γ-rays while exposed to x-ray pulses. X-ray exposure of the crystal, read out with a photodiode, revealed 15% afterglow fraction after 3 ms. The NaI(Tl)-PMT assembly showed disturbances up to 10 ms after 10 ms LED exposure. After x-ray exposure however, responses showed elevated baselines, with 60 ms decay-time. Both for x-ray and LED exposure and after baseline subtraction, probe-pulse analysis revealed disturbed pulse height measurements shortly after exposure. X-ray exposure of the Diacam corroborated the elementary experiments. Up to 50 ms after an x-ray pulse, no events are registered, followed by apparent energy elevations up to 100 ms after exposure. Limiting the dose to 0.02 nGy/pulse prevents detrimental effects. Conventional gamma cameras exhibit substantial dead-time and mis-registration of photon energies up to 100 ms after intense x-ray pulses. This is due PMT limitations and due to afterglow in the crystal. Using PMTs with modified circuitry, we show that deteriorative afterglow effects can be reduced without noticeable effects on the PMT performance, up to x-ray pulse doses of 1 nGy.

Background: Limited treatment options exist for patients with locoregional recurrences of head and neck squamous cell carcinoma (HNSCC). In the palliative setting, a single session, minimally invasive, and relatively safe therapy is desirable. This case series illustrates the feasibility of a direct intratumoral injection of radioactive holmium-166 microspheres (HoMS) in patients as a palliative treatment for recurrent HNSCC., Patients and Methods: In this retrospective analysis, patients with already reirradiated irresectable recurrent HNSCC, for whom palliative chemotherapy was unsuccessful or impossible, were offered microbrachytherapy with HoMS. The intratumoral injection was administered manually under ultrasound guidance. Parameters scored were technical feasibility (i.e. administration, leakage, and distribution), clinical response (response evaluation criteria in solid tumors 1.1), and complications (Common Terminology Criteria for Adverse Events 4.3)., Results: From 2015 to 2017, three patients were treated. None of the patients experienced adverse events; however, therapeutic effects were minimal. Technical difficulties, including precipitating of microspheres and high intratumoral pressure, resulted in suboptimal distribution of the microspheres., Conclusion: Intratumoral injections with HoMS are minimally invasive and relatively safe in palliation of HNSCC patients. Careful patient selection and improved administration techniques are required to provide a more effective treatment. Further investigation of this novel treatment modality should be carried out because of the absence of side effects and lack of other treatment options.

Background: Predictors of recurrent ischemic stroke are less well known in patients with a recent ischemic stroke than in patients with transient ischemic attack (TIA). We identified clinical and radiological factors for predicting recurrent ischemic stroke in patients with recent ischemic stroke., Methods: A systematic search in PubMed, Embase, Cochrane Library, and CINAHL was performed with the terms "ischemic stroke," "predictors/determinants," and "recurrence." Quality assessment of the articles was performed and the level of evidence was graded for the articles included for the meta-analysis. Pooled risk ratios (RR) and heterogeneity (I2) were calculated using inverse variance random effects models., Results: Ten articles with high-quality results were identified for meta-analysis. Past medical history of stroke or TIA was a predictor of recurrent ischemic stroke (pooled RR 2.5, 95% CI 2.1-3.1). Small vessel strokes were associated with a lower risk of recurrence than large vessel strokes (pooled RR 0.3, 95% CI 0.1-0.7). Patients with stroke of an undetermined cause had a lower risk of recurrence than patients with large artery atherosclerosis (pooled RR 0.5, 95% CI 0.2-1.1). We found no studies using CT or ultrasound for the prediction of recurrent ischemic stroke. The following MRI findings were predictors of recurrent ischemic stroke: multiple lesions (pooled RR 1.7, 95% CI 1.5-2.0), multiple stage lesions (pooled RR 4.1, 95% CI 3.1-5.5), multiple territory lesions (pooled RR 2.9, 95% CI 2.0-4.2), chronic infarcts (pooled RR 1.5, 95% CI 1.2-1.9), and isolated cortical lesions (pooled RR 2.2, 95% CI 1.5-3.2)., Conclusions: In patients with a recent ischemic stroke, a history of stroke or TIA and the subtype large artery atherosclerosis are associated with an increased risk of recurrent ischemic stroke. Predictors evaluated with MRI include multiple ischemic changes and isolated cortical lesions. Predictors of recurrent ischemic stroke concerning CT or ultrasound have not been published., (© 2018 S. Karger AG, Basel.)

Introduction: Hemorrhagic transformation (HT) in acute ischemic stroke can occur as a result of reperfusion treatment. While withholding treatment may be warranted in patients with increased risk of HT, prediction of HT remains difficult. Nonlinear regression analysis can be used to estimate blood-brain barrier permeability (BBBP). The aim of this study was to identify a combination of clinical and imaging variables, including BBBP estimations, that can predict HT., Materials and Methods: From the Dutch acute stroke study, 545 patients treated with intravenous recombinant tissue plasminogen activator and/or intra-arterial treatment were selected, with available admission extended computed tomography (CT) perfusion and follow-up imaging. Patient admission treatment characteristics and CT imaging parameters regarding occlusion site, stroke severity, and BBBP were recorded. HT was assessed on day 3 follow-up imaging. The association between potential predictors and HT was analyzed using univariate and multivariate logistic regression. To compare the added value of BBBP, areas under the curve (AUCs) were created from 2 models, with and without BBBP., Results: HT occurred in 57 patients (10%). In univariate analysis, older age (OR 1.03, 95% CI 1.006-1.05), higher admission National Institutes of Health Stroke Scale (NIHSS; OR 1.13, 95% CI 1.08-1.18), higher clot burden (OR 1.28, 95% CI 1.16-1.41), poor collateral score (OR 3.49, 95% CI 1.85-6.58), larger Alberta Stroke Program Early CT Score cerebral blood volume deficit size (OR 1.26, 95% CI 1.14-1.38), and increased BBBP (OR 2.22, 95% CI 1.46-3.37) were associated with HT. In multivariate analysis with age and admission NIHSS, the addition of BBBP did not improve the AUC compared to both independent predictors alone (AUC 0.77, 95% CI 0.71-0.83)., Conclusion: BBBP predicts HT but does not improve prediction with age and admission NIHSS., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Internal radiation therapy with radionuclides (i.e., radionuclide therapy) owes its success to the many advantages over other, more conventional, treatment options. One distinct advantage of radionuclide therapies is the potential to use (part of) the emitted radiation for imaging of the radionuclide distribution. The combination of diagnostic and therapeutic properties in a set of matched radiopharmaceuticals (sometimes combined in a single radiopharmaceutical) is often referred to as theranostics and allows accurate diagnostic imaging before therapy. The use of imaging benefits treatment planning, dosimetry, and assessment of treatment response. This paper focuses on a selection of advances in imaging technology relevant for image guidance of radionuclide therapy. This involves developments in nuclear imaging modalities, as well as other anatomic and functional imaging modalities. The quality and quantitative accuracy of images used for guidance of radionuclide therapy is continuously being improved, which in turn may improve the therapeutic outcome and efficiency of radionuclide therapies., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Radioembolisation with yttrium-90 ( 90 Y) is increasingly used as a treatment of unresectable liver malignancies. For safety, a scout dose of technetium-99m macroaggregated albumin ( 99m Tc-MAA) is used prior to the delivery of the therapeutic activity to mimic the deposition of 90 Y. One-day procedures are currently limited by the lack of nuclear images in the intervention room. To cope with this limitation, an interventional simultaneous fluoroscopic and nuclear imaging device is currently being developed. The purpose of this simulation study was to evaluate the accuracy of estimating the lung shunt fraction (LSF) of the scout dose in the intervention room with this device and compare it against current clinical methods., Methods: A male and female XCAT phantom, both with two respiratory profiles, were used to simulate various LSFs resulting from a scout dose of 150 MBq 99m Tc-MAA. Hybrid images were Monte Carlo simulated for breath-hold (5 s) and dynamic breathing (10 frames of 0.5 s) acquisitions. Nuclear images were corrected for attenuation with the fluoroscopic image and for organ overlap effects using a pre-treatment CT-scan. For comparison purposes, planar scintigraphy and mobile gamma camera images (both 300 s acquisition time) were simulated. Estimated LSFs were evaluated for all methods and compared to the phantom ground truth., Results: In the clinically relevant range of 10-20% LSF, hybrid imaging overestimated LSF with approximately 2 percentage points (pp) and 3 pp for the normal and irregular breathing phantoms, respectively. After organ overlap correction, LSF was estimated with a more constant error. Errors in planar scintigraphy and mobile gamma camera imaging were more dependent on LSF, body shape and breathing profile., Conclusion: LSF can be estimated with a constant minor error with a hybrid imaging device. Estimated LSF is highly dependent on true LSF, body shape and breathing pattern when estimated with current clinical methods. The hybrid imaging device is capable of accurately estimating LSF within a few seconds in an interventional setting.

Purpose: Respiratory motion may impose significant inaccuracies on emission activity estimation in quantitative SPECT. This effect may be a major issue in dosimetry as used in the management of liver radioembolization. The purpose of this study was to investigate the impact of respiratory motion on radioembolization liver dosimetry for different SPECT acquisition settings., Methods: In a series of SPECT/CT Monte Carlo simulations using several digital XCAT phantoms, the following parameters were varied: breathing/nonbreathing, liver tumor size (0.3-35 ml) and location, patient properties (body mass index ranging from underweight to obese; male and female), acquisition time (10-30 s/view), collimator setup (High Sensitivity, High Resolution, Ultra High Resolution) and tumor VOI. The effect of applying a respiratory gating scheme was examined as well., Results: Breathing decreased activity recovery and tumor/non-tumor (T/N) ratios on average from 90% to 66%. VOIs based on SPECT images instead of breath-hold CT improved T/N values significantly. The most accurate results were obtained using a gating scheme combined with SPECT-based VOIs. Scan duration, body mass index, sex, and location all had a minor effect. Lung shunt fraction estimations were relatively unaffected by any of the varied parameters., Conclusions: Respiratory motion has a large effect on SPECT activity quantitation of liver tumors as used in radioembolization treatment planning and assessment. As compared with the other parameters that were varied in this study, respiration is the predominant degrading effect on image quantitation. Gating alleviates much of this detrimental effect., (© 2017 American Association of Physicists in Medicine.)

Purpose: The isotope 123 I is commonly labeled with meta-iodobenzylguanidine (mIBG) for imaging of neuroendocrine tumors, such as pheochromocytomas and neuroblastomas. 123 I-mIBG SPECT/CT imaging is performed for staging, follow-up and selection of patients for treatment with 131 I mIBG. As an alternative to 123 I, 124 I-mIBG PET/CT may be used, potentially taking advantage of the superior PET image quality. The purpose of this study was to investigate whether 124 I PET/CT improves image quality as compared with 123 I SPECT/CT for equal patient effective radiation dose (in mSv)., Methods: Phantom measurements were performed using the NEMA-2007 image quality phantom. SPECT and PET reconstruction settings were used with and without time-of-flight (TOF) and point-spread-function (PSF) modeling. As a measure of image quality, the contrast-to-noise ratio (CNR) was calculated. The ratio of the 123 I to 124 I activity concentration was determined at which the contrast-to-noise ratio was equal for both modalities. This metric was defined as the contrast equivalent activity ratio (CEAR)., Results: CEARs of 47.7, 25.6, 23.1, 14.6, 10.0, and 9.1 were obtained for a TOF and PSF modeled 124 I reconstruction method and an attenuation and scatter-corrected 123 I reconstruction method for sphere sizes of 10 to 37 mm, respectively. As the effective radiation dose of 124 I-mIBG is higher than of 123 I-mIBG (in mSv/MBq), an equal effective dose corresponds to a CEAR of 5 to 10. Therefore, CEARs higher than 5 to 10 indicate that 124 I PET/CT outperforms 123 I SPECT/CT in the sense of image quality for equal patient effective radiation dose., Conclusion: The CEAR is much larger than a factor of 5 to 10 (needed for equal patient effective radiation dose) for most of the reconstruction methods and sphere sizes. Therefore, 124 I-mIBG PET/CT is expected to improve image quality and/or may be used to reduce effective patient dose as compared with 123 I-mIBG SPECT/CT., (© 2017 American Association of Physicists in Medicine.)