Guozhi Zhang

Sequential Systemic Administrations of Combretastatin A4 Phosphate and Radioiodinated Hypericin Exert Synergistic Targeted Theranostic Effects with Prolonged Survival on SCID Mice Carrying Bifocal Tumor Xenografts

Objectives: Based on the soil-to-seeds principle, we explored the small-molecular sequential dual-targeting theranostic strategy (SMSDTTS) for prolonged survival and imaging detectability in a xenograft tumor model. Materials and Methods: Thirty severe combined immunodeficiency (SCID) mice bearing bilateral radiation-induced fibrosarcoma-1 (RIF-1) subcutaneously were divided into group A of SMSDTTS with sequential intravenous injections of combretastatin A4 phosphate (CA4P) and 131I-iodohypericin (131I-Hyp) at a 24 h interval; group B of single targeting control with CA4P and vehicle of 131I-Hyp; and group C of vehicle control (10 mice per group). Tumoricidal events were monitored by in vivo magnetic resonance imaging (MRI) and planar gamma scintiscan, and validated by ex vivo autoradiography and histopathology. Besides, 9 mice received sequential intravenous injections of CA4P and 131I-Hyp were subjected to biodistribution analysis at 24, 72 and 120 h. Results: Gamma counting revealed fast clearance of 131I-Hyp from normal organs but intense accumulation in necrotic tumor over 120 h. After only one treatment, significantly prolonged survival (p<0.001) was found in group A compared to group B and C with median survival of 33, 22, and 21 days respectively. Tumor volume on day 15 was 2.0 ± 0.89, 5.66 ± 1.66, and 5.02 ± 1.0 cm3 with tumor doubling time 7.8 ± 2.8, 4.4 ± 0.67, and 4.5 ± 0.5 days respectively. SMSDTTS treated tumors were visualized as hot spots on gamma scintiscans, and necrosis over tumor ratio remained consistently high on MRI, autoradiography and histology. Conclusion: The synergistic antitumor effects, multifocal targetability, simultaneous theranostic property, and good tolerance of the SMSDTTS were evident in this experiment, which warrants further development for preclinical and clinical applications.

Simulation of 3D objects into breast tomosynthesis images.

Digital breast tomosynthesis is a new three-dimensional (3D) breast-imaging modality that produces images of cross-sectional planes parallel to the detector plane from a limited number of X-ray projections over a limited angular range. Several technical and clinical parameters have not yet been completely optimised. Some of the open questions could be addressed experimentally; other parameter settings cannot be easily realised in practice and the associated optimisation process requires therefore a theoretical approach. Rather than simulating the complete 3D imaging chain, it is hypothesised that the simulation of small lesions into clinical (or test object) images can be of help in the optimisation process. In the present study, small 3D objects have been simulated into real projection images. Subsequently, these hybrid projection images are reconstructed using the routine clinical reconstruction tools. In this study, the validation of this simulation framework is reported through the comparison between simulated and real objects in reconstructed planes. The results confirm that there is no statistically significant difference between the simulated and the real objects. This suggests that other small mathematical or physiological objects could be simulated with the same approach.

Segmentation of Trabecular Jaw Bone on Cone Beam CT Datasets.

BACKGROUND The term bone quality is often used in a dentomaxillofacial context, for example in implant planning, as bone density and bone structure have been linked to primary implant success. PURPOSE This research aimed to investigate the performance of adaptive thresholding of trabecular bone in cone beam CT (CBCT) images. The segmentation quality was assessed for different imaging devices and upper and lower jaws. MATERIALS AND METHODS Four jaws were scanned with eight CBCT scanners and one micro-CT device. Images of the jaws were spatially aligned with the micro-CT images. Two volumes of interest for each jaw were manually delineated. Trabecular bone in the volumes of interest in the micro-CT images was segmented so that the micro-CT images could serve as high-resolution ground truth images. The volumes of interest in the CBCT images were segmented using both global and adaptive thresholding. RESULTS Segmentation was significantly better for the lower jaw than for the upper jaw. Differences in performance between the scanners were significant for both jaws. Adaptive thresholding performed significantly better in segmenting the bone structure out of CBCT images. CONCLUSIONS When assessing jaw bone structure, the observer should always choose adaptive thresholding. It remains a challenge to identify the optimal threshold selection for the structural assessment of jaw bone.

Design and application of a structured phantom for detection performance comparison between breast tomosynthesis and digital mammography.

This paper introduces and applies a structured phantom with inserted target objects for the comparison of detection performance of digital breast tomosynthesis (DBT) against 2D full field digital mammography (FFDM). The phantom consists of a 48 mm thick breast-shaped polymethyl methacrylate (PMMA) container filled with water and PMMA spheres of different diameters. Three-dimensionally (3D) printed spiculated masses (diameter range: 3.8-9.7 mm) and non-spiculated masses (1.6-6.2 mm) along with microcalcifications (90-250 µm) were inserted as targets. Reproducibility of the phantom application was studied on a single system using 30 acquisitions. Next, the phantom was evaluated on five different combined FFDM & DBT systems and target detection was compared for FFDM and DBT modes. Ten phantom images in both FFDM and DBT modes were acquired on these 5 systems using automatic exposure control. Five readers evaluated target detectability. Images were read with the four-alternative forced-choice (4-AFC) paradigm, with always one segment including a target and 3 normal background segments. The percentage of correct responses (PC) was assessed based on 10 trials of each reader for each object type, size and imaging modality. Additionally, detection threshold diameters at 62.5 PC were assessed via non-linear regression fitting of the psychometric curve. The reproducibility study showed no significant differences in PC values. Evaluation of target detection in FFDM showed that microcalcification detection thresholds ranged between 110 and 118 µm and were similar compared to the detection in DBT (range of 106-158 µm). In DBT, detection of both mass types increased significantly (p  =  0.0001 and p  =  0.0002 for non-spiculated and spiculated masses respectively) compared to FFDM, achieving almost 100% detection for all spiculated mass diameters. In conclusion, a structured phantom with inserted targets was able to show evidence for detectability differences between FFDM and DBT modes for five commercial systems. This phantom has potential for application in task-based assessment at acceptance and commissioning testing of DBT systems.This paper introduces and applies a structured phantom with target objects for the comparison of detection performance of digital breast tomosynthesis (DBT) against full field digital mammography (FFDM). The phantom consists of a 48 mm thick breast-shaped polymethyl methacrylate (PMMA) container filled with water and PMMA spheres of different diameters. Three-dimensionally (3D) printed spiculated masses (diameter range: 3.8-9.7 mm) and non-spiculated masses (1.6-6.2 mm) along with microcalcifications (90-250 µm) were inserted as targets. Reproducibility of the phantom application was studied on a single system using 30 acquisitions. Next, the phantom was evaluated on five different combined FFDM & DBT systems and target detection was compared for FFDM and DBT modes. Ten phantom images in both FFDM and DBT modes were acquired on these 5 systems using automatic exposure control (AEC). Five readers evaluated target detectability. Images were read with the four-alternative forced-choice (4-AFC) paradigm, with always one segment including a target and 3 normal background segments. The percentage of correct responses (PC) was assessed based on 10 trials of each reader for each object type, size and modality. Additionally, detection threshold diameters at 62.5 PC were assessed via non-linear regression fitting of the psychometric curve. The reproducibility study showed no significant differences in PC values. Evaluation of target detection in FFDM showed that microcalcification detection thresholds ranged between 110 and 118 µm and were similar compared to the detection in DBT (range of 106-158 µm). In DBT, detection of both mass types increased significantly (p=0.0001 and p=0.0002 for non-spiculated and spiculated masses respectively) compared to FFDM, achieving almost 100% detection for all spiculated mass diameters. In conclusion, a structured phantom with inserted targets was able to show evidence for detectability differences between FFDM and DBT modes for five commercial systems. This phantom has potential for application in task-based assessment at acceptance and commissioning testing of DBT systems.

Two examples of indication specific radiation dose calculations in dental CBCT and Multidetector CT scanners

PURPOSE To calculate organ doses and estimate the effective dose for justification purposes in patients undergoing orthognathic treatment planning purposes and temporal bone imaging in dental cone beam CT (CBCT) and Multidetector CT (MDCT) scanners. METHODS The radiation dose to the ICRP reference male voxel phantom was calculated for dedicated orthognathic treatment planning acquisitions via Monte Carlo simulations in two dental CBCT scanners, Promax 3D Max (Planmeca, FI) and NewTom VGi evo (QR s.r.l, IT) and in Somatom Definition Flash (Siemens, DE) MDCT scanner. For temporal bone imaging, radiation doses were calculated via MC simulations for a CBCT protocol in NewTom 5G (QR s.r.l, IT) and with the use of a software tool (CT-expo) for Somatom Force (Siemens, DE). All procedures had been optimized at the acceptance tests of the devices. RESULTS For orthognathic protocols, dental CBCT scanners deliver lower doses compared to MDCT scanners. The estimated effective dose (ED) was 0.32mSv for a normal resolution operation mode in Promax 3D Max, 0.27mSv in VGi-evo and 1.18mSv in the Somatom Definition Flash. For temporal bone protocols, the Somatom Force resulted in an estimated ED of 0.28mSv while for NewTom 5G the ED was 0.31 and 0.22mSv for monolateral and bilateral imaging respectively. CONCLUSIONS Two clinical exams which are carried out with both a CBCT or a MDCT scanner were compared in terms of radiation dose. Dental CBCT scanners deliver lower doses for orthognathic patients whereas for temporal bone procedures the doses were similar.

Comparing different methods for estimating radiation dose to the conceptus

AbstractPurposeTo compare different methods available in the literature for estimating radiation dose to the conceptus (Dconceptus) against a patient-specific Monte Carlo (MC) simulation and a commercial software package (CSP).MethodEight voxel models from abdominopelvic CT exams of pregnant patients were generated. Dconceptus was calculated with an MC framework including patient-specific longitudinal tube current modulation (TCM). For the same patients, dose to the uterus, Duterus, was calculated as an alternative for Dconceptus, with a CSP that uses a standard-size, non-pregnant phantom and a generic TCM curve. The percentage error between Duterus and Dconceptus was studied. Dose to the conceptus and percent error with respect to Dconceptus was also estimated for three methods in the literature.ResultsThe percentage error ranged from -15.9% to 40.0% when comparing MC to CSP. When comparing the TCM profiles with the generic TCM profile from the CSP, differences were observed due to patient habitus and conceptus position. For the other methods, the percentage error ranged from -30.1% to 13.5% but applicability was limited.ConclusionsEstimating an accurate Dconceptus requires a patient-specific approach that the CSP investigated cannot provide. Available methods in the literature can provide a better estimation if applicable to patient-specific cases.Key Points• A patient’s internal anatomy affects the dose to the conceptus. • Conceptus position has an influence on its dose estimation. • Patient anatomy and specific TCM must be considered for accurate conceptus dosimetry. • Duterusto a standard-size phantom should not be used as Dconceptus.

Implementing the complete beam hardening effect of the bowtie filter versus scaling beam intensities: effects on dosimetric applications in computed tomography

Abstract. The bowtie filter is an essential element of computed tomography scanners. Implementation of this filter in a Monte Carlo dosimetry platform can be based on Turner’s method, which describes how to measure the filter thickness and relate the x-ray beam as a function of bowtie angle to the central beam. In that application, the beam hardening is accounted for by means of weighting factors that are associated to the photons according to their position (fan angle) and energy. We assessed an alternative approximation in which the photon spectrum is given a fan angle-dependent scaling factor. The aim of our investigation was to evaluate the effects on dose accuracy estimation when using the gold standard bowtie filter method versus a beam scaling approximation method. In particular, we wanted to assess the percentage dose differences between the two methods for several water thicknesses representative for different patients of different body mass index. The largest percentage differences were found for the thickest part of the bowtie filter and increased with patient size.

A single-dose toxicity study on non-radioactive iodinated hypericin for a targeted anticancer therapy in mice.

Aim:Hypericin (Hyp) and its radio-derivatives have been investigated in animal models with ischemic heart diseases and malignancies for diagnostic and therapeutic purposes. Before radioiodinated Hyp (123I-Hyp or 131I-Hyp) can be considered as a clinically useful drug, vigorous evaluations on its chemotoxicity are necessary. In the present study, we examined the toxicity of a single dose of non-radioactive 127I-Hyp in normal mice for 24 h and 14 d.Methods:Studies were performed on 132 normal mice. 127I -Hyp at a clinically relevant dose of 0.1 mg/kg body weight and a 100-times higher dose of 10 mg/kg was intravenously injected into 40 mice. The safety aspects of clinical manifestations, serological biochemistry, and histopathology were assessed. In another 72 mice, 127I-Hyp was administered intravenously at assumed values to bracket the value of LD50. The rest 20 mice were used in the control groups.Results:At 24 h and 14 d following the injection of 127I -Hyp at either 0.1 or 10 mg/kg, all mice tolerated well without mortality or any observable treatment-related symptoms. No significant differences were found in blood biochemical parameters between the test and control groups. All organs presented normal appearances upon histopathological inspection. The value of LD50 of 127I-Hyp in mice through intravenous injection was 20.26 mg/kg, with the 95% confidence interval between 18.90 and 21.55 mg/kg.Conclusion:The current study reveals a broad safety range of 127I-Hyp, which not only supports the use of 123I-Hyp or 131I-Hyp in the necrosis targeting theragnostic strategy, but also serves as a valuable reference for exploring other possible applications for iodinated Hyp.

Software framework for simulating clusters of microcalcifications in digital mammography

Observer performance experiments for lesion detection are an accepted means of assessing the imaging performance of radiological imaging systems Simulation methods for clusters of microcalcifications have been proposed for creating images with abnormal pathology for its use in such experiments We report on a software tool that can generate simulated clusters of microcalcifications for different exposure parameters and different digital mammography systems The effect of the simulation steps on microcalcification templates, (namely exposure settings, breast thickness, modulation transfer function (MTF) and pixel size) is demonstrated and validated Results were evaluated in terms of the clusters peak contrast (PC) for three cases: for different exposure conditions within a given system, for different systems and for different system MTF calculation methods As expected, with higher tube voltage and for insertion into thicker breast simulating material, the lesion contrast decreases while the position of the peak remains unchanged When different systems are considered with the same exposure settings, the observed difference in the PCs is related to the blurring due to the different MTF and the pixel size of the systems; a shift in the peak position is also observed, due to resampling This functional and user-friendly system could be used by other researchers for performing comparative studies of mammographic imaging systems.

A model-based volume restoration approach for Monte Carlo scatter correction in image reconstruction of cone beam CT with limited field of view

Scatter remains a major cause of image artifacts in cone beam CT (CBCT). To correct the scatter for improved image reconstruction, the Monte Carlo simulation technique has been useful in estimating the scatter distribution. This technique, however, requires a 3D computational phantom of the patient, which is typically obtained from the reconstructed 3D image and is not fully available for CBCT scans with limited field of view. This study proposes a novel approach to restore the volume of the patient in such cases by use of a standard patient model and image registration techniques. As demonstrated for the 6 x 6 em oral CBCT scan, a full-field image of the model could be registered to the truncated patient image and was then successfully imported to Monte Carlo simulation for scatter estimation. Scatter correction was achieved by subtracting the Monte Carlo scatter data from the raw data on a projection-by-projection basis. Compared to the original data, the reconstructed image with scatter correction showed reduced streak artifacts and an improved contrast resolution of up to 15% between the soft and bony tissue. This approach exploits the low-frequency characteristic of the scatter distribution. The procedure could use more suitable models, and it could in a next step be further automated. It would then be an interesting candidate to improve image quality in practice.