Sergey Shcherbinin

Accuracy of quantitative reconstructions in SPECT/CT imaging

The goal of this study was to determine the quantitative accuracy of our OSEM-APDI reconstruction method based on SPECT/CT imaging for Tc-99m, In-111, I-123, and I-131 isotopes. Phantom studies were performed on a SPECT/low-dose multislice CT system (Infinia-Hawkeye-4 slice, GE Healthcare) using clinical acquisition protocols. Two radioactive sources were centrally and peripherally placed inside an anthropometric Thorax phantom filled with non-radioactive water. Corrections for attenuation, scatter, collimator blurring and collimator septal penetration were applied and their contribution to the overall accuracy of the reconstruction was evaluated. Reconstruction with the most comprehensive set of corrections resulted in activity estimation with error levels of 3-5% for all the isotopes.

Detection of Alpha-Rod Protein Repeats Using a Neural Network and Application to Huntingtin

A growing number of solved protein structures display an elongated structural domain, denoted here as alpha-rod, composed of stacked pairs of anti-parallel alpha-helices. Alpha-rods are flexible and expose a large surface, which makes them suitable for protein interaction. Although most likely originating by tandem duplication of a two-helix unit, their detection using sequence similarity between repeats is poor. Here, we show that alpha-rod repeats can be detected using a neural network. The network detects more repeats than are identified by domain databases using multiple profiles, with a low level of false positives (<10%). We identify alpha-rod repeats in approximately 0.4% of proteins in eukaryotic genomes. We then investigate the results for all human proteins, identifying alpha-rod repeats for the first time in six protein families, including proteins STAG1-3, SERAC1, and PSMD1-2 & 5. We also characterize a short version of these repeats in eight protein families of Archaeal, Bacterial, and Fungal species. Finally, we demonstrate the utility of these predictions in directing experimental work to demarcate three alpha-rods in huntingtin, a protein mutated in Huntingtons disease. Using yeast two hybrid analysis and an immunoprecipitation technique, we show that the huntingtin fragments containing alpha-rods associate with each other. This is the first definition of domains in huntingtin and the first validation of predicted interactions between fragments of huntingtin, which sets up directions toward functional characterization of this protein. An implementation of the repeat detection algorithm is available as a Web server with a simple graphical output: http://www.ogic.ca/projects/ard. This can be further visualized using BiasViz, a graphic tool for representation of multiple sequence alignments.

Patient-Specific Radiation Dosimetry of 99mTc-HYNIC-Tyr3-Octreotide in Neuroendocrine Tumors

99mTc-hydrazinonicotinamide-Tyr3-octreotide (99mTc-HYNIC-TOC) is increasingly gaining acceptance as a new radiopharmaceutical for the diagnosis of pathologic lesions overexpressing somatostatin receptors. However, little information has been published about the radiation dosimetry of this agent. The aim of this study was to assess the biodistribution and radiation dosimetry of commercially available 99mTc-HYNIC-TOC. A dose calculation procedure designed to be feasible to implement in a busy clinical environment was used. Methods: Twenty-eight patients were imaged for suspected neuroendocrine tumors using a series of whole-body planar, dynamic planar, and SPECT/CT studies, after injection with 99mTc-HYNIC-TOC. Patient-specific dosimetry was performed using the OLINDA/EXM software with time-integrated activity coefficients estimated from a hybrid planar/SPECT technique. A phantom experiment was performed to establish adaptive thresholds for determination of source region volumes and activities. Results: Pathologic uptake, diagnosed as due to neuroendocrine tumors, was observed in 12 patients. Normal organs with significant uptake included the kidneys, liver, and spleen. The mean effective dose after 99mTc-HYNIC-TOC injection was 4.6 ± 1.1 mSv. Average normal-organ doses were 0.030 ± 0.012, 0.021 ± 0.007, and 0.012 ± 0.005 mGy/MBq for the spleen, kidneys, and liver, respectively. The interpatient kidney dose ranged from 0.011 to 0.039 mGy/MBq, whereas the range of tumor doses varied from 0.003 to 0.053 mGy/MBq. The ratio of tumor to kidney dose ranged from 0.13 to 2.9. The optimal thresholds for recovery of true activity in the phantom study were significantly lower than those used for volume determination. Conclusion: The patient-specific 3-dimensional dosimetry protocol used in this study is a clinically feasible technique that has been applied to demonstrate large dose variations in tumors and normal organs between patients imaged with 99mTc-HYNIC-TOC.

Assessment of the severity of partial volume effects and the performance of two template-based correction methods in a SPECT/CT phantom experiment

We investigated the severity of partial volume effects (PVE), which may occur in SPECT/CT studies, and the performance of two template-based correction techniques. A hybrid SPECT/CT system was used to scan a thorax phantom that included lungs, a heart insert and six cylindrical containers of different sizes and activity concentrations. This phantom configuration allowed us to have non-uniform background activity and a combination of spill-in and spill-out effects for several compartments. The reconstruction with corrections for attenuation, scatter and resolution loss but not PVE correction accurately recovered absolute activities in large organs. However, the activities inside segmented 17-120 mL containers were underestimated by 20%-40%. After applying our PVE correction to the data pertaining to six small containers, the accuracy of the recovered total activity improved with errors ranging between 3% and 22% (non-iterative method) and between 5% and 15% (method with an iteratively updated background activity). While the non-iterative template-based algorithm demonstrated slightly better accuracy for cases with less severe PVE than the iterative algorithm, it underperformed in situations with considerable spill out and/or mixture of spill-in and spill-out effects.

An enhancement of quantitative accuracy of the SPECT/CT activity distribution reconstructions: Physical phantom experiments

For many clinical SPECT studies, it is important to know not only the total activity in an organ of interest, but also the details regarding the activity distribution. In our approach, the anatomical information significantly contributes to improve reconstructed images through CT-based attenuation, scatter, and voxelized partial volume effect corrections. Our method uses the low dose CT image of each particular organ or object (e.g., tumor) to create an object-specific numeric template. Assuming that the sequential projection and reconstruction of this template result in a similar deterioration as in the real image, the template information is being used to correct this image on a voxel-by-voxel basis. In our phantom experiments using clinical camera and protocols, we recovered total activities with errors less than approximately 6% for 33ml tumor models and approximately 9% for 120ml heart insert.

Functional and Genomic Analyses of Alpha-Solenoid Proteins

Alpha-solenoids are flexible protein structural domains formed by ensembles of alpha-helical repeats (Armadillo and HEAT repeats among others). While homology can be used to detect many of these repeats, some alpha-solenoids have very little sequence homology to proteins of known structure and we expect that many remain undetected. We previously developed a method for detection of alpha-helical repeats based on a neural network trained on a dataset of protein structures. Here we improved the detection algorithm and updated the training dataset using recently solved structures of alpha-solenoids. Unexpectedly, we identified occurrences of alpha-solenoids in solved protein structures that escaped attention, for example within the core of the catalytic subunit of PI3KC. Our results expand the current set of known alpha-solenoids. Application of our tool to the protein universe allowed us to detect their significant enrichment in proteins interacting with many proteins, confirming that alpha-solenoids are generally involved in protein-protein interactions. We then studied the taxonomic distribution of alpha-solenoids to discuss an evolutionary scenario for the emergence of this type of domain, speculating that alpha-solenoids have emerged in multiple taxa in independent events by convergent evolution. We observe a higher rate of alpha-solenoids in eukaryotic genomes and in some prokaryotic families, such as Cyanobacteria and Planctomycetes, which could be associated to increased cellular complexity. The method is available at http://cbdm.mdc-berlin.de/~ard2/.

Quantitative SPECT/CT reconstruction for 177Lu and 177Lu/90Y targeted radionuclide therapies

We investigated the quantitative accuracy of SPECT/CT imaging studies as would be performed before and after targeted radionuclide therapy (TRT) using phantom experiments with (i) (99m)Tc, (ii) ¹⁷⁷Lu and (iii) ⁹⁰Y/¹⁷⁷Lu. While the experiment with (99m)Tc imitated a diagnostic scan, the experiments with ¹⁷⁷Lu and ⁹⁰Y/¹⁷⁷Lu modeled post-therapy acquisitions. At the next stage, we reconstructed images from pre- and post-therapy patient studies. The data were first reconstructed using two methods with limited corrections for the physics effects. Then, to generate quantitatively accurate absolute activity distributions, we applied a hybrid (model-based and window-based) reconstruction strategy where some of the physics effects were accurately modeled while corrections for other effects were empirical and based on information obtained from the projection data. The accuracies of absolute activity recovered by the hybrid method from the six phantom experiments were very similar to each other and acceptable for potential use in TRT. When measured in identical regions of interest, the (99m)Tc ⁹⁰activity was reconstructed with errors ranging between -3.3% and 2.9%, while the ¹⁷⁷Lu activity was reconstructed from experiments with ¹⁷⁷Lu and Y/¹⁷⁷Lu with errors ranging between -1.6% and 1.6%. The reconstruction algorithms with limited corrections led to larger and case-specific errors as might have been expected. From a clinical prospective, our results showed that physics-based reconstructions improved resolution of images corresponding to both diagnostic scans with (99m)Tc and post-therapy scans with ¹⁷⁷Lu. Our analysis of patient study demonstrated that lack of corrections led to overestimation of activities in organs and tumor by 29-39% for the diagnostic scan with (99m)Tc and by 105-218% for post-therapy scan with ¹⁷⁷Lu.

The accuracy and reproducibility of SPECT target volumes and activities estimated using an iterative adaptive thresholding technique.

Objective Our aim was to design a practical and reproducible image segmentation method for calculations of total absorbed doses in organs and tumours for internally delivered radioisotopes. We have built upon our previously proposed use of two separate thresholds and employed an iterative technique for semiautomatic selection of background regions for segmenting an object of interest using thresholds that depend on the source-to-background ratio of activity concentrations. Methods The parameters of curves relating volume and activity thresholds to source-to-background ratio were established using phantoms with 20 different inserts. The accuracy of our technique was validated using a second phantom experiment, whereas the reproducibility of volume, activity and dose estimates of organs and tumours was investigated using 13 patient studies. The accuracy and reproducibility of segmentations achieved were assessed using images reconstructed with three different methods that ranged from a standard clinical reconstruction to an advanced quantitative reconstruction approach. Results In the validation phantom experiment, bottle volumes and activities measured using iterative adaptive thresholding agreed on average with the true values to within 4%, regardless of the reconstruction method used. In the patient studies, volumes and activities estimated from the single-photon emission computed tomography images reconstructed with clinical software agreed with the volumes and activities estimated using the advanced reconstruction approach to within 6%, whereas the corresponding doses agreed to within 4%. Conclusion The proposed iterative adaptive thresholding technique can accurately determine object volume and activity, which allows standard clinical reconstructions to generate absorbed dose estimates that are similar to those values obtained using more advanced reconstruction methods.

Complexity and accuracy of image registration methods in SPECT-guided radiation therapy.

The use of functional imaging in radiotherapy treatment (RT) planning requires accurate co-registration of functional imaging scans to CT scans. We evaluated six methods of image registration for use in SPECT-guided radiotherapy treatment planning. Methods varied in complexity from 3D affine transform based on control points to diffeomorphic demons and level set non-rigid registration. Ten lung cancer patients underwent perfusion SPECT-scans prior to their radiotherapy. CT images from a hybrid SPECT/CT scanner were registered to a planning CT, and then the same transformation was applied to the SPECT images. According to registration evaluation measures computed based on the intensity difference between the registered CT images or based on target registration error, non-rigid registrations provided a higher degree of accuracy than rigid methods. However, due to the irregularities in some of the obtained deformation fields, warping the SPECT using these fields may result in unacceptable changes to the SPECT intensity distribution that would preclude use in RT planning. Moreover, the differences between intensity histograms in the original and registered SPECT image sets were the largest for diffeomorphic demons and level set methods. In conclusion, the use of intensity-based validation measures alone is not sufficient for SPECT/CT registration for RTTP. It was also found that the proper evaluation of image registration requires the use of several accuracy metrics.

An innovative iterative thresholding algorithm for tumour segmentation and volumetric quantification on SPECT images: Monte Carlo-based methodology and validation

PURPOSE Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging play an important role in the segmentation of functioning parts of organs or tumours, but an accurate and reproducible delineation is still a challenging task. In this work, an innovative iterative thresholding method for tumour segmentation has been proposed and implemented for a SPECT system. This method, which is based on experimental threshold-volume calibrations, implements also the recovery coefficients (RC) of the imaging system, so it has been called recovering iterative thresholding method (RIThM). The possibility to employ Monte Carlo (MC) simulations for system calibration was also investigated. METHODS The RIThM is an iterative algorithm coded using MATLAB: after an initial rough estimate of the volume of interest, the following calculations are repeated: (i) the corresponding source-to-background ratio (SBR) is measured and corrected by means of the RC curve; (ii) the threshold corresponding to the amended SBR value and the volume estimate is then found using threshold-volume data; (iii) new volume estimate is obtained by image thresholding. The process goes on until convergence. The RIThM was implemented for an Infinia Hawkeye 4 (GE Healthcare) SPECT/CT system, using a Jaszczak phantom and several test objects. Two MC codes were tested to simulate the calibration images: SIMIND and SimSet. For validation, test images consisting of hot spheres and some anatomical structures of the Zubal head phantom were simulated with SIMIND code. Additional test objects (flasks and vials) were also imaged experimentally. Finally, the RIThM was applied to evaluate three cases of brain metastases and two cases of high grade gliomas. RESULTS Comparing experimental thresholds and those obtained by MC simulations, a maximum difference of about 4% was found, within the errors (+/- 2% and +/- 5%, for volumes > or = 5 ml or < 5 ml, respectively). Also for the RC data, the comparison showed differences (up to 8%) within the assigned error (+/- 6%). ANOVA test demonstrated that the calibration results (in terms of thresholds or RCs at various volumes) obtained by MC simulations were indistinguishable from those obtained experimentally. The accuracy in volume determination for the simulated hot spheres was between -9% and 15% in the range 4-270 ml, whereas for volumes less than 4 ml (in the range 1-3 ml) the difference increased abruptly reaching values greater than 100%. For the Zubal head phantom, errors ranged between 9% and 18%. For the experimental test images, the accuracy level was within +/- 10%, for volumes in the range 20-110 ml. The preliminary test of application on patients evidenced the suitability of the method in a clinical setting. CONCLUSIONS The MC-guided delineation of tumor volume may reduce the acquisition time required for the experimental calibration. Analysis of images of several simulated and experimental test objects, Zubal head phantom and clinical cases demonstrated the robustness, suitability, accuracy, and speed of the proposed method. Nevertheless, studies concerning tumors of irregular shape and/or nonuniform distribution of the background activity are still in progress.