IMPROVEMENTS OF 111IN SPECT IMAGES RECONSTRUCTED WITH SPARSELY ACQUIRED PROJECTIONS BY DEEP LEARNING GENERATED SYNTHETIC PROJECTIONS.

The aim was to improve single-photon emission computed tomography (SPECT) quality for sparsely acquired 111In projections by adding deep learning generated synthetic intermediate projections (SIPs). Method: The recently constructed deep convolutional network for generating synthetic intermediate projections (CUSIP) was used for improving 20 sparsely acquired 111In-octreotide SPECTs. Reconstruction was performed with 120 (120P) or 30 (30P) projections, or 120 projections with 90 SIPs generated from 30 projections (30-120SIP). The SPECT reconstructions were performed with attenuation, scatter and collimator response corrections. Postfiltered 30P reconstructed SPECT was also analyzed. Image quality were quantitatively evaluated with root-mean-square error, peak signal-to-noise ratio and structural similarity index metrics. Result: The 30-120SIP reconstructed SPECT had statistically significant improved image quality parameters compared to 30P reconstructed SPECT with and without post filtering. The images visual appearance was similar to slightly filtered 120P SPECTs. Thereby, substantial acquisition time reduction with SIPs seems possible without image quality degradation.

Establishment of a clinical SPECT/CT protocol for imaging of 161Tb.

BACKGROUND: It has been proposed, and preclinically demonstrated, that 161Tb is a better alternative to 177Lu for the treatment of small prostate cancer lesions due to its high emission of low-energy electrons. 161Tb also emits photons suitable for single-photon emission computed tomography (SPECT) imaging. This study aims to establish a SPECT protocol for 161Tb imaging in the clinic. MATERIALS AND METHODS: Optimal settings using various γ-camera collimators and energy windows were explored by imaging a Jaszczak phantom, including hollow-sphere inserts, filled with 161Tb. The collimators examined were extended low-energy general purpose (ELEGP), medium-energy general purpose (MEGP), and low-energy high resolution (LEHR), respectively. In addition, three ordered subset expectation maximization (OSEM) algorithms were investigated: attenuation-corrected OSEM (A-OSEM); attenuation and dual- or triple-energy window scatter-corrected OSEM (AS-OSEM); and attenuation, scatter, and collimator-detector response-corrected OSEM (ASC-OSEM), where the latter utilized Monte Carlo-based reconstruction. Uniformity corrections, using intrinsic and extrinsic correction maps, were also investigated. Image quality was assessed by estimated recovery coefficients (RC), noise, and signal-to-noise ratio (SNR). Sensitivity was determined using a circular flat phantom. RESULTS: The best RC and SNR were obtained at an energy window between 67.1 and 82.1 keV. Ring artifacts, caused by non-uniformity, were removed with extrinsic uniformity correction for the energy window between 67.1 and 82.1 keV, but not with intrinsic correction. Analyzing the lower energy window between 48.9 and 62.9 keV, the ring artifacts remained after uniformity corrections. The recovery was similar for the different collimators when using a specific OSEM reconstruction. Recovery and SNR were highest for ASC-OSEM, followed by AS-OSEM and A-OSEM. When using the optimized parameter setting, the resolution of 161Tb was higher than for 177Lu (8.4 ± 0.7 vs. 10.4 ± 0.6 mm, respectively). The sensitivities for 161Tb and 177Lu were 7.41 and 8.46 cps/MBq, respectively. CONCLUSION: SPECT with high resolution is feasible with 161Tb; however, extrinsic uniformity correction is recommended to avoid ring artifacts. The LEHR collimator was the best choice of the three tested to obtain a high-resolution image. Due to the complex emission spectrum of low-energy photons, window-based scatter correction had a minor impact on the image quality compared to using attenuation correction only. On the other hand, performing attenuation, scatter, and collimator-detector correction clearly improved image quality. Based on these data, SPECT-based dosimetry for 161Tb-labeled radiopharmaceuticals is feasible.

Fast GPU-based Monte Carlo code for SPECT/CT reconstructions generates improved 177Lu images.

BACKGROUND: Full Monte Carlo (MC)-based SPECT reconstructions have a strong potential for correcting for image degrading factors, but the reconstruction times are long. The objective of this study was to develop a highly parallel Monte Carlo code for fast, ordered subset expectation maximum (OSEM) reconstructions of SPECT/CT images. The MC code was written in the Compute Unified Device Architecture language for a computer with four graphics processing units (GPUs) (GeForce GTX Titan X, Nvidia, USA). This enabled simulations of parallel photon emissions from the voxels matrix (1283 or 2563). Each computed tomography (CT) number was converted to attenuation coefficients for photo absorption, coherent scattering, and incoherent scattering. For photon scattering, the deflection angle was determined by the differential scattering cross sections. An angular response function was developed and used to model the accepted angles for photon interaction with the crystal, and a detector scattering kernel was used for modeling the photon scattering in the detector. Predefined energy and spatial resolution kernels for the crystal were used. The MC code was implemented in the OSEM reconstruction of clinical and phantom 177Lu SPECT/CT images. The Jaszczak image quality phantom was used to evaluate the performance of the MC reconstruction in comparison with attenuated corrected (AC) OSEM reconstructions and attenuated corrected OSEM reconstructions with resolution recovery corrections (RRC). RESULT: The performance of the MC code was 3200 million photons/s. The required number of photons emitted per voxel to obtain a sufficiently low noise level in the simulated image was 200 for a 1283 voxel matrix. With this number of emitted photons/voxel, the MC-based OSEM reconstruction with ten subsets was performed within 20 s/iteration. The images converged after around six iterations. Therefore, the reconstruction time was around 3 min. The activity recovery for the spheres in the Jaszczak phantom was clearly improved with MC-based OSEM reconstruction, e.g., the activity recovery was 88% for the largest sphere, while it was 66% for AC-OSEM and 79% for RRC-OSEM. CONCLUSION: The GPU-based MC code generated an MC-based SPECT/CT reconstruction within a few minutes, and reconstructed patient images of 177Lu-DOTATATE treatments revealed clearly improved resolution and contrast.

The importance of grade 2 ischemic mitral regurgitation in coronary artery bypass grafting.

OBJECTIVE: To study if grade 2 ischemic mitral regurgitation (MR) influences outcome after coronary artery bypass grafting (CABG). METHODS: Results of all CABG patients with grade 2/4 ischemic MR operated during 1995--1998 (n = 89) were compared with all CABG patients without MR (n = 4709) during the same period. To further evaluate patients with grade 2 ischemic MR, a case-control study focusing on functional status was performed. Control patients without MR (n = 89) were matched for age, gender and left ventricular ejection fraction. All patients were interviewed regarding angina symptoms and functional status. RESULTS: Survival according to Kaplan--Meier at 1 and 3 years were inferior in the MR group compared to all CABG patients (91 vs 96% and 84 vs 92%, respectively (P = 0.0017). However, MR patients were older (68 +/- 9 vs 65 +/- 9 years (mean +/- SD), P = 0.008) and had an inferior preoperative left ventricular ejection fraction (42 +/- 14 vs 58 +/- 14%, P < 0.0001). In the case-control study, New York Heart Association (NYHA) class and Higgins' risk score differed preoperatively between the MR group and controls. Neither 30-day mortality (4,5% in both groups) nor survival at 1 (91 vs 93%) and 3 years (84 vs 88%) differed significantly. NYHA class and angina class (Canadian Cardiovascular Society, CCS) improved similarly in both groups. Postoperatively, 62% of the patients in the MR group had reduced, 36% unchanged and 2% increased MR. CONCLUSIONS: CABG on patients with grade 2 ischemic MR reduces angina pectoris and improves functional status to the same extent as in CABG patients without MR. Postoperative morbidity and mortality do not differ significantly between the groups. Grade of MR is reduced or unchanged after CABG in patients with grade 2 ischemic MR. The study supports an operative strategy where grade 2 ischemic mitral regurgitation is treated by CABG alone but the result do not exclude that there might be individual patients that would benefit from a valvular or annular procedure in combination with CABG. How these patients should be identified remains unclear.

Likelihood-ratio tests for hidden Markov models.

We consider hidden Markov models as a versatile class of models for weakly dependent random phenomena. The topic of the present paper is likelihood-ratio testing for hidden Markov models, and we show that, under appropriate conditions, the standard asymptotic theory of likelihood-ratio tests is valid. Such tests are crucial in the specification of multivariate Gaussian hidden Markov models, which we use to illustrate the applicability of our general results. Finally, the methodology is illustrated by means of a real data set.

Mutation of the C/EBP binding sites in the Rous sarcoma virus long terminal repeat and gag enhancers.

Several C/EBP binding sites within the Rous sarcoma virus (RSV) long terminal repeat (LTR) and gag enhancers were mutated, and the effect of these mutations on viral gene expression was assessed. Minimal site-specific mutations in each of three adjacent C/EBP binding sites in the LTR reduced steady-state viral RNA levels. Double mutation of the two 5' proximal LTR binding sites resulted in production of 30% of wild-type levels of virus. DNase I footprinting analysis of mutant DNAs indicated that the mutations blocked C/EBP binding at the affected sites. Additional C/EBP binding sites were identified upstream of the 3' LTR and within the 5' end of the LTRs. Point mutations in the RSV gag intragenic enhancer region, which blocked binding of C/EBP at two of three adjacent C/EBP sites, also reduced virus production significantly. Nuclear extracts prepared from both chicken embryo fibroblasts (CEFs) and chicken muscle contained proteins binding to the same RSV DNA sites as did C/EBP, and mutations that prevented C/EBP binding also blocked binding of these chicken proteins. It appears that CEFs and chicken muscle contain distinct proteins binding to these RSV DNA sites; the CEF binding protein was heat stable, as is C/EBP, while the chicken muscle protein was heat sensitive.

Avian retroviral long terminal repeats bind CCAAT/enhancer-binding protein.

DNA-protein interactions involving enhancer and promoter sequences within the U3 regions of several avian retroviral long terminal repeats (LTRs) were studied by DNase I footprinting. The rat CCAAT/enhancer-binding protein, C/EBP, bound to all four viral LTRs examined. The Rous sarcoma virus binding site corresponded closely to the 5' limit of the LTR enhancer; nucleotides -225 to -188 were protected as a pair of adjacent binding domains. The Fujinami sarcoma virus LTR bound C/EBP at a single site at nucleotides -213 to -195. C/EBP also bound to the promoter region of the enhancerless Rous-associated virus-0 LTR at nucleotides -77 to -57. The avian myeloblastosis virus LTR bound C/EBP at three sites: nucleotides -262 to -246, -154 to -134, and -55 to -39. We have previously observed binding of C/EBP to an enhancer in the gag gene of avian retroviruses. A heat-treated nuclear extract from chicken liver bound to all of the same retroviral sequences as did C/EBP. Alignment of the avian retroviral binding sequences with the published binding sites for C/EBP in two CCAAT boxes and in the simian virus 40, polyoma, and murine sarcoma virus enhancers suggested TTGNNGCTAATG as a consensus sequence for binding of C/EBP. When two bases of this consensus sequence were altered by site-specific mutagenesis of the Rous sarcoma virus LTR, binding of the heat-stable chicken protein was eliminated.

Localization and footprinting of an enhancer within the avian sarcoma virus gag gene.

A cis-acting regulatory element within the gag gene of avian retroviruses has been localized by deletion analysis, and sites of protein interaction have been studied by DNase I footprinting. Unidirectional deletions were made from both the 5' and 3' ends of a 656-base-pair fragment of the gag gene of Fujinami sarcoma virus. These deletion mutants were tested for enhancer activity in a chloramphenicol acetyltransferase transient expression assay. A sharp 5' boundary for enhancer activity was observed between 776 and 786 nucleotides downstream from the transcription initiation site. In contrast, deletion from the 3' side resulted in a gradual loss of enhancer activity, reaching a near basal level of activity by nucleotide 868. Internal deletion of 76 nucleotides just downstream of the 5' boundary abolished enhancement. Mutagenesis of a consensus enhancer core sequence (GTGGTTTG) showed that this sequence was not necessary for enhancer activity in our transient assays. DNase I footprinting with both a highly purified enhancer-binding protein from rat liver (EBP20) and a partially purified chicken liver nuclear extract showed specific protection of nucleotides 813 to 872 within the localized enhancer region. Footprinting of unidirectional deletion mutants that had lost activity indicated that this binding was not sufficient to confer enhancement.

Role of de novo DNA methylation in the glucocorticoid resistance of a T-lymphoid cell line.

A correlation has been shown between changes in the methylation pattern of cytosine residues in DNA and the expression of specific genes in differentiated tissues. The pattern of DNA methylation is conserved, through cell division, by a maintenance methylase but the mechanism by which a given pattern of methylation is established is unknown. De novo methylation of foreign DNA molecules has been shown to occur in several systems, and may serve as a signal to arrest gene expression. Conversely, treatment of cultured cell lines with 5-azacytidine results in DNA hypomethylation and leads to transcriptional activation of previously unexpressed genes. The results described here demonstrate spontaneous de novo methylation of DNA in a T-lymphoid cell line previously treated with 5-azacytidine to generate glucocorticoid sensitivity. This de novo methylation is accompanied by the acquisition of the glucocorticoid-resistant phenotype.

Transformation by avian sarcoma viruses leads to phosphorylation of multiple cellular proteins on tyrosine residues.

Phosphoamino acid compositions were determined for 10 size classes of cellular proteins, separated by electrophoresis through one-dimensional sodium dodecyl sulfate-polyacrylamide gels. Phosphotyrosine-containing proteins were observed in uninfected chicken embryo fibroblasts in every size class analyzed, ranging from approximately 20,000 to greater than 200,000 daltons. Transformation of chicken embryo fibroblasts by Rous sarcoma virus or PRC II avian sarcoma virus led to increases in phosphorylation of proteins at tyrosine residues in all of these size classes. A large fraction of the phosphotyrosine-containing protein molecules observed in Rous sarcoma virus-transformed cells was larger than 100,000 daltons with a second broad peak in the 35,000- to 60,000-dalton range. This study suggests that there are a number of substrates of viral or cellular tyrosine-specific protein kinases, which have not yet been identified by other methods.