Evaluation of MR-derived simulated CT-like images and simulated radiographs compared to conventional radiography in patients with shoulder pain: a proof-of-concept study.

BACKGROUND: To evaluate the diagnostic value of MR-derived CT-like images and simulated radiographs compared with conventional radiographs in patients with suspected shoulder pathology. METHODS: 3 T MRI of the shoulder including a 3D T1-weighted gradient echo sequence was performed in 25 patients (mean age 52.4 ± 18 years, 13 women) with suspected shoulder pathology. Subsequently a cone-beam forward projection algorithm was used to obtain intensity-inverted CT-like images and simulated radiographs. Two radiologists evaluated the simulated images separately and independently using the conventional radiographs as the standard of reference, including measurements of the image quality, acromiohumeral distance, critical shoulder angle, degenerative joint changes and the acromial type. Additionally, the CT-like MR images were evaluated for glenoid defects, subcortical cysts and calcifications. Agreement between the MR-derived simulated radiographs and conventional radiographs was calculated using Cohen's Kappa. RESULTS: Measurements on simulated radiographs and conventional radiographs overall showed a substantial to almost perfect inter- and intra-rater agreement (κ = 0.69-1.00 and κ = 0.65-0.85, respectively). Image quality of the simulated radiographs was rated good to excellent (1.6 ± 0.7 and 1.8 ± 0.6, respectively) by the radiologists. A substantial agreement was found regarding diagnostically relevant features, assessed on Y- and anteroposterior projections (κ = 0.84 and κ = 0.69 for the measurement of the CSA; κ = 0.95 and κ = 0.60 for the measurement of the AHD; κ = 0.77 and κ = 0.77 for grading of the Samilson-Prieto classification; κ = 0.83 and κ = 0.67 for the grading of the Bigliani classification, respectively). CONCLUSION: In this proof-of-concept study, clinically relevant features of the shoulder joint were assessed reliably using MR-derived CT-like images and simulated radiographs with an image quality equivalent to conventional radiographs. MR-derived CT-like images and simulated radiographs may provide useful diagnostic information while reducing the amount of radiation exposure.

Multi-detector CT imaging: impact of virtual tube current reduction and sparse sampling on detection of vertebral fractures.

PURPOSE: To systematically evaluate the effects of virtual tube current reduction and sparse sampling on image quality and vertebral fracture diagnostics in multi-detector computed tomography (MDCT). MATERIALS AND METHODS: In routine MDCT scans of 35 patients (80.0% females, 70.6 ± 14.2 years, 65.7% showing vertebral fractures), reduced radiation doses were retrospectively simulated by virtually lowering tube currents and applying sparse sampling, considering 50%, 25%, and 10% of the original tube current and projections, respectively. Two readers evaluated items of image quality and presence of vertebral fractures. Readout between the evaluations in the original images and those with virtually lowered tube currents or sparse sampling were compared. RESULTS: A significant difference was revealed between the evaluations of image quality between MDCT with virtually lowered tube current and sparse-sampled MDCT (p < 0.001). Sparse-sampled data with only 25% of original projections still showed good to very good overall image quality and contrast of vertebrae as well as minimal artifacts. There were no missed fractures in sparse-sampled MDCT with 50% reduction of projections, and clinically acceptable determination of fracture age was possible in MDCT with 75% reduction of projections, in contrast to MDCT with 50% or 75% virtual tube current reduction, respectively. CONCLUSION: Sparse-sampled MDCT provides adequate image quality and diagnostic accuracy for vertebral fracture detection with 50% of original projections in contrast to corresponding MDCT with lowered tube current. Thus, sparse sampling is a promising technique for dose reductions in MDCT that could be introduced in future generations of scanners. KEY POINTS: • MDCT with a reduction of projection numbers of 50% still showed high diagnostic accuracy without any missed vertebral fractures. • Clinically acceptable determination of vertebral fracture age was possible in MDCT with a reduction of projection numbers of 75%. • With sparse sampling, higher reductions in radiation exposure can be achieved without compromised image or diagnostic quality in routine MDCT of the spine as compared to MDCT with reduced tube currents.

Sparse sampling computed tomography (SpSCT) for detection of pulmonary embolism: a feasibility study.

OBJECTIVES: Evaluation of sparse sampling computed tomography (SpSCT) regarding subjective and objective image criteria for the detection of pulmonary embolism (PE) at different simulated dose levels. METHODS: Computed tomography pulmonary angiography (CTPA) scans of 20 clinical patients were used to obtain simulated low-dose scans with 100%-50%-25%-12.5%-6.3%-3.1% of the clinical dose, resulting in a total of six dose levels (DL). From these full sampling (FS) data, every second (2-SpSCT) or fourth (4-SpSCT) projection was used to obtain simulated sparse sampling scans. Each image set was evaluated by four blinded radiologists regarding subjective image criteria (artifacts, image quality) and diagnostic performance (confidence, sensitivity, specificity, accuracy, and area under the curve). Additionally, the contrast-to-noise ratio (CNR) was evaluated for objective image quality. RESULTS: Sensitivity was 100% with 2-SpSCT and 4-SpSCT at the 25% DL and the 12.5% DL for all localizations of PE (one subgroup 98.5%). With FS, the sensitivity decreased to 90% at the 12.5% DL. 2-SpSCT and 4-SpSCT showed higher values for sensitivity, specificity, accuracy, and the area under the curve at all DL compared with FS. Subjective image quality was significantly higher for 4-SpSCT compared with FS at each dose level (p < 0.01, paired t test). Only with 4-SpSCT, all examinations were rated as showing diagnostic image quality at the 12.5% DL. CONCLUSIONS: Via SpSCT, a dose reduction down to a 12.5% dose level (corresponding to a mean effective dose of 0.38 mSv in the current study) for CTPA is possible while maintaining high image quality and full diagnostic confidence. KEY POINTS: • With sparse sampling CT, radiation dose could be significantly reduced in clinical routine. • Sparse sampling CT is a novel hardware solution with which less projection images are acquired. • In the current study, a dose reduction of 87.5% (corresponding to a mean effective dose of 0.38 mSv) for CTPA could be achieved while maintaining excellent diagnostic performance.

Evaluation of MR-derived CT-like images and simulated radiographs compared to conventional radiography in patients with benign and malignant bone tumors.

OBJECTIVES: To evaluate the diagnostic value of MR-derived CT-like images and simulated radiographs compared with conventional radiographs in patients with benign and malignant bone tumors. METHODS: In 32 patients with a benign or malignant bone lesion (mean age 33.9 ± 18.5 years, 17 females), 3-T MR imaging was performed including a 3D T1-weighted gradient echo sequence as the basis for the CT-like images. From these, intensity-inverted MR image volumes were converted into 2D images via a forward projection to obtain simulated radiographs. Two radiologists assessed these images as well as conventional radiographs for the type of periosteal reaction, matrix mineralization and destruction pattern. Agreement between the modalities was calculated using Cohen's κ. RESULTS: The agreement between conventional radiographs and MR-derived CT-like images in combination with simulated radiographs was substantial (periosteal reaction, κ = 0.67; destruction pattern, κ = 0.75), and the sensitivity of both modalities for the final diagnosis of the lesion (aggressive vs. nonaggressive) was high (MR-derived CT-like images, 86.2% vs. conventional radiographs, 90.0%). Additional information on soft tissue extension (MR-derived CT-like images, 21.9% vs. conventional radiographs, 12.5%; p = 0.009) and lobulation (9.4% vs. 0%; p < 0.001) was significantly more often found on MR-derived CT-like images compared with conventional radiographs. CONCLUSIONS: The assessment of the destruction patterns, periosteal reaction and distinction between aggressive and nonaggressive tumors was feasible using MR-derived CT-like images and simulated radiographs and is comparable to that of conventional radiographs. Moreover, MR-derived CT-like images provided additional information on soft tissue extension and tumor architecture. KEY POINTS: • CT-like images and simulated radiographs can be generated from 3D MRI. • Evaluation of bone tumors is feasible with MR-derived images. • CT-like images and simulated radiographs provide additional information on bone tumors.

DXA-equivalent quantification of bone mineral density using dual-layer spectral CT scout scans.

OBJECTIVES: To develop and evaluate a method for areal bone mineral density (aBMD) measurement based on dual-layer spectral CT scout scans. METHODS: A post-processing algorithm using a pair of 2D virtual mono-energetic scout images (VMSIs) was established in order to semi-automatically compute the aBMD at the spine similarly to DXA, using manual soft tissue segmentation, semi-automatic segmentation for the vertebrae, and automatic segmentation for the background. The method was assessed based on repetitive measurements of the standardized European Spine Phantom (ESP) using the standard scout scan tube current (30 mA) and other tube currents (10 to 200 mA), as well as using fat-equivalent extension rings simulating different patient habitus, and was compared to dual-energy X-ray absorptiometry (DXA). Moreover, the feasibility of the method was assessed in vivo in female patients. RESULTS: Derived from standard scout scans, aBMD values measured with the proposed method significantly correlated with DXA measurements (r = 0.9925, p < 0.001), and mean accuracy (DXA, 4.12%; scout, 1.60%) and precision (DXA, 2.64%; scout, 2.03%) were comparable between the two methods. Moreover, aBMD values assessed at different tube currents did not differ significantly (p ≥ 0.20 for all), suggesting that the presented method could be applied to scout scans with different settings. Finally, data derived from sample patients were concordant with BMD values from a reference age-matched population. CONCLUSIONS: Based on dual-layer spectral scout scans, aBMD measurements were fast and reliable and significantly correlated with the according DXA measurements in phantoms. Considering the number of CT acquisitions performed worldwide, this method could allow truly opportunistic osteoporosis screening. KEY POINTS: • 2D scout scans (localizer radiographs) from a dual-layer spectral CT scanner, which are mandatory parts of a CT examination, can be used to automatically determine areal bone mineral density (aBMD) at the spine. • The presented method allowed fast (< 25 s/patient), semi-automatic, and reliable DXA-equivalent aBMD measurements for state-of-the-art DXA phantoms at different tube settings and for various patient habitus, as well as for sample patients. • Considering the number of CT scout scan acquisitions performed worldwide on a daily basis, the presented technique could enable truly opportunistic osteoporosis screening with DXA-equivalent metrics, without involving higher radiation exposure since it only processes existing data that is acquired during each CT scan.

Bone mineral density measurements derived from dual-layer spectral CT enable opportunistic screening for osteoporosis.

OBJECTIVE: To investigate the in vivo applicability of non-contrast-enhanced hydroxyapatite (HA)-specific bone mineral density (BMD) measurements based on dual-layer CT (DLCT). METHODS: A spine phantom containing three artificial vertebral bodies with known HA densities was measured to obtain spectral data using DLCT and quantitative CT (QCT), simulating different patient positions and grades of obesity. BMD was calculated from virtual monoenergetic images at 50 and 200 keV. HA-specific BMD values of 174 vertebrae in 33 patients (66 ± 18 years; 33% women) were determined in non-contrast routine DLCT and compared with corresponding QCT-based BMD values. RESULTS: Examining the phantom, HA-specific BMD measurements were on a par with QCT measurements. In vivo measurements revealed strong correlations between DLCT and QCT (r = 0.987 [95% confidence interval, 0.963-1.000]; p < 0.001) and substantial agreement in a Bland-Altman plot. CONCLUSION: DLCT-based HA-specific BMD measurements were comparable with QCT measurements in in vivo analyses. This suggests that opportunistic DLCT-based BMD measurements are an alternative to QCT, without requiring phantoms and specific protocols. KEY POINTS: • DLCT-based hydroxyapatite-specific BMD measurements show a substantial agreement with QCT-based BMD measurements in vivo. • DLCT-based hydroxyapatite-specific measurements are on a par with QCT in spine phantom measurements. • Opportunistic DLCT-based BMD measurements may be a feasible alternative for QCT, without requiring dedicated examination protocols or a phantom.

Tube Current Reduction in CT Angiography: How Low Can We Go in Imaging of Patients With Suspected Acute Stroke?

OBJECTIVE. The purpose of this study was to systematically evaluate image quality, detectability of large-vessel occlusion or dissection, and diagnostic confidence in CT angiography (CTA) with virtually lowered tube current and iterative reconstruction in patients with suspected acute stroke. MATERIALS AND METHODS. Thirty patients (15 with large-vessel occlusion or dissection) underwent CTA of the supraaortal up to the intracranial arterial vessels. CTA scans were simulated as if they were made at 50% (D50), 25% (D25), and 10% (D10) of the original tube current. Image reconstruction was achieved with two levels of iterative reconstruction (A, similar to clinical reconstructions; B, two times stronger regularization). Two readers performed qualitative image evaluation considering overall image quality, artifacts, vessel contrast, detection of vessel abnormalities, and diagnostic confidence. RESULTS. Level B of iterative reconstruction was favorable regarding overall image quality and artifacts for D10, whereas level A was favorable for D100 and D50. CTA scans at D25 and both levels of iterative reconstruction still showed good vessel contrast, with even peripheral arterial branches of the anterior, middle, and posterior cerebral arteries being clearly detectable. Furthermore, CTA scans at D25 and level A of iterative reconstruction showed an adequate level of diagnostic confidence without any missed large-vessel occlusion or dissection according to evaluations by both readers. CONCLUSION. CTA with iterative reconstruction and tube currents decreased to 25% of that for original imaging is feasible without limitations in vessel contrast or detection of vessel abnormalities in patients with suspected acute stroke. Thus, the approach evaluated enables substantial reductions in radiation exposure for patients undergoing head and neck CTA.

Effect of Statistically Iterative Image Reconstruction on Vertebral Bone Strength Prediction Using Bone Mineral Density and Finite Element Modeling: A Preliminary Study.

Statistical iterative reconstruction (SIR) using multidetector computed tomography (MDCT) is a promising alternative to standard filtered back projection (FBP), because of lower noise generation while maintaining image quality. Hence, we investigated the feasibility of SIR in predicting MDCT-based bone mineral density (BMD) and vertebral bone strength from finite element (FE) analysis. The BMD and FE-predicted bone strength derived from MDCT images reconstructed using standard FBP (FFBP) and SIR with (FSIR) and without regularization (FSIRB0) were validated against experimental failure loads (Fexp). Statistical iterative reconstruction produced the best quality images with regard to noise, signal-to-noise ratio, and contrast-to-noise ratio. Fexp significantly correlated with FFBP, FSIR, and FSIRB0. FFBP had a significant correlation with FSIRB0 and FSIR. The BMD derived from FBP, SIRB0, and SIR were significantly correlated. Effects of regularization should be further investigated with FE and BMD analysis to allow for an optimal iterative reconstruction algorithm to be implemented in an in vivo scenario.

Experimental feasibility of spectral photon-counting computed tomography with two contrast agents for the detection of endoleaks following endovascular aortic repair.

OBJECTIVES: After endovascular aortic repair (EVAR), discrimination of endoleaks and intra-aneurysmatic calcifications within the aneurysm often requires multiphase computed tomography (CT). Spectral photon-counting CT (SPCCT) in combination with a two-contrast agent injection protocol may provide reliable detection of endoleaks with a single CT acquisition. METHODS: To evaluate the feasibility of SPCCT, the stent-lined compartment of an abdominal aortic aneurysm phantom was filled with a mixture of iodine and gadolinium mimicking enhanced blood. To represent endoleaks of different flow rates, the adjacent compartments contained either one of the contrast agents or calcium chloride to mimic intra-aneurysmatic calcifications. After data acquisition with a SPCCT prototype scanner with multi-energy bins, material decomposition was performed to generate iodine, gadolinium and calcium maps. RESULTS: In a conventional CT slice, Hounsfield units (HU) of the compartments were similar ranging from 147 to 168 HU. Material-specific maps differentiate the distributions within the compartments filled with iodine, gadolinium or calcium. CONCLUSION: SPCCT may replace multiphase CT to detect endoleaks without sacrificing diagnostic accuracy. It is a unique feature of our method to capture endoleak dynamics and allow reliable distinction from intra-aneurysmatic calcifications in a single scan, thereby enabling a significant reduction of radiation exposure. KEY POINTS: • SPCCT might enable advanced endoleak detection. • Material maps derived from SPCCT can differentiate iodine, gadolinium and calcium. • SPCCT may potentially reduce radiation burden for EVAR patients under post-interventional surveillance.

Effect of radiation dose reduction on texture measures of trabecular bone microstructure: an in vitro study.

Osteoporosis is characterized by bone loss and degradation of bone microstructure leading to fracture particularly in elderly people. Osteoporotic bone degeneration and fracture risk can be assessed by bone mineral density and trabecular bone score from 2D projection dual-energy X-ray absorptiometry images. However, multidetector computed tomography image based quantification of trabecular bone microstructure showed significant improvement in prediction of fracture risk beyond that from bone mineral density and trabecular bone score; however, high radiation exposure limits its use in routine clinical in vivo examinations. Hence, this study investigated reduction of radiation dose and its effects on image quality of thoracic midvertebral specimens. Twenty-four texture features were extracted to quantify the image quality from multidetector computed tomography images of 11 thoracic midvertebral specimens, by means of statistical moments, the gray-level co-occurrence matrix, and the gray-level run-length matrix, and were analyzed by an independent sample t-test to observe differences in image texture with respect to radiation doses of 80, 150, 220, and 500 mAs. The results showed that three features-namely, global variance, energy, and run percentage, were not statistically significant ([Formula: see text]) for low doses with respect to 500 mAs. Hence, it is evident that these three dose-independent features can be used for disease monitoring with a low-dose imaging protocol.

Multidetector Computed Tomography Imaging: Effect of Sparse Sampling and Iterative Reconstruction on Trabecular Bone Microstructure.

Multidetector computed tomography-based trabecular bone microstructure analysis ensures promising results in fracture risk prediction caused by osteoporosis. Because multidetector computed tomography is associated with high radiation exposure, its clinical routine use is limited. Hence, in this study, we investigated in 11 thoracic midvertebral specimens whether trabecular texture parameters are comparable derived from (1) images reconstructed using statistical iterative reconstruction (SIR) and filtered back projection as criterion standard at different exposures (80, 150, 220, and 500 mAs) and (2) from SIR-based sparse sampling projections (12.5%, 25%, 50%, and 100%) and equivalent exposures as criterion standard. Twenty-four texture features were computed, and those that showed similar values between (1) filtered back projection and SIR at the different exposure levels and (2) sparse sampling and equivalent exposures and reconstructed with SIR were identified. These parameters can be of equal value in determining trabecular bone microstructure with lower radiation exposure using sparse sampling and SIR.

Three-material decomposition with dual-layer spectral CT compared to MRI for the detection of bone marrow edema in patients with acute vertebral fractures.

OBJECTIVES: To assess whether bone marrow edema in patients with acute vertebral fractures can be accurately diagnosed based on three-material decomposition with dual-layer spectral CT (DLCT). MATERIALS AND METHODS: Acute (n = 41) and chronic (n = 18) osteoporotic thoracolumbar vertebral fractures as diagnosed by MRI (hyperintense signal in STIR sequences) in 27 subjects (72 ± 11 years; 17 women) were assessed with DLCT. Spectral data were decomposed into hydroxyapatite, edema-equivalent, and fat-equivalent density maps using an in-house-developed algorithm. Two radiologists, blinded to clinical and MR findings, assessed DLCT and conventional CT independently, using a Likert scale (1 = no edema; 2 = likely no edema; 3 = likely edema; 4 = edema). For DLCT and conventional CT, accuracy, sensitivity, and specificity for identifying acute fractures (Likert scale, 3 and 4) were analyzed separately using MRI as standard of reference. RESULTS: For the identification of acute fractures, conventional CT showed a sensitivity of 0.73-0.76 and specificity of 0.78-0.83, whereas the sensitivity (0.93-0.95) and specificity (0.89) of decomposed DLCT images were substantially higher. Accuracy increased from 0.76 for conventional CT to 0.92-0.93 using DLCT. Interreader agreement for fracture assessment was high in conventional CT (weighted κ [95% confidence interval]; 0.81 [0.70; 0.92]) and DLCT (0.96 [0.92; 1.00]). CONCLUSIONS: Material decomposition of DLCT data substantially improved accuracy for the diagnosis of acute vertebral fractures, with a high interreader agreement. This may spare patients additional examinations and facilitate the diagnosis of vertebral fractures.

Assessment of quantification accuracy and image quality of a full-body dual-layer spectral CT system.

The performance of a recently introduced spectral computed tomography system based on a dual-layer detector has been investigated. A semi-anthropomorphic abdomen phantom for CT performance evaluation was imaged on the dual-layer spectral CT at different radiation exposure levels (CTDIvol of 10 mGy, 20 mGy and 30 mGy). The phantom was equipped with specific low-contrast and tissue-equivalent inserts including water-, adipose-, muscle-, liver-, bone-like materials and a variation in iodine concentrations. Additionally, the phantom size was varied using different extension rings to simulate different patient sizes. Contrast-to-noise (CNR) ratio over the range of available virtual mono-energetic images (VMI) and the quantitative accuracy of VMI Hounsfield Units (HU), effective-Z maps and iodine concentrations have been evaluated. Central and peripheral locations in the field-of-view have been examined. For all evaluated imaging tasks the results are within the calculated theoretical range of the tissue-equivalent inserts. Especially at low energies, the CNR in VMIs could be boosted by up to 330% with respect to conventional images using iDose/spectral reconstructions at level 0. The mean bias found in effective-Z maps and iodine concentrations averaged over all exposure levels and phantom sizes was 1.9% (eff. Z) and 3.4% (iodine). Only small variations were observed with increasing phantom size (+3%) while the bias was nearly independent of the exposure level (±0.2%). Therefore, dual-layer detector based CT offers high quantitative accuracy of spectral images over the complete field-of-view without any compromise in radiation dose or diagnostic image quality.

Spectral Photon-counting CT: Initial Experience with Dual-Contrast Agent K-Edge Colonography.

Purpose To investigate the feasibility of using spectral photon-counting computed tomography (CT) to differentiate between gadolinium-based and nonionic iodine-based contrast material in a colon phantom by using the characteristic k edge of gadolinium. Materials and Methods A custom-made colon phantom was filled with nonionic iodine-based contrast material, and a gadolinium-filled capsule representing a contrast material-enhanced polyp was positioned on the colon wall. The colon phantom was scanned with a preclinical spectral photon-counting CT system to obtain spectral and conventional data. By fully using the multibin spectral information, material decomposition was performed to generate iodine and gadolinium maps. Quantitative measurements were performed within the lumen and polyp to quantitatively determine the absolute content of iodine and gadolinium. Results In a conventional CT section, absorption values of both contrast agents were similar at approximately 110 HU. Contrast material maps clearly differentiated the distributions, with gadolinium solely in the polyp and iodine in the lumen of the colon. Quantitative measurements of contrast material concentrations in the colon and polyp matched well with those of actual prepared mixtures. Conclusion Dual-contrast spectral photon-counting CT colonography with iodine-filled lumen and gadolinium-tagged polyps may enable ready differentiation between polyps and tagged fecal material. © RSNA, 2016.

Is multidetector CT-based bone mineral density and quantitative bone microstructure assessment at the spine still feasible using ultra-low tube current and sparse sampling?

OBJECTIVE: Osteoporosis diagnosis using multidetector CT (MDCT) is limited to relatively high radiation exposure. We investigated the effect of simulated ultra-low-dose protocols on in-vivo bone mineral density (BMD) and quantitative trabecular bone assessment. MATERIALS AND METHODS: Institutional review board approval was obtained. Twelve subjects with osteoporotic vertebral fractures and 12 age- and gender-matched controls undergoing routine thoracic and abdominal MDCT were included (average effective dose: 10 mSv). Ultra-low radiation examinations were achieved by simulating lower tube currents and sparse samplings at 50%, 25% and 10% of the original dose. BMD and trabecular bone parameters were extracted in T10-L5. RESULTS: Except for BMD measurements in sparse sampling data, absolute values of all parameters derived from ultra-low-dose data were significantly different from those derived from original dose images (p<0.05). BMD, apparent bone fraction and trabecular thickness were still consistently lower in subjects with than in those without fractures (p<0.05). CONCLUSION: In ultra-low-dose scans, BMD and microstructure parameters were able to differentiate subjects with and without vertebral fractures, suggesting osteoporosis diagnosis is feasible. However, absolute values differed from original values. BMD from sparse sampling appeared to be more robust. This dose-dependency of parameters should be considered for future clinical use. KEY POINTS: • BMD and quantitative bone parameters are assessable in ultra-low-dose in vivo MDCT scans. • Bone mineral density does not change significantly when sparse sampling is applied. • Quantitative trabecular bone microstructure measurements are sensitive to dose reduction. • Osteoporosis subjects could be differentiated even at 10% of original dose. • Radiation exposure should be considered when comparing quantitative bone parameters.

Monitoring dynamic glycosylation in vivo using supersensitive click chemistry.

To monitor the kinetics of biological processes that take place within the minute time scale, simple and fast analytical methods are required. In this article, we present our discovery of an azide with an internal Cu(I)-chelating motif that enabled the development of the fastest protocol for Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) to date, and its application toward following the dynamic process of glycan biosynthesis. We discovered that an electron-donating picolyl azide boosted the efficiency of the ligand-accelerated CuAAC 20-38-fold in living systems with no apparent toxicity. With a combination of this azide and BTTPS, a tris(triazolylmethyl)amine-based ligand for Cu(I), we were able to detect newly synthesized cell-surface glycans by flow cytometry using as low as 1 nM of a metabolic precursor. This supersensitive chemistry enabled us to monitor the dynamic glycan biosynthesis in mammalian cells and in early zebrafish embryogenesis. In live mammalian cells, we discovered that it takes approximately 30-45 min for a monosaccharide building block to be metabolized and incorporated into cell-surface glycoconjugates. In zebrafish embryos, the labeled glycans could be detected as early as the two-cell stage. To our knowledge, this was the first time that newly synthesized glycans were detected at the cleavage period (0.75-2 hpf) in an animal model using bioorthogonal chemistry.

A diversity-oriented synthesis approach to macrocycles via oxidative ring expansion.

Macrocycles are key structural elements in numerous bioactive small molecules and are attractive targets in the diversity-oriented synthesis of natural product-based libraries. However, efficient and systematic access to diverse collections of macrocycles has proven difficult using classical macrocyclization reactions. To address this problem, we have developed a concise, modular approach to the diversity-oriented synthesis of macrolactones and macrolactams involving oxidative cleavage of a bridging double bond in polycyclic enol ethers and enamines. These substrates are assembled in only four or five synthetic steps and undergo ring expansion to afford highly functionalized macrocycles bearing handles for further diversification. In contrast to macrocyclization reactions of corresponding seco acids, the ring expansion reactions are efficient and insensitive to ring size and stereochemistry, overcoming key limitations of conventional approaches to systematic macrocycle synthesis. Cheminformatic analysis indicates that these macrocycles access regions of chemical space that overlap with natural products, distinct from currently targeted synthetic drugs.

CT-Guided Liver Biopsy: Evaluation of Spectral Data From Dual-Layer Detector CT for Improved Lesion Detection.

PURPOSE: Evaluation of dual-layer spectral computed tomography (CT) for contrast enhancement during image-guided biopsy of liver lesions using virtual monoenergetic images (VMI) and virtual non-contrast (VNC) images. METHODS: Spectral CT data of 20 patients receiving CT-guided needle biopsy of focal liver lesions were used to generate VMI at energy levels from 40 to 200 keV and VNC images. Images were analyzed objectively regarding contrast-to-noise ratio between lesion center (CNRcent) or periphery (CNRperi) and normal liver parenchyma. Lesion visibility and image quality were evaluated on a 4-point Likert scale by two radiologists. RESULTS: Using VMI/VNC images, readers reported an increased visibility of the lesion compared to the conventional CT images in 18/20 cases. In 75% of cases, the highest visibility was derived by VMI-40. Showing all reconstructions simultaneously, VMI-40 offered the highest visibility in 75% of cases, followed by VNC in 12.5% of cases. Either CNRcent (17/20) or/and CNRperi (17/20) was higher (CNR increase > 50%) in 19/20 cases for VMI-40 or VNC images compared to conventional CT images. VMI-40 showed the highest CNRcent in 14 cases and the highest CNRperi in 12 cases. High image quality was present for all reconstructions with a minimum median of 3.5 for VMI-40 and VMI-50. CONCLUSIONS: When implemented in the CT scanner software, automated contrast enhancement of liver lesions during image-guided biopsy may facilitate the procedure.

Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer.

Deregulation of the BCL-2 family interaction network ensures cancer resistance to apoptosis and is a major challenge to current treatments. Cancer cells commonly evade apoptosis through upregulation of the BCL-2 anti-apoptotic proteins; however, more resistant cancers also downregulate or inactivate pro-apoptotic proteins to suppress apoptosis. Here, we find that apoptosis resistance in a diverse panel of solid and hematological malignancies is mediated by both overexpression of BCL-XL and an unprimed apoptotic state, limiting direct and indirect activation mechanisms of pro-apoptotic BAX. Both survival mechanisms can be overcome by the combination of an orally bioavailable BAX activator, BTSA1.2 with Navitoclax. The combination demonstrates synergistic efficacy in apoptosis-resistant cancer cells, xenografts, and patient-derived tumors while sparing healthy tissues. Additionally, functional assays and genomic markers are identified to predict sensitive tumors to the combination treatment. These findings advance the understanding of apoptosis resistance mechanisms and demonstrate a novel therapeutic strategy for cancer treatment.

Sparse-sampling computed tomography for detection of endoleak after endovascular aortic repair (EVAR).

OBJECTIVES: To evaluate sparse sampling computed tomography (SpSCT) for detection of endoleak after endovascular aortic repair (EVAR) at different dose levels in terms of subjective image criteria and diagnostic accuracy. METHODS: Twenty clinically indicated computed tomography aortic angiography (CTA) scans were used to obtain simulated low-dose scans with 100%, 50%, 25%, 12.5% and 6.25% of the applicated clinical dose, resulting in five dose levels (DL). From full sampling (FS) data sets, every second (2-SpSCT) or fourth (4-SpSCT) projection was used to generate simulated sparse sampling scans. All examinations were evaluated by four blinded radiologists regarding subjective image criteria and diagnostic performance. RESULTS: Sensitivity was higher than 93% in 4-SpSCT at the 25% DL which is the same as with FS at full dose (100% DL). High accuracies and relative high AUC-values were obtained for 2- and 4-SpSCT down to the 12.5% DL, while for FS similar values were shown down to 25% DL only. Subjective image quality was significantly higher for 4-SpSCT compared to FS at each dose level. More than 90% of all cases were rated with a high or medium confidence for FS and 2-SpSCT at the 50% DL and for 4-SpSCT at the 25% DL. At DL 25% and 12.5%, more cases showed a high confidence using 2- and 4-SpSCT compared with FS. CONCLUSIONS: Via SpSCT, a dose reduction down to a 25% dose level (mean effective dose of 1.49 mSv in the current study) for CTA is possible while maintaining high image quality and full diagnostic confidence.