Clinical feasibility and impact of data-driven respiratory motion compensation studied in 200 whole-body 18F-FDG PET/CT scans.

BACKGROUND: This study examines the clinical feasibility and impact of implementing a fully automated whole-body PET protocol with data-driven respiratory gating in patients with a broad range of oncological and non-oncological pathologies 592 FDG PET/CT patients were prospectively included. 200 patients with lesions in the torso were selected for further analysis, and ungated (UG), belt gated (BG) and data-driven gating (DDG) images were reconstructed. All images were reconstructed using the same data and without prolonged acquisition time for gated images. Images were quantitatively analysed for lesion uptake and metabolic volume, complemented by a qualitative analysis of visual lesion detection. In addition, the impact of gating on treatment response evaluation was evaluated in 23 patients with malignant lymphoma. RESULTS: Placement of the belt needed for BG was associated with problems in 27% of the BG scans, whereas no issues were reported using DDG imaging. For lesion quantification, DDG and BG images had significantly greater SUV values and smaller volumes than UG. The physicians reported notable image blurring in 44% of the UG images that was problematic for clinical evaluation in 4.5% of cases. CONCLUSION: Respiratory motion compensation using DDG is readily integrated into clinical routine and produce images with more accurate and significantly greater SUV values and smaller metabolic volumes. In our broad cohort of patients, the physicians overwhelmingly preferred gated over ungated images, with a slight preference for DDG images. However, even in patients with malignant disease in the torso, no additional diagnostic information was obtained by the gated images that could not be derived from the ungated images.

Clinical Evaluation of a Data-Driven Respiratory Gating Algorithm for Whole-Body PET with Continuous Bed Motion.

Respiratory gating is the standard to prevent respiration effects from degrading image quality in PET. Data-driven gating (DDG) using signals derived from PET raw data is a promising alternative to gating approaches requiring additional hardware (e.g., pressure-sensitive belt gating [BG]). However, continuous-bed-motion (CBM) scans require dedicated DDG approaches for axially extended PET, compared with DDG for conventional step-and-shoot scans. In this study, a CBM-capable DDG algorithm was investigated in a clinical cohort and compared with BG using optimally gated (OG) and fully motion-corrected (elastic motion correction [EMOCO]) reconstructions. Methods: Fifty-six patients with suspected malignancies in the thorax or abdomen underwent whole-body 18F-FDG CBM PET/CT using DDG and BG. Correlation analyses were performed on both gating signals. Besides static reconstructions, OG and EMOCO reconstructions were used for BG and DDG. The metabolic volume, SUVmax, and SUVmean of lesions were compared among the reconstructions. Additionally, the quality of lesion delineation in the different PET reconstructions was independently evaluated by 3 experts. Results: The global correlation coefficient between BG and DDG signals was 0.48 ± 0.11, peaking at 0.89 ± 0.07 when scanning the kidney and liver region. In total, 196 lesions were analyzed. SUV measurements were significantly higher in BG-OG, DDG-OG, BG-EMOCO, and DDG-EMOCO than in static images (P < 0.001; median SUVmax: static, 14.3 ± 13.4; BG-EMOCO, 19.8 ± 15.7; DDG-EMOCO, 20.5 ± 15.6; BG-OG, 19.6 ± 17.1; and DDG-OG, 18.9 ± 16.6). No significant differences between BG-OG and DDG-OG or between BG-EMOCO and DDG-EMOCO were found. Visual lesion delineation was significantly better in BG-EMOCO and DDG-EMOCO than in static reconstructions (P < 0.001); no significant difference was found when comparing BG and DDG for either EMOCO or OG reconstruction. Conclusion: DDG-based motion compensation of CBM PET acquisitions outperforms static reconstructions, delivering qualities comparable to BG approaches. The new algorithm may be a valuable alternative for CBM PET systems.

The effect of high count rates on cardiac perfusion quantification in a simultaneous PET-MR system using a cardiac perfusion phantom.

BACKGROUND: PET-MRI is under investigation as a new strategy for quantitative myocardial perfusion imaging. Consideration is required as to the maximum scanner count rate in order to limit dead-time losses resulting from administered activity in the scanner field of view during the first pass of the radiotracer. RESULTS: We performed a decaying-source experiment to investigate the high count-rate performance of a PET-MR system (Siemens mMR) over the expected range of activities during a clinical study. We also performed imaging of a cardiac perfusion phantom, which provides an experimental simulation of clinical transit of a simultaneous radiotracer (phantom injected activities range 252 to 997 MBq) and gadolinium-based contrast agent (GBCA). Time-activity and time-intensity curves of the aorta and myocardium compartments from PET and MR images were determined, and quantification of perfusion was then performed using a standard cardiac kinetic model. The decaying-source experiment showed a maximum noise equivalent count rate (NECRmax) of 286 kcps at a singles rate of 47.1 Mcps. NECR was maintained within 5% (NECR95%) of the NECRmax with a singles rate of 34.1 Mcps, corresponding to 310 MBq in the phantom. Count-rate performance was degraded above the singles rate of 64.9 Mcps due to the number of detection events impacting the quantitative accuracy of reconstructed images. A 10% bias in image activity concentration was observed between singles rates of 78.2 and 82.9 Mcps. Perfusion phantom experiments showed that image-based activity concentration and quantified values of perfusion were affected by count losses when the total singles rate was greater than 64.9 Mcps. This occurred during the peak arterial input function (AIF) phase of imaging for injected activities to the phantom of 600 MBq and greater. CONCLUSIONS: Care should be taken to avoid high count-rate losses in simultaneous PET-MRI studies. Based on our results in phantoms, bias in reconstructed images should be avoided by adhering to a singles rate lower than 64.9 Mcps on the mMR system. Quantification of perfusion values using singles rates higher than 64.9 Mcps on this system may be compromised and should be avoided.

An experimental phantom study of the effect of gadolinium-based MR contrast agents on PET attenuation coefficients and PET quantification in PET-MR imaging: application to cardiac studies.

BACKGROUND: Simultaneous cardiac perfusion studies are an increasing trend in PET-MR imaging. During dynamic PET imaging, the introduction of gadolinium-based MR contrast agents (GBCA) at high concentrations during a dual injection of GBCA and PET radiotracer may cause increased attenuation effects of the PET signal, and thus errors in quantification of PET images. We thus aimed to calculate the change in linear attenuation coefficient (LAC) of a mixture of PET radiotracer and increasing concentrations of GBCA in solution and furthermore, to investigate if this change in LAC produced a measurable effect on the image-based PET activity concentration when attenuation corrected by three different AC strategies. FINDINGS: We performed simultaneous PET-MR imaging of a phantom in a static scenario using a fixed activity of 40 MBq [18 F]-NaF, water, and an increasing GBCA concentration from 0 to 66 mM (based on an assumed maximum possible concentration of GBCA in the left ventricle in a clinical study). This simulated a range of clinical concentrations of GBCA. We investigated two methods to calculate the LAC of the solution mixture at 511 keV: (1) a mathematical mixture rule and (2) CT imaging of each concentration step and subsequent conversion to LAC at 511 keV. This comparison showed that the ranges of LAC produced by both methods are equivalent with an increase in LAC of the mixed solution of approximately 2% over the range of 0-66 mM. We then employed three different attenuation correction methods to the PET data: (1) each PET scan at a specific millimolar concentration of GBCA corrected by its corresponding CT scan, (2) each PET scan corrected by a CT scan with no GBCA present (i.e., at 0 mM GBCA), and (3) a manually generated attenuation map, whereby all CT voxels in the phantom at 0 mM were replaced by LAC = 0.1 cm-1. All attenuation correction methods (1-3) were accurate to the true measured activity concentration within 5%, and there were no trends in image-based activity concentrations upon increasing the GBCA concentration of the solution. CONCLUSION: The presence of high GBCA concentration (representing a worst-case scenario in dynamic cardiac studies) in solution with PET radiotracer produces a minimal effect on attenuation-corrected PET quantification.

Feasibility of simultaneous PET-MR perfusion using a novel cardiac perfusion phantom.

BACKGROUND: PET-MR scanners are beginning to be employed for quantitative myocardial perfusion imaging. In order to examine simultaneous perfusion calculations, this work describes a feasibility study of simultaneous PET-MR of gadolinium-based contrast agent (GBCA) and PET radiotracer in a novel cardiac perfusion phantom. RESULTS: [18F]F- and GBCA were injected simultaneously into a cardiac phantom using a range of ground-truth myocardial perfusion rates of 1 to 5 ml/g/min. PET quantification of K1 (ml/g/min) was performed using a single tissue compartment model. MR perfusion was calculated using a model-independent signal deconvolution technique. PET and MR signal traces from the phantom aorta and myocardial sections show true simultaneous PET and MR arterial input functions (AIF) and myocardial uptake respectively at each perfusion rate. Calculation of perfusion parameters showed both K1 and h(t = 0) (PET and MR perfusion parameters respectively) to be linearly related with the ground truth perfusion rate (PT ), and also linearly related to each other (R2 = 0.99). The highest difference in perfusion values between K1 and PT was 16% at 1 ml/g/min, and the mean difference for all other perfusion rates was <3%. CONCLUSIONS: The perfusion phantom allows accurate and reproducible simulation of the myocardial kinetics for simultaneous PET-MR imaging, and may find use in protocol design and development of PET-MR based quantification techniques and direct comparison of quantification of the two modalities.

Electrophilic Aromatic Substitution: New Insights into an Old Class of Reactions.

The classic SEAr mechanism of electrophilic aromatic substitution (EAS) reactions described in textbooks, monographs, and reviews comprises the obligatory formation of arenium ion intermediates (σ complexes) in a two-stage process. Our findings from several studies of EAS reactions challenge the generality of this mechanistic paradigm. This Account focuses on recent computational and experimental results for three types of EAS reactions: halogenation with molecular chlorine and bromine, nitration by mixed acid (mixture of nitric and sulfuric acids), and sulfonation with SO3. Our combined computational and experimental investigation of the chlorination of anisole with molecular chlorine in CCl4 found that addition-elimination pathways compete with the direct substitution processes. Detailed NMR investigation of the course of experimental anisole chlorination at varying temperatures revealed the formation of addition byproducts. Moreover, in the absence of Lewis acid catalysis, the direct halogenation processes do not involve arenium ion intermediates but instead proceed via concerted single transition states. We also obtained analogous results for the chlorination and bromination of several arenes in nonpolar solvents. We explored by theoretical computations and experimental spectroscopic studies the classic reaction of benzene nitration by mixed acid. The structure of the first intermediate in this process has been a subject of contradicting views. We have reported clear experimental UV/vis spectroscopic evidence for the formation of the first intermediate in this reaction. Our broader theoretical modeling of the process considers the effects of the medium as a bulk solvent but also the specific interactions of a H2SO4 solvent molecule with intermediates and transition states along the reaction path. In harmony with the obtained spectroscopic data, our computational results reveal that the structure of the initial π complex precludes the possibility of electronic charge transfer from the benzene π system to the nitronium unit. In contrast to usual interpretations, our computational results provide compelling evidence that in nonpolar, noncomplexing media and in the absence of catalysts, the mechanism of aromatic sulfonation with sulfur trioxide is concerted and does not involve the conventional σ-complex (Wheland) intermediates. Stable under such conditions, (SO3)2 dimers react with benzene much more readily than monomeric sulfur trioxide. In polar (complexing) media, the reaction follows the classic two-stage SEAr mechanism. Still, the rate-controlling transition state involves two SO3 molecules. The reactivity and regioselectivity in EAS reactions that follow the classic mechanistic scheme are quantified using a theoretically evaluated quantity, the electrophile affinity (Eα), which measures the stabilization energy associated with the formation of arenium ions. Examples of applications are provided.

[18]Annulene put into a new perspective.

New insights into [18]annulene were gained by looking more closely at its X-ray structure, revealing a close face-to-face stacking of 3.16 Å in a herringbone-like crystal packing. Hexadehydro[18]annulene was co-crystalized in a benzene matrix, demonstrating the stabilizing role of intercalated solvent molecules in solid annulenes.

The Design of "Neutral" Carbanions with Intramolecular Charge Compensation.

Strategies to construct zwitterionic anions from the parent anions are proposed. Two principles are employed; the cationic counterpart is (a) attached as a substituent or (b) inserted as an integral part at a remote location in the assembly. The optimized geometries reveal that a striking similarity exists between the zwitterions and the respective precursor parent anion. The computed vibrational frequencies emphasize that these novel entities are minima on their respective potential energy surfaces. A substantial HOMO-LUMO gap indicates that the proposed structures do not show instability in their respective electronic states and that the higher energy configuration states do not contribute to the ground state viability. The separation of charge between the monopoles in these zwitterions is demonstrated by moderately large nonzero dipole moments. Significant large energy barriers for rearrangement to the closely related positional isomers, demonstrated in a few cases, advocate the thermal stability (associated with spectroscopic viability) of the novel molecules. The donor capacity (basicity) of the anionic subunit in these zwitterions is comparable to that of the respective parent anions. Since the qualitative and quantitative features in the designed charged compensated complexes are conserved as anions, these molecules may perhaps be employed in synthetic organic or organometallic chemistry.

Pitfalls and Artifacts in the Use of PET/CT in Oncology Imaging.

Accurate reporting of combined PET/CT imaging requires a thorough understanding of the normal and variant physiological distribution of tracers as well as common incidental findings and technical artifacts. We describe these pitfalls and artifacts, what action may help to mitigate them in clinical practice, and what further action may be appropriate. This review presents these in a region-based approach, in order to closely mimic clinical practice, and focuses on technical artifacts followed by a description of two commonly used oncologic tracers: FDG and choline.

An Experimentally Established Key Intermediate in Benzene Nitration with Mixed Acid.

Experimental evidence is reported for the first intermediate in the classic SEAr reaction of benzene nitration with mixed acid. The UV/Vis spectroscopic investigation of the reaction showed an intense absorption at 320 nm (appearing as a band shoulder) arising from a reaction intermediate. Our theoretical modeling shows that the interaction between the two principal reactants with solvent (H2SO4) molecules significantly affects the structure of the initial complex. In this complex, a larger distance between the aromatic ring and nitronium ion precludes the possibility for electronic charge transfer from the benzene π-system to the electrophile. The computational modeling of the potential energy surface reveals that the reaction favors a stepwise mechanism with intermediate formation of π- and σ-(arenium ion) complexes.

Bonding, aromaticity, and planar tetracoordinated carbon in Si2CH 2 and Ge 2CH 2.

Natural bond orbital (NBO) analyses and dissected nucleus-independent chemical shifts (NICS π z z ) were computed to evaluate the bonding (bond type, electron occupation, hybridization) and aromatic character of the three lowest-lying Si2CH2 (1-Si, 2-Si, 3-Si) and Ge2CH2 (1-Ge, 2-Ge, 3-Ge) isomers. While their carbon C3H2 analogs favor classical alkene, allene, and alkyne type bonding, these Si and Ge derivatives are more polarizable and can favor "highly electron delocalized"? and "non-classical"? structures. The lowest energy Si 2CH2 and Ge 2CH2 isomers, 1-Si and 1-Ge, exhibit two sets of 3-center 2-electron (3c-2e) bonding; a π-3c-2e bond involving the heavy atoms (C-Si-Si and C-Ge-Ge), and a σ-3c-2e bond (Si-H-Si, Ge-H-Ge). Both 3-Si and 3-Ge exhibit π and σ-3c-2e bonding involving a planar tetracoordinated carbon (ptC) center. Despite their highly electron delocalized nature, all of the Si2CH2 and Ge2CH2 isomers considered display only modest two π electron aromatic character (NICS(0) π z z =--6.2 to -8.9 ppm, computed at the heavy atom ring center) compared to the cyclic-C 3H2 (-13.3 ppm). Graphical Abstract The three lowest Si2CH2 and Ge2CH2 isomers.

Four Decades of the Chemistry of Planar Hypercoordinate Compounds.

The idea of planar tetracoordinate carbon (ptC) was considered implausible for a hundred years after 1874. Examples of ptC were then predicted computationally and realized experimentally. Both electronic and mechanical (e.g., small rings and cages) effects stabilize these unusual bonding arrangements. Concepts based on the bonding motifs of planar methane and the planar methane dication can be extended to give planar hypercoordinate structures of other chemical elements. Numerous planar configurations of various central atoms (main-group and transition-metal elements) with coordination numbers up to ten are discussed herein. The evolution of such planar configurations from small molecules to clusters, to nanospecies and to bulk solids is delineated. Some experimentally fabricated planar materials have been shown to possess unusual electrical and magnetic properties. A fundamental understanding of planar hypercoordinate chemistry and its potential will help guide its future development.

Stabilization of elusive silicon oxides.

Molecular SiO2 and other simple silicon oxides have remained elusive despite the indispensable use of silicon dioxide materials in advanced electronic devices. Owing to the great reactivity of silicon-oxygen double bonds, as well as the low oxidation state of silicon atoms, the chemistry of simple silicon oxides is essentially unknown. We now report that the soluble disilicon compound, L:Si=Si:L (where L: = :C{N(2,6-(i)Pr2C6H3)CH}2), can be directly oxidized by N2O and O2 to give the carbene-stabilized Si2O3 and Si2O4 moieties, respectively. The nature of the silicon oxide units in these compounds is probed by spectroscopic methods, complementary computations and single-crystal X-ray diffraction.

The 9-homocubyl cation rearrangement revisited.

Complexity of the potential energy surface of the 9-homocubyl cation is revealed by Born-Oppenheimer molecular dynamics simulations and high ab initio levels. The stereospecific automerizations observed experimentally involve bridged ions, which have either an aromatic or an anti-aromatic character. New pathways leading to more stable isomers are unveiled.

Aromaticity evaluations of planar [6]radialenes.

The aromatic character of fused polycyclic systems varies with the nature of their annulated rings. Computed extra cyclic resonance energies (ECREs) reveal that the central six membered rings (6MRs) of the heterocyclic fused congeners 1-5 are "[6]radialene-like", but that the central 6MRs of triphenylene 9, coronene 10, and isocoronene 11 are "benzene-like." Comparisons with geometric (harmonic oscillator model of aromaticity, HOMA) and magnetic (nucleus independent chemical shifts, NICS) criteria illustrate the multifaceted nature of aromaticity in 1-11.

Reciprocal hydrogen bonding-aromaticity relationships.

Computed association energies and dissected nucleus-independent chemical shifts (NICS) document the mutual enhancement (or reduction) of intermolecular interactions and the aromaticity of H-bonded substrates. H-bonding interactions that increase cyclic 4n + 2 π-electron delocalization boost aromaticity. Conversely, such interactions are weakened when aromaticity is decreased as a result of more localized quinoidal π character. Representative examples of the tautomeric equilibria of π-conjugated heterocyclic compounds in protic solvents and other H-bonding environments also illustrate such H-bonding/aromaticity interplay.

Al2C monolayer: the planar tetracoordinate carbon global minimum.

Inspired by our theoretical finding that C2Al6(2-) has a planar D2h minimum with two planar tetracoordinate carbons (ptCs), we computationally designed a new two-dimensional (2D) inorganic material, an Al2C monolayer. All carbons in this monolayer are ptC's, stabilized inductively by binding to four electropositive Al atoms in the same plane. The Al2C monolayer is semiconducting with an indirect minimum band gap and a slightly larger direct band gap. Good persistence of the Al2C monolayer is indicated by its moderate cohesive energy, the absence of imaginary modes in its phonon spectrum, and the high melting point predicted by molecular dynamics (MD) simulations. Moreover, a particle-swarm optimization (PSO) global minimum search found the Al2C monolayer to be the lowest-energy 2D structure compared to other Al2C alternatives. Dividing the Al2C monolayer results in one-dimensional (1D) Al2C nanoribbons, which are computed to have quite rich characteristics such as direct or indirect band gaps with various values, depending on the direction of the division and the resulting edge configuration.

Arenium ions are not obligatory intermediates in electrophilic aromatic substitution.

Our computational and experimental investigation of the reaction of anisole with Cl2 in nonpolar CCl4 solution challenges two fundamental tenets of the traditional SEAr (arenium ion) mechanism of aromatic electrophilic substitution. Instead of this direct substitution process, the alternative addition-elimination (AE) pathway is favored energetically. This AE mechanism rationalizes the preferred ortho and para substitution orientation of anisole easily. Moreover, neither the SEAr nor the AE mechanisms involve the formation of a σ-complex (Wheland-type) intermediate in the rate-controlling stage. Contrary to the conventional interpretations, the substitution (SEAr) mechanism proceeds concertedly via a single transition state. Experimental NMR investigations of the anisole chlorination reaction course at various temperatures reveal the formation of tetrachloro addition by-products and thus support the computed addition-elimination mechanism of anisole chlorination in nonpolar media. The important autocatalytic effect of the HCl reaction product was confirmed by spectroscopic (UV-visible) investigations and by HCl-augmented computational modeling.

Dynamic complexation of copper(I) chloride by carbene-stabilized disilicon.

Reaction of N-heterocyclic-carbene (NHC)-stabilized disilicon (1) with CuCl gave a carbene-stabilized disilicon-copper(I) chloride complex (2). The nature of the structure and bonding in 2 has been investigated by crystallographic, spectroscopic, and computational methods. The dynamic complexation behavior of 2 was experimentally explored by variable-temperature NMR analysis.