Observation of interfractional variations in lung tumor position using respiratory gated and ungated megavoltage cone-beam computed tomography.

PURPOSE: To evaluate the use of megavoltage cone-beam computed tomography (MV CBCT) to measure interfractional variation in lung tumor position. METHODS AND MATERIALS: Eight non-small-cell lung cancer patients participated in the study, 4 with respiratory gating and 4 without. All patients underwent MV CBCT scanning at weekly intervals. Contoured planning CT and MV CBCT images were spatially registered based on vertebral anatomy, and displacements of the tumor centroid determined. Setup error was assessed by comparing weekly portal orthogonal radiographs with digitally reconstructed radiographs generated from planning CT images. Hypothesis testing was performed to test the statistical significance of the volume difference, centroid displacement, and setup uncertainty. RESULTS: The vertebral bodies and soft tissue portions of tumor within lung were visible on the MV CBCT scans. Statistically significant systematic volume decrease over the course of treatment was observed for 1 patient. The average centroid displacement between simulation CT and MV CBCT scans were 2.5 mm, -2.0 mm, and -1.5 mm with standard deviations of 2.7 mm, 2.7 mm, and 2.6 mm in the right-left, anterior-posterior and superior-inferior directions. The mean setup errors were smaller than the centroid shifts, while the standard deviations were comparable. In most cases, the gross tumor volume (GTV) defined on the MV CBCT was located on average at least 5 mm inside a 10 mm expansion of the GTV defined on the planning CT scan. CONCLUSIONS: The MV CBCT technique can be used to image lung tumors and may prove valuable for image-guided radiotherapy. Our conclusions must be verified in view of the small patient number.

A patient-specific respiratory model of anatomical motion for radiation treatment planning.

The modeling of respiratory motion is important for a more accurate understanding and accounting of its effect on dose to cancers in the thorax and abdomen by radiotherapy. We have developed a model of respiration-induced organ motion in the thorax without the commonly adopted assumption of repeatable breath cycles. The model describes the motion of a volume of interest within the patient based on a reference three-dimensional (3D) image (at end expiration) and the diaphragm positions at different time points. The input data are respiration-correlated CT (RCCT) images of patients treated for non-small- cell lung cancer, consisting of 3D images, including the diaphragm positions, at ten phases of the respiratory cycle. A deformable image registration algorithm calculates the deformation field that maps each 3D image to the reference 3D image. A principal component analysis is performed to parameterize the 3D deformation field in terms of the diaphragm motion. We show that the first two principal components are adequate to accurately and completely describe the organ motion in the data of four patients. Artifacts in the RCCT images that commonly occur at the mid-respiration states are reduced in the model-generated images. Further validation of the model is demonstrated in the successful application of the parameterized 3D deformation field to RCCT data of the same patient but acquired several days later. We have developed a method for predicting respiration-induced organ motion in patients that has potential for improving the accuracy of dose calculation in radiotherapy. Possible limitations of the model are cases where the correlation between lung tumor and diaphragm position is less reliable such as superiorly situated tumors and interfraction changes in tumor-diaphragm correlation. The limited number of clinical cases examined suggests, but does not confirm, the model's applicability to a wide range of patients.

Time-resolved absorption and UV resonance Raman spectra reveal stepwise formation of T quaternary contacts in the allosteric pathway of hemoglobin.

Hemoglobin undergoes a series of molecular changes on the nanosecond and microsecond time-scale following photodissociation of CO ligands. We have monitored these processes with a combination of transient absorption and resonance Raman (RR) spectroscopy. The latter have been acquired at higher data rates than previously available, thanks to kilohertz Ti:sapphire laser technology, with frequency-quadrupling into the ultraviolet. As a result of improved resolution of the UVRR time-course, a new intermediate has been identified in the pathway from the R (HbCO) to the T (deoxyHb) state. This intermediate is not detected via absorption transients, since the change in heme absorption is insignificant, but its lifetime agrees with a reported magnetic circular dichroism transient, which has been attributed to a quaternary tryptophan interaction. The new UVRR data allow elaboration of the allosteric pathway by establishing that the T-state quaternary contacts are formed in two well-separated steps, with time constants of 2.9 micros and 21 micros, instead of a single 20 micros process. The first step involves the "hinge" region contacts, as monitored by the Trp beta 37...Asp alpha 94 H-bond, while the second involves the "switch" region, as monitored by the Tyr alpha 42...Asp beta 99 H-bond. A working model for the allosteric pathway is presented.

Hemoglobin site-mutants reveal dynamical role of interhelical H-bonds in the allosteric pathway: time-resolved UV resonance Raman evidence for intra-dimer coupling.

The dynamical effect of eliminating specific tertiary H-bonds in the hemoglobin (Hb) tetramer has been investigated by site-directed mutagenesis and time-resolved absorption and ultraviolet resonance Raman (UVRR) spectroscopy. The Trp alpha 14...Thr alpha 67 and Trp beta 15...Ser beta 72 H-bonds connect the A and E helices in the alpha and beta chains, and are proposed to break in the earliest protein intermediate (Rdeoxy) following photo-deligation of HbCO, along with a second pair of H-bonds involving tyrosine residues. Mutation of the acceptor residues Thr alpha 67 and Ser beta 72 to Val and Ala eliminates the A-E H-bonds, but has been shown to have no significant effect on ligand-binding affinity or cooperativity, or on spectroscopic markers of the T-state quaternary interactions. However, the mutations have profound and unexpected effects on the character of the Rdeoxy intermediate, and on the dynamics of the subsequent steps leading to the T state. Formation of the initial quaternary contact (RT intermediate) is accelerated, by an order of magnitude, but the locking-in of the T state is delayed by a factor of 2. These rate effects are essentially the same for either mutation, or for the double mutation, suggesting that the alpha beta dimer behaves as a mechanically coupled dynamical unit. Further evidence for intra-dimer coupling is provided by the Rdeoxy UVRR spectrum, in which either or both mutations eliminate the tyrosine difference intensity, although only tryptophan H-bonds are directly affected. A possible mechanism for mechanical coupling is outlined, involving transmission of forces through the alpha(1)beta(1) (and alpha(2)beta(2)) interface. The present observations establish that quaternary motions can occur on the approximately 100 ns time-scale. They show also that a full complement of interhelical H-bonds actually slows the initial quaternary motion in Hb, but accelerates the locking in of the T-contacts.

Effect of motion on tracer activity determination in CT attenuation corrected PET images: a lung phantom study.

Respiratory motion is known to affect the quantitation of 18FDG uptake in lung lesions. The aim of the study was to investigate the magnitude of errors in tracer activity determination due to motion, and its dependence upon CT attenuation at different phases of the motion cycle. To estimate these errors we have compared maximum activity concentrations determined from PET/CT images of a lung phantom at rest and under simulated respiratory motion. The NEMA 2001 IEC body phantom, containing six hollow spheres with diameters 37, 28, 22, 17, 13, and 10 mm, was used in this study. To mimic lung tissue density, the phantom (excluding spheres) was filled with low density polystyrene beads and water. The phantom spheres were filled with 18FDG solution setting the target-to-background activity concentration ratio at 8:1. PET/CT data were acquired with the phantom at rest, and while it was undergoing periodic motion along the longitudinal axis of the scanner with a range of displacement being 2 cm, and a period of 5 s. The phantom at rest and in motion was scanned using manufacturer provided standard helical/clinical protocol, a helical CT scan followed by a PET emission scan. The moving phantom was also scanned using a 4D-CT protocol that provides volume image sets at different phases of the motion cycle. To estimate the effect of motion on quantitation of activities in six spheres, we have examined the activity concentration data for (a) the stationary phantom, (b) the phantom undergoing simulated respiratory motion, and (c) a moving phantom acquired with PET/4D-CT protocol in which attenuation correction was performed with CT images acquired at different phases of motion cycle. The data for the phantom at rest and in motion acquired with the standard helical/clinical protocol showed that the activity concentration in the spheres can be underestimated by as much as 75%, depending on the sphere diameter. We have also demonstrated that fluctuations in sphere's activity concentration from one PET/CT scan to another acquired with standard helical/clinical protocol can arise as a consequence of spatial mismatch between the sphere's location in PET emission and the CT data.

Measurement of lung tumor motion using respiration-correlated CT.

PURPOSE: We investigate the characteristics of lung tumor motion measured with respiration-correlated computed tomography (RCCT) and examine the method's applicability to radiotherapy planning and treatment. METHODS AND MATERIALS: Six patients treated for non-small-cell lung carcinoma received a helical single-slice computed tomography (CT) scan with a slow couch movement (1 mm/s), while simultaneously respiration is recorded with an external position-sensitive monitor. Another 6 patients receive a 4-slice CT scan in a cine mode, in which sequential images are acquired for a complete respiratory cycle at each couch position while respiration is recorded. The images are retrospectively resorted into different respiration phases as measured with the external monitor (4-slice data) or patient surface displacement observed in the images (single-slice data). The gross tumor volume (GTV) in lung is delineated at one phase and serves as a visual guide for delineation at other phases. Interfractional GTV variation is estimated by scaling diaphragm position variations measured in gated radiographs at treatment with the ratio of GTV:diaphragm displacement observed in the RCCT data. RESULTS: Seven out of 12 patients show GTV displacement with respiration of more than 1 cm, primarily in the superior-inferior (SI) direction; 2 patients show anterior-posterior displacement of more than 1 cm. In all cases, extremes in GTV position in the SI direction are consistent with externally measured extremes in respiration. Three patients show evidence of hysteresis in GTV motion, in which the tumor trajectory is displaced 0.2 to 0.5 cm anteriorly during expiration relative to inspiration. Significant (>1 cm) expansion of the GTV in the SI direction with respiration is observed in 1 patient. Estimated intrafractional GTV motion for gated treatment at end expiration is 0.6 cm or less in all cases; however; interfraction variation estimates (systematic plus random) are more than 1 cm in 3/9 patients. CONCLUSION: Respiration-correlated CT can be performed with currently available CT equipment and acquisition settings. RCCT provides not only three-dimensional information on intrafractional tumor motion and deformation, but also allows estimates of interfractional tumor variation when combined with radiographic measurements of diaphragm position variation during treatment.

Effect of motion on tracer activity determination in CT attenuation corrected PET images: A lung phantom study.

Respiratory motion is known to affect the quantitation of FDG18 uptake in lung lesions. The aim of the study was to investigate the magnitude of errors in tracer activity determination due to motion, and its dependence upon CT attenuation at different phases of the motion cycle. To estimate these errors we have compared maximum activity concentrations determined from PET/CT images of a lung phantom at rest and under simulated respiratory motion. The NEMA 2001 IEC body phantom, containing six hollow spheres with diameters 37, 28, 22, 17, 13, and 10 mm, was used in this study. To mimic lung tissue density, the phantom (excluding spheres) was filled with low density polystyrene beads and water. The phantom spheres were filled with FDG18 solution setting the target-to-background activity concentration ratio at 8:1. PET/CT data were acquired with the phantom at rest, and while it was undergoing periodic motion along the longitudinal axis of the scanner with a range of displacement being 2 cm, and a period of 5 s. The phantom at rest and in motion was scanned using manufacturer provided standard helical/clinical protocol, a helical CT scan followed by a PET emission scan. The moving phantom was also scanned using a 4D-CT protocol that provides volume image sets at different phases of the motion cycle. To estimate the effect of motion on quantitation of activities in six spheres, we have examined the activity concentration data for (a) the stationary phantom, (b) the phantom undergoing simulated respiratory motion, and (c) a moving phantom acquired with PET/4D-CT protocol in which attenuation correction was performed with CT images acquired at different phases of motion cycle. The data for the phantom at rest and in motion acquired with the standard helical/clinical protocol showed that the activity concentration in the spheres can be underestimated by as much as 75%, depending on the sphere diameter. We have also demonstrated that fluctuations in sphere's activity concentration from one PET/CT scan to another acquired with standard helical/clinical protocol can arise as a consequence of spatial mismatch between the sphere's location in PET emission and the CT data.

IR spectroscopic studies of major cellular components. III. Hydration of protein, nucleic acid, and phospholipid films.

The IR absorption spectra of protein, DNA, RNA, and phospholipid films as a function of the water content are reported. We find that the hydration of protein films affects the peak intensity of amide I and amide II bands and the shape of the amide III band. For nucleic acids, the symmetric (nu(S) PO(2) (-)) and antisymmetric (nu(AS) PO(2) (-)) stretching vibrations of the phosphate linkage are the most affected by hydration, because both intensity changes and frequency shifts are observed. The spectra of phospholipid films are also sensitive to hydration, and they exhibit changes in the peak intensities and frequencies of both nu(S) PO(2) (-) and nu(AS) PO(2) (-) vibrations. We interpret the spectral differences between water saturated and dried films both in terms of structural changes and the change in the local dielectric in the vicinity of the polar and solvent exposed groups. In addition, we observe that the most significant change in the absorption intensity, frequency, and shape of the water sensitive vibrations occurs at high hydration levels. The principal component analysis of hydration results and the kinetics of water removal from sample films are also discussed. In addition, protein spectra acquired using film and KBr pellet sampling techniques are compared.