Improved accuracy of quantitative parameter estimates in dynamic contrast-enhanced CT study with low temporal resolution.

PURPOSE: A previously proposed method to reduce radiation dose to patient in dynamic contrast-enhanced (DCE) CT is enhanced by principal component analysis (PCA) filtering which improves the signal-to-noise ratio (SNR) of time-concentration curves in the DCE-CT study. The efficacy of the combined method to maintain the accuracy of kinetic parameter estimates at low temporal resolution is investigated with pixel-by-pixel kinetic analysis of DCE-CT data. METHODS: The method is based on DCE-CT scanning performed with low temporal resolution to reduce the radiation dose to the patient. The arterial input function (AIF) with high temporal resolution can be generated with a coarsely sampled AIF through a previously published method of AIF estimation. To increase the SNR of time-concentration curves (tissue curves), first, a region-of-interest is segmented into squares composed of 3 × 3 pixels in size. Subsequently, the PCA filtering combined with a fraction of residual information criterion is applied to all the segmented squares for further improvement of their SNRs. The proposed method was applied to each DCE-CT data set of a cohort of 14 patients at varying levels of down-sampling. The kinetic analyses using the modified Tofts' model and singular value decomposition method, then, were carried out for each of the down-sampling schemes between the intervals from 2 to 15 s. The results were compared with analyses done with the measured data in high temporal resolution (i.e., original scanning frequency) as the reference. RESULTS: The patients' AIFs were estimated to high accuracy based on the 11 orthonormal bases of arterial impulse responses established in the previous paper. In addition, noise in the images was effectively reduced by using five principal components of the tissue curves for filtering. Kinetic analyses using the proposed method showed superior results compared to those with down-sampling alone; they were able to maintain the accuracy in the quantitative histogram parameters of volume transfer constant [standard deviation (SD), 98th percentile, and range], rate constant (SD), blood volume fraction (mean, SD, 98th percentile, and range), and blood flow (mean, SD, median, 98th percentile, and range) for sampling intervals between 10 and 15 s. CONCLUSIONS: The proposed method of PCA filtering combined with the AIF estimation technique allows low frequency scanning for DCE-CT study to reduce patient radiation dose. The results indicate that the method is useful in pixel-by-pixel kinetic analysis of DCE-CT data for patients with cervical cancer.

Quality assurance of asymmetric jaw alignment using 2D diode array.

PURPOSE: A method using a 2D diode array is proposed to measure the junction gap (or overlap) and dose with high precision for routine quality assurance of the asymmetric jaw alignment. METHODS: The central axis (CAX) of the radiation field was determined with a 15 × 15 cm(2) photon field at four cardinal collimator angles so that the junction gap (or overlap) can be measured with respect to the CAX. Two abutting fields having a field size of 15 cm (length along the axis parallel to the junction) × 7.5 cm (width along the axis perpendicular to the junction) were used to irradiate the 2D diode array (MapCHECK2) with 100 MU delivered at the photon energy of 6 MV. The collimator was slightly rotated at 15° with respect to the beam central axis to increase the number of diodes effective on the measurement of junction gap. The junction gap and dose measured in high spatial resolution were compared to the conventional methods using an electronic portal imaging device (EPID) and radiochromic film, respectively. In addition, the reproducibility and sensitivity of the proposed method to the measurements of junction gap and dose were investigated. RESULTS: The junction gap (or overlap) and dose measured by MapCHECK2 agreed well to those measured by the conventional methods of EPID and film (the differences ranged from -0.01 to 0 cm and from -1.34% to 0.6% for the gap and dose, respectively). No variation in the repeat measurements of the junction gap was found whereas the measurements of junction dose were found to vary in quite a small range over the days of measurement (0.21%-0.35%). While the sensitivity of the measured junction gap to the actual junction gap applied was the ideal value of 1 cm∕cm as expected, the sensitivity of the junction dose to the actual junction gap increased as the junction gap (or overlap) decreased (maximum sensitivity: 201.7%∕cm). CONCLUSIONS: The initial results suggest that the method is applicable for a comprehensive quality assurance of the asymmetric jaw alignment.

A comparison of dynamic contrast-enhanced CT and MR imaging-derived measurements in patients with cervical cancer.

This work is to compare the kinetic parameters derived from the DCE-CT and -MR data of a group of 37 patients with cervical cancer. The modified Tofts model and the reference tissue method were applied to estimate kinetic parameters. In the MR kinetic analyses using the modified Tofts model for each patient data set, both the arterial input function (AIF) measured from DCE-MR images and a population-averaged AIF from the literature were applied to the analyses, while the measured AIF was used for the CT kinetic analysis. The kinetic parameters obtained from both modalities were compared. Significant moderate correlations were found in modified Tofts parameters [volume transfer constant(K(trans) ) and rate constant (k(ep) )] between CT and MR analysis for MR with the measured AIFs (R = 0·45, P<0·01 and R = 0·40, P<0·01 in high-K(trans) region; R = 0·38, P<0·01 and R = 0·80, P<0·01 in low-K(trans) region) as well as with the population-averaged AIF (R = 0·59, P<0·01 and R = 0·62, P<0·01 in high-K(trans) region; R = 0·50, P<0·01 and R = 0·63, P<0·01 in low-K(trans) region), respectively. In addition, from the Bland-Altman plot analysis, it was found that the systematic biases (the mean difference) between the modalities were drastically reduced in magnitude by adopting the population-averaged AIF for the MR analysis instead of the measured ones (from 51·5% to 18·9% for K(trans) and from 21·7% to 4·1% for k(ep) in high-K(trans) region; from 73·0% to 29·4% for K(trans) and from 63·4% to 24·5% for k(ep) in low-K(trans) region). The preliminary results showed the feasibility in the interchangeable use of the two imaging modalities in assessing cervical cancers.

A method for patient dose reduction in dynamic contrast enhanced CT study.

PURPOSE: In dynamic contrast enhanced CT (DCE-CT) study, prolonged CT scanning with high temporal resolution is required to give accurate and precise estimates of kinetic parameters. However, such scanning protocol could lead to substantial radiation dose to the patient. A novel method is proposed to reduce radiation dose to patient, while maintaining high accuracy for kinetic parameter estimates in DCE-CT study. METHODS: The method is based on a previous investigation that the arterial impulse response (AIR) in DCE-CT study can be predicted using a population-based scheme. In the proposed method, DCE-CT scanning is performed with relatively low temporal resolution, hence, giving rise to reduction in patient dose. A novel method is proposed to estimate the arterial input function (AIF) based on the coarsely sampled AIF. By using the estimated AIF in the tracer kinetic analysis of the coarsely sampled DCE-CT study, the calculated kinetic parameters are able to achieve a high degree of accuracy. The method was tested on a DCE-CT data set of 48 patients with cervical cancer scanned at high temporal resolution. A random cohort of 34 patients was chosen to construct the orthonormal bases of the AIRs via singular value decomposition method. The determined set of orthonormal bases was used to fit the AIFs in the second cohort (14 patients) at varying levels of down sampling. For each dataset in the second cohort, the estimated AIF was used for kinetic analyses of the modified Tofts and adiabatic tissue homogeneity models for each of the down-sampling schemes between intervals from 2 to 15 s. The results were compared with analyses done with the "raw" down-sampled AIF. RESULTS: In the first group of 34 patients, there were 11 orthonormal bases identified to describe the AIRs. The AIFs in the second group were estimated in high accuracy based on the 11 orthonormal bases established in the first group along with down-sampled AIFs. Using the 11 orthonormal bases, the estimated AIFs for the second group were found to have an averaged maximal percentage error of 3.4% ± 7.5% in all sampling schemes up to 15 s. The results of kinetic analysis with the proposed method compared with down sampling alone showed that the proposed method is superior in maintaining the accuracy in volume transfer constant (K(trans) ) after 9 s down-sampling interval, blood volume (v(b) ) for almost all down-sampling intervals, and blood flow (F) after 11 s down-sampling interval. The preliminary results suggested that the proposed method is able to support scanning intervals of 10-15 s at a cost of 6.2%-10.0% loss in accuracy of K(trans) and 10.9%-19.4% in v(b), and the scanning intervals of 12-15 s at a cost of 9.7%-14.6% for F in DEC-CT studies for patients with cervix cancer. CONCLUSIONS: The proposed method of AIF estimation allows low scanning frequency in DCE-CT study to reduce radiation dose to patient, while maintaining relatively high accuracy in the kinetic parameter estimates. The initial results suggested that the method is applicable for DCE-CT studies for patients with cervical cancer.

Spinal cord blood flow and blood vessel permeability measured by dynamic computed tomography imaging in rats after localized delivery of fibroblast growth factor.

Following spinal cord injury, profound vascular changes lead to ischemia and hypoxia of spinal cord tissue. Since fibroblast growth factor 2 (FGF2) has angiogenic effects, its delivery to the injured spinal cord may attenuate the tissue damage associated with ischemia. To limit systemic mitogenic effects, FGF2 was delivered to the spinal cord via a gel of hyaluronan and methylcellulose (HAMC) injected into the intrathecal space, and compared to controls receiving HAMC alone and artificial cerebrospinal fluid (aCSF) alone. Dynamic perfusion computed tomography (CT) was employed for the first time in small animals to serially measure blood flow and permeability in the injured and uninjured spinal cord. Spinal cord blood flow (SCBF) and permeability-surface area (PS) measurements were obtained near the injury epicenter, and at two regions rostral to the epicenter in animals that received a 26-g clip compression injury. As predicted, SCBF measurements decreased and PS increased after injury. FGF2 delivered via HAMC after injury restored SCBF towards pre-injury values in all regions, and increased blood flow rates at 7 days post-injury compared to pre-injury measurements. PS was stabilized at regions rostral to the epicenter of injury when FGF2 was delivered with HAMC, with significantly lower values than aCSF controls at 7 days in the region farthest from the epicenter. Laminin staining for blood vessels showed a qualitative increase in vessel density after 7 days when FGF2 was locally delivered. Additionally, permeability stains showed that FGF2 moderately decreased permeability at 7 days post-injury. These data demonstrate that localized delivery of FGF2 improves spinal cord hemodynamics following injury, and that perfusion CT is an important technique to serially measure these parameters in small animal models of spinal cord injury.

Genistein can mitigate the effect of radiation on rat lung tissue.

We investigated whether genistein could protect the lung from radiation-induced injury. We hypothesized that genistein would reduce the levels of inflammatory cytokines and ROS after irradiation and therefore lead to reduced DNA damage and functional deficits. Whole lungs of Sprague-Dawley rats were irradiated with 18 Gy at approximately 0.5 Gy/min. At 28 weeks a micronucleus assay was used to examine DNA damage and, using immunohistochemical analysis, expression of IL-1alpha, IL-1beta, IL-6, TNF-alpha and TGF-beta, macrophage activation, oxidative stress (8-OHdG) and collagen levels were measured. A TBARS assay was used to measure the level of malondialdehyde. Functional damage was assessed by measuring the breathing rate of the rats over the course of the experiment. The increase in breathing rate after irradiation was damped in rats receiving genistein during the phase of pneumonitis (6-10 weeks), and there was a 50-80-day delay in lethality in this group. Genistein treatment also decreased the levels of the inflammatory cytokines TNF-alpha, IL-1beta and TGF-beta and led to a reduction in collagen content, a reduction in 8-OHdG levels, and complete protection against DNA damage measured in surviving rats at 28 weeks after irradiation. These results demonstrates that genistein treatment can provide partial protection against the early (pneumonitis) effects of lung irradiation and reduce the extent of fibrosis, although not sufficiently to prevent lethality at the radiation dose used in this study.

Effects of genistein following fractionated lung irradiation in mice.

BACKGROUND AND PURPOSE: This study investigated protection of lung injury by genistein following fractionated doses of radiation and its effect on tumor response. MATERIAL AND METHODS: C3H/HeJ mice were irradiated (100 kVp X-rays) with 9 fractions of 3.1 Gy over 30 days (approximately equivalent to 10 Gy single dose) and were maintained on a genistein diet ( approximately 10mg/kg). Damage was assessed over 28 weeks in lung cells by a cytokinesis block micronucleus (MN) assay and by changes in breathing rate and histology. Tumor protection was assessed using a colony assay to determine cell survival following in situ irradiation of small lung nodules (KHT fibrosarcoma). RESULTS: Genistein caused about a 50% reduction in the MN damage observed during the fractionated radiation treatment and this damage continued to decrease at later times to background levels by 16 weeks. In mice not receiving Genistein MN levels remained well above background out to 28 weeks after irradiation. Genistein reduced macrophage accumulation by 22% and reduced collagen deposition by 28%. There was minimal protection against increases in breathing rate or severe morbidity during pneumonitis. No tumor protection by genistein treatment was observed. CONCLUSIONS: Genistein at the dose levels used in this study partially reduced the extent of fibrosis developing in mouse lung caused by irradiation but gave minimal protection against pneumonitis. There was no evidence that genistein caused protection of small tumors growing in the lung.

A dual modality phantom for cone beam CT and ultrasound image fusion in prostate implant.

In transrectal ultrasound (TRUS) guided prostate seed brachytherapy, TRUS provides good delineation of the prostate while x-ray imaging, e.g., C-arm, gives excellent contrast for seed localization. With the recent availability of cone beam CT (CBCT) technology, the combination of the two imaging modalities may provide an ideal system for intraoperative dosimetric feedback during implantation. A dual modality phantom made of acrylic and copper wire was designed to measure the accuracy and precision of image coregistration between a C-arm based CBCT and 3D TRUS. The phantom was scanned with TRUS and CBCT under the same setup condition. Successive parallel transverse ultrasound (US) images were acquired through manual stepping of the US probe across the phantom at an increment of 1 mm over 7.5 cm. The CBCT imaging was done with three reconstructed slice thicknesses (0.4, 0.8, and 1.6 mm) as well as at three different tilt angles (0 degrees, 15 degrees, 30 degrees), and the coregistration between CBCT and US images was done using the Variseed system based on four fiducial markers. Fiducial localization error (FLE), fiducial registration error (FRE), and target registration error (TRE) were calculated for all registered image sets. Results showed that FLE were typically less than 0.4 mm, FRE were less than 0.5 mm, and TRE were typically less than 1 mm within the range of operation for prostate implant (i.e., < 6 cm to surface of US probe). An analysis of variance test showed no significant difference in TRE for the CBCT-US fusion among the three slice thicknesses (p = 0.37). As a comparison, the experiment was repeated with a US-conventional CT scanner combination. No significant difference in TRE was noted between the US-conventional CT fusion and that for all three CBCT image slice thicknesses (p = 0.21). CBCT imaging was also performed at three different C-arm tilt angles of 0 degrees, 15 degrees and 30 degrees and reconstructed at a slice thickness of 0.8 mm. There is no significant difference in TRE between 0 degrees and 15 degrees (p = 0.191) as well as between 0 degrees and 30 degrees (p = 0.275), which suggests that the C-arm may be tilted intraoperatively to acquire CBCT images without compromising the quality of image fusion. The results conclude a high degree of accuracy and precision for the CBCT-TRUS fusion, which could be useful toward achieving real time intraoperative dosimetry in prostate brachytherapy.

Partial volume rat lung irradiation: the protective/mitigating effects of Eukarion-189, a superoxide dismutase-catalase mimetic.

BACKGROUND AND PURPOSE: The purpose of the current study was to elucidate the protective/mitigating effects of a SOD-catalase mimetic, Eukarion-189 (EUK-189), on DNA damage in rat lung following irradiation. The particular focus of these studies was the efficacy of EUK-189 when given after irradiation (mitigation). PATIENTS AND METHODS: We exposed whole or lower lungs of female Sprague-Dawley rats to doses ranging from 10 to 20.5 Gray (Gy) of (60)Co gamma rays. Animals in the EUK-189 treated groups received 2 or 30 mg/kg intraperitoneally (i.p.) at various times postirradiation (PI). A micronucleus assay was used to examine DNA damage at various times up to 16 weeks PI. RESULTS: Our results indicated that EUK-189 administration after irradiation is effective at reducing micronucleus formation in lung fibroblasts at various times following radiation exposure. Treatment with EUK-189 in the first 3 days after thoracic irradiation did not, however, modify the dose required to cause severe morbidity at 2-3 months after irradiation. CONCLUSIONS: The protection produced when Eukarion-189 was given shortly after irradiation suggests that DNA damage observed in the lung may be caused by chronic production of ROS induced by a chronic inflammatory response initiated by the radiation treatment. We speculate that our failure to observe protection against severe morbidity at 2-3 months may be because our treatment regime only blocked the initial wave of ROS production and that treatment needs to be more prolonged to suppress the effects of a chronic inflammatory response.

Partial volume rat lung irradiation: temporal fluctuations of in-field and out-of-field DNA damage and inflammatory cytokines following irradiation.

PURPOSE: The current study investigated the early activation of inflammatory cytokines and macrophages in different regions of the lung following partial volume irradiation. We examined temporal fluctuations in DNA damage, cytokine expression and macrophage activation during 16 weeks post-irradiation. MATERIALS AND METHODS: We irradiated the lower lung of Sprague-Dawley rats with 10 Gy. A micronucleus assay was used to examine DNA damage. Real-time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) was used to analyse the RNA expression of Interleukin-1 alpha (IL-1a), Interleukin-1 beta (IL-1ss), Interleukin-6 (IL-6), Tumour Necrosis Factor alpha (TNF-a) and Transforming Growth Factor beta (TGF-ss) relative to Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH). The activation of macrophages was determined using the antibody ED-1 for immunohistochemical analysis. RESULTS: The expression of DNA damage, the activation of macrophages and the expression of inflammatory cytokines all fluctuated in a cyclic pattern. The initial induction of cytokine expression and the activation of macrophages occurred at very early times (1 h) following irradiation. Waves of cytokine expression and macrophage activation were also seen at later times (up to 16 weeks) following irradiation. DNA damage also occurred in a cyclic pattern though this was less pronounced out-of-field. The levels of cytokines and activated macrophages were elevated to a similar degree both in- and out-of-field, whereas there was a greater micronuclei yield in-field than out-of-field. CONCLUSIONS: An inflammatory response triggered by the partial volume irradiation occurs in the whole rat lung at very early times following irradiation and is maintained in a cyclic pattern to later times when the onset of functional symptoms is expected. We hypothesize that Reactive Oxygen Species (ROS) induced by this response play an important role in the induction of both in-field and out-of-field DNA damage.

Functional CT imaging of prostate cancer.

The purpose of this paper is to investigate the distribution of blood flow (F), mean capillary transit time (Tc), capillary permeability (PS) and blood volume (vb) in prostate cancer using contrast-enhanced CT. Nine stage T2-T3 prostate cancer patients were enrolled in the study. Following bolus injection of a contrast agent, a time series of CT images of the prostate was acquired. Functional maps showing the distribution of F, Tc, PS and vb within the prostate were generated using a distributed parameter tracer kinetic model, the adiabatic approximation to the tissue homogeneity model. The precision of the maps was assessed using covariance matrix analysis. Finally, maps were compared to the findings of standard clinical investigations. Eight of the functional maps demonstrated regions of increased F, PS and vb, the locations of which were consistent with the results of standard clinical investigations. However, model parameters other than F could only be measured precisely within regions of high F. In conclusion functional CT images of cancer-containing prostate glands demonstrate regions of elevated F, PS and Vb. However, caution should be used when applying a complex tracer kinetic model to the study of prostate cancer since not all parameters can be measured precisely in all areas.

Partial volume rat lung irradiation; assessment of early DNA damage in different lung regions and effect of radical scavengers.

PURPOSE: These studies were designed to examine radiation-induced in-field and out-of-field DNA damage in rat lung as a function of dose and various volumes of irradiation. They also determined whether superoxide dismutase (SOD) and nitro-L-arginine methyl ester (L-NAME) protected against this damage. METHODS AND MATERIALS: The whole lung, or various volumes of the lower or upper lungs of Sprague-Dawley rats were exposed to doses up to 20 Gy of 60Co gamma rays. Radiation-induced DNA damage was quantified in fibroblasts obtained at 18 h after irradiation from both irradiated and shielded lung regions using a micronucleus assay. The radioprotective role of SOD (CuZnSOD: 10 mg/kg body weight; MnSOD: 50-100mg/kg body weight) and L-NAME (0.2 mg/kg body weight.) in vivo was determined by injecting them into rats 30 min before or immediately after a dose of 10 Gy. RESULTS: Micronucleus formation was approximately linear with dose up to 15 Gy. When 70% of the lung volume was irradiated with 10 Gy, irradiated lower lung gave similar numbers of micronuclei (MN)/binucleate cell (BN) to that observed following whole lung irradiation (0.91 MN/BN), whereas the irradiated upper lung gave only 0.66 MN/BN. Following lower lung irradiation, the shielded upper lung (30% of lung volume) showed substantial (out-of-field) damage (0.43 MN/BN). When 30% of the lung was given 10 Gy, irradiated upper or lower lung showed similar amounts of in-field damage (0.43 MN/BN) but this was smaller than that seen following irradiation of 70% of the lung volume. For 30% lower lung irradiation, the shielded upper lung showed only a small out-of-field effect (0.1 MN/BN). For both volumes of irradiation there was a similar or smaller effect in the shielded lower lung after upper lung irradiation. Injection of SOD before or L-NAME after 10 Gy to the lower 70% lung volume resulted in a reduction in DNA damage both in-field and out-of-field but the percentage was much greater for out-of-field damage (50-60%) than for in-field damage (10-30%). Following whole lung irradiation (10 Gy) significantly greater DNA damage was observed in fibroblasts from the left lung than from the right lung (0.93 MN/BN vs. 0.82 MN/BN). Following whole lung irradiation there was no significant difference in DNA damage observed in fibroblasts from the lower lung and the upper lung. CONCLUSIONS: With partial lung irradiation the lower lung sustains more in-field DNA damage following irradiation than the upper lung, whereas out-of-field effects are observed primarily in the upper lung (i.e. following lower lung irradiation). Following whole lung irradiation the left lung sustains more damage than the right lung but there is no difference between the upper and lower lung. The protective effects of SOD and L-NAME suggest that inflammatory cytokines induced by the irradiation may be involved in the initiation of a reaction resulting in the production of reactive oxyradicals and nitric oxide that cause indirect DNA damage both in and out of the radiation field.