Dynamic volume vs respiratory correlated 4DCT for motion assessment in radiation therapy simulation.

PURPOSE: Conventional (i.e., respiratory-correlated) 4DCT exploits the repetitive nature of breathing to provide an estimate of motion; however, it has limitations due to binning artifacts and irregular breathing in actual patient breathing patterns. The aim of this work was to evaluate the accuracy and image quality of a dynamic volume, CT approach (4D(vol)) using a 320-slice CT scanner to minimize these limitations, wherein entire image volumes are acquired dynamically without couch movement. This will be compared to the conventional respiratory-correlated 4DCT approach (RCCT). METHODS: 4D(vol) CT was performed and characterized on an in-house, programmable respiratory motion phantom containing multiple geometric and morphological "tumor" objects over a range of regular and irregular patient breathing traces obtained from 3D fluoroscopy and compared to RCCT. The accuracy of volumetric capture and breathing displacement were evaluated and compared with the ground truth values and with the results reported using RCCT. A motion model was investigated to validate the number of motion samples needed to obtain accurate motion probability density functions (PDF). The impact of 4D image quality on this accuracy was then investigated. Dose measurements using volumetric and conventional scan techniques were also performed and compared. RESULTS: Both conventional and dynamic volume 4DCT methods were capable of estimating the programmed displacement of sinusoidal motion, but patient breathing is known to not be regular, and obvious differences were seen for realistic, irregular motion. The mean RCCT amplitude error averaged at 4 mm (max. 7.8 mm) whereas the 4D(vol) CT error stayed below 0.5 mm. Similarly, the average absolute volume error was lower with 4D(vol) CT. Under irregular breathing, the 4D(vol) CT method provides a close description of the motion PDF (cross-correlation 0.99) and is able to track each object, whereas the RCCT method results in a significantly different PDF from the ground truth, especially for smaller tumors (cross-correlation ranging between 0.04 and 0.69). For the protocols studied, the dose measurements were higher in the 4D(vol) CT method (40%), but it was shown that significant mAs reductions can be achieved by a factor of 4-5 while maintaining image quality and accuracy. CONCLUSIONS: 4D(vol) CT using a scanner with a large cone-angle is a promising alternative for improving the accuracy with which respiration-induced motion can be characterized, particularly for patients with irregular breathing motion. This approach also generates 4DCT image data with a reduced total scan time compared to a RCCT scan, without the need for image binning or external respiration signals within the 16 cm scan length. Scan dose can be made comparable to RCCT by optimization of the scan parameters. In addition, it provides the possibility of measuring breathing motion for more than one breathing cycle to assess stability and obtain a more accurate motion PDF, which is currently not feasible with the conventional RCCT approach.

Phantom Validation of a Conservation of Activity-Based Partial Volume Correction Method for Arterial Input Function in Dynamic PET Imaging.

Dynamic PET (dPET) imaging can be utilized to perform kinetic modelling of various physiologic processes, which are exploited by the constantly expanding range of targeted radiopharmaceuticals. To date, dPET remains primarily in the research realm due to a number of technical challenges, not least of which is addressing partial volume effects (PVE) in the input function. We propose a series of equations for the correction of PVE in the input function and present the results of a validation study, based on a purpose built phantom. 18F-dPET experiments were performed using the phantom on a set of flow tubes representing large arteries, such as the aorta (1" 2.54 cm ID), down to smaller vessels, such as the iliac arteries and veins (1/4" 0.635 cm ID). When applied to the dPET experimental images, the PVE correction equations were able to successfully correct the image-derived input functions by as much as 59 ± 35% in the presence of background, which resulted in image-derived area under the curve (AUC) values within 8 ± 9% of ground truth AUC. The peak heights were similarly well corrected to within 9 ± 10% of the scaled DCE-CT curves. The same equations were then successfully applied to correct patient input functions in the aorta and internal iliac artery/vein. These straightforward algorithms can be applied to dPET images from any PET-CT scanner to restore the input function back to a more clinically representative value, without the need for high-end Time of Flight systems or Point Spread Function correction algorithms.

3'-Deoxy-3'-(18F) Fluorothymidine Positron Emission Tomography/Computed Tomography in Non-small Cell Lung Cancer Treated With Stereotactic Body Radiation Therapy: A Pilot Study.

Purpose: The primary objective was to compare 3'-deoxy-3'-(18F) fluorothymidine (FLT) positron emission tomography (PET)/computed tomography (CT) uptake in 3 cohorts of stereotactic body radiation therapy (SBRT) patients: (1) pre-SBRT, (2) stable post-SBRT lung fibrosis, and (3) suspicious or proven local recurrence post-SBRT. The secondary objectives were to optimize FLT-PET imaging by comparing FLT uptake in respiratory-gated (4-dimensional) versus nongated (3-dimensional) FLT-PET scans. Methods: Patients with early-stage non-small cell lung cancer planned or treated with SBRT at the institution with radiographic findings of fibrosis or recurrence were eligible for the study. All patients underwent imaging with FLT-PET/CT before SBRT in cohort 1 and at fibrosis or recurrence in cohort 2 and 3, respectively. The planned sample size was 20 patients in each cohort, with 60 patients total. FLT-PET standardized uptake value (SUV) variables including SUVmax, SUVmean, SUVpeak, SUV50, and SUV95 were compared among the 3 cohorts using the Kruskal-Wallis test. The correlation of respiratory-gated and nongated FLT-PET SUV variables was performed using the Spearman correlation coefficient. Results: Forty-one patients were recruited for the study (20 in cohort 1, 16 in cohort 2, and 5 in cohort 3) between 2015 and 2019. The majority received a diagnosis of stage I lung cancer (86%), and the most common prescription was 48 Gy in 4 fractions (59%). Respiratory-gated FLT-PET was performed in 35 patients. The FLT SUV variables were well correlated between respiratory-gated and nongated scans (r = 0.8-1.0). The SUVpeak, SUVmean, and SUVmax were significantly lower in the fibrosis cohort compared with the recurrence and pretreatment cohorts. The SUV50 and SUV95 values in the recurrence cohort were statistically similar to the pretreatment cohort. Conclusions: FLT-PET/CT may be helpful in differentiating SBRT-related fibrosis from recurrence. Nongated FLT-PET/CT with reporting of SUVmax and SUV95 values is recommended.

Noise-Based Image Harmonization Significantly Increases Repeatability and Reproducibility of Radiomics Features in PET Images: A Phantom Study.

For multicenter clinical studies, characterizing the robustness of image-derived radiomics features is essential. Features calculated on PET images have been shown to be very sensitive to image noise. The purpose of this work was to investigate the efficacy of a relatively simple harmonization strategy on feature robustness and agreement. A purpose-built texture pattern phantom was scanned on 10 different PET scanners in 7 institutions with various different image acquisition and reconstruction protocols. An image harmonization technique based on equalizing a contrast-to-noise ratio was employed to generate a "harmonized" alongside a "standard" dataset for a reproducibility study. In addition, a repeatability study was performed with images from a single PET scanner of variable image noise, varying the binning time of the reconstruction. Feature agreement was measured using the intraclass correlation coefficient (ICC). In the repeatability study, 81/93 features had a lower ICC on the images with the highest image noise as compared to the images with the lowest image noise. Using the harmonized dataset significantly improved the feature agreement for five of the six investigated feature classes over the standard dataset. For three feature classes, high feature agreement corresponded with higher sensitivity to the different patterns, suggesting a way to select suitable features for predictive models.

Selective enhancement of the uptake and bioactivity of a TAT-conjugated peptide inhibitor of glycogen synthase kinase-3.

The use of cell-penetrating peptides as transduction vectors is a promising approach to deliver peptides and proteins into cells. However, the uptake and bioavailability of trans-activating transcriptor (TAT)-conjugated molecules vary depending on the cell type and the cargo. This study aimed to determine whether a low-voltage electrical pulse can enhance the TAT-mediated delivery of peptide cargoes in different cell types. In TF-1 and mouse embryonic stem cells, the uptake of a novel detachable TAT-conjugated glycogen synthase kinase-3 (GSK-3) peptide inhibitor was enhanced by an order of magnitude without affecting the cell viability. A similar increase in uptake was achieved in primary mouse bone marrow cells while maintaining >80% of their viability. Interestingly, under these low-voltage conditions, the uptake of a control peptide not conjugated to TAT was not significantly increased. A T-cell factor/lymphoid enhancer factor (TCF/LEF) luciferase reporter assay was also used to assess the bioactivity of the TAT construct. The results indicated that cells loaded with a low-voltage electrical pulse had a twofold increase in TCF/LEF activity, which was equivalent to a level of GSK-3 inhibition similar to that of cells treated with 20 mmol/l lithium or 500 nmol/l (2'Z,3'E)-6-bromoindirubin-3'-oxime. These results demonstrate the usefulness of low-voltage electrical pulses to enhance the uptake and bioactivity of TAT-conjugated molecules in different cell types.

4D-CT Attenuation Correction in Respiratory-Gated PET for Hypoxia Imaging: Is It Really Beneficial?

Previous literature has shown that 4D respiratory-gated positron emission tomography (PET) is beneficial for quantitative analysis and defining targets for boosting therapy. However the case for addition of a phase-matched 4D-computed tomography (CT) for attenuation correction (AC) is less clear. We seek to validate the use of 4D-CT for AC and investigate the impact of motion correction for low signal-to-background PET imaging of hypoxia using radiotracers such as FAZA and FMISO. A new insert for the Modus Medicals' QUASAR™ Programmable Respiratory Motion Phantom was developed in which a 3D-printed sphere was placed within the "lung" compartment while an additional compartment is added to simulate muscle/blood compartment required for hypoxia quantification. Experiments are performed at 4:1 or 2:1 signal-to-background ratio consistent with clinical FAZA and FMISO imaging. Motion blur was significant in terms of SUVmax, mean, and peak for motion ≥1 cm and could be significantly reduced (from 20% to 8% at 2-cm motion) for all 4D-PET-gated reconstructions. The effect of attenuation method on precision was significant (σ2 hCT-AC = 5.5%/4.7%/2.7% vs σ2 4D-CT-AC = 0.5%/0.6%/0.7% [max%/peak%/mean% variance]). The simulated hypoxic fraction also significantly decreased under conditions of 2-cm amplitude motion from 55% to 20% and was almost fully recovered (HF = 0.52 for phase-matched 4D-CT) using gated PET. 4D-gated PET is valuable under conditions of low radiotracer uptake found in hypoxia imaging. This work demonstrates the importance of using 4D-CT for AC when performing gated PET based on its significantly improved precision over helical CT.

A prospective, multi-centre trial of multi-parametric MRI as a biomarker in anal carcinoma.

BACKGROUND AND PURPOSE: To investigate the role of multi-parametric magnetic resonance imaging (MP-MRI) as a biomarker for squamous cell carcinoma of the anal canal (SCCAC). MATERIALS AND METHODS: From January 2013 to January 2017, 25 patients with non-metastatic SCCAC were enrolled in a multi-centre prospective clinical trial, of whom 20 completed protocol treatment. MP-MRIs, incorporating diffusion weighted magnetic resonance imaging (DW-MRI) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) sequences, were performed before (baseline), during the second and fourth weeks of chemo-radiotherapy (CRT), and 8 weeks following treatment completion. Histogram analysis of multi-parametric maps generated maximum, mean, median, minimum, skewness, kurtosis, and standard deviation metrics. Exact logistic regression and ROC AUC analyses were performed for each metric at every timepoint. An elastic net LASSO logistic regression was also performed using all measures at each timepoint. RESULTS: With a median follow up of 17.1 months, 3/20 patients had a local recurrence, and 5/20 had any recurrence. Several apparent diffusion coefficient (ADC) metrics extracted from DW-MRIs correlated with local recurrence and demonstrated excellent discrimination: baseline skewness (p = 0.04, ROC AUC 0.90) and standard deviation (SD) (p = 0.02, ROC AUC 0.90), week 2 skewness (p = 0.02, ROC AUC 0.91) and SD (p = 0.01, ROC AUC 0.94), week 4 kurtosis (p = 0.01, AUC 0.92) and SD (p = 0.01, ROC AUC 0.96). Changes in minimum ADC between baseline and week 2 (p = 0.02, ROC AUC 0.94) and baseline and week 4 (p = 0.02, ROC AUC 0.94) were prognostic for local recurrence. For prediction of any recurrence, ADC minimum (p = 0.02, ROC AUC 0.87) and SD (p = 0.01, ROC AUC 0.85) at baseline, and ADC maximum (p = 0.03, ROC AUC 0.77) and SD (p = 0.02, ROC AUC 0.81) at week 4 were significant. On LASSO logistic regression, ADC minimum and SD at baseline were retained for any recurrence. The only significant finding for DCE-MRI was a correlation of k-trans min at the second follow-up with local recurrence (p = 0.05, AUC 0.84). CONCLUSION: Several ADC parameters at various time points correlate with recurrence suggesting DW-MRI is a potential biomarker for SCCAC.

Accuracy and Performance of Functional Parameter Estimation Using a Novel Numerical Optimization Approach for GPU-Based Kinetic Compartmental Modeling.

Quantitative kinetic parameters derived from dynamic contrast-enhanced (DCE) data are dependent on signal measurement quality and choice of pharmacokinetic model. However, the fundamental optimization analysis method is equally important and its impact on pharmacokinetic parameters has been mostly overlooked. We examine the effects of those choices on accuracy and performance of parameter estimation using both computer processing unit and graphical processing unit (GPU) numerical optimization implementations and evaluate the improvements offered by a novel optimization approach. A test framework was developed where experimentally derived population-average arterial input function and randomly sampled parameter sets {Ktrans , Kep , Vb , τ} were used to generate known tissue curves. Five numerical optimization algorithms were evaluated: sequential quadratic programming, downhill simplex (Nelder-Mead), pattern search, simulated annealing, and differential evolution. This was combined with various objective function implementation details: delay approximation, discretization and varying sampling rates. Then, impact of noise and CPU/GPU implementation was tested for speed and accuracy. Finally, the optimal method was compared to conventional implementation as applied to clinical DCE computed tomography. Nelder-Mead, differential evolution and sequential quadratic programming produced good results on clean and noisy input data outperforming simulated annealing and pattern search in terms of speed and accuracy in the respective order of 10-8%, 10-7%, and ×10-6%). A novel approach for DCE numerical optimization (infinite impulse response with fractional delay approximation) was implemented on GPU for speed increase of at least 2 orders of magnitude. Applied to clinical data, the magnitude of overall parameter error was <10%.

Unified platform for multimodal voxel-based analysis to evaluate tumour perfusion and diffusion characteristics before and after radiation treatment evaluated in metastatic brain cancer.

OBJECTIVE:: Early changes in tumour behaviour following stereotactic radiosurgery) are potential biomarkers of response. To-date quantitative model-based measures of dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) MRI parameters have shown widely variable findings, which may be attributable to variability in image acquisition, post-processing and analysis. Big data analytic approaches are needed for the automation of computationally intensive modelling calculations for every voxel, independent of observer interpretation. METHODS:: This unified platform is a voxel-based, multimodality architecture that brings complimentary solute transport processes such as perfusion and diffusion into a common framework. The methodology was tested on synthetic data and digital reference objects and consequently evaluated in patients who underwent volumetric DCE-CT, DCE-MRI and DWI-MRI scans before and after treatment. Three-dimensional pharmacokinetic parameter maps from both modalities were compared as well as the correlation between apparent diffusion coefficient (ADC) values and the extravascular, extracellular volume (Ve). Comparison of histogram parameters was done via Bland-Altman analysis, as well as Student's t-test and Pearson's correlation using two-sided analysis. RESULTS:: System testing on synthetic Tofts model data and digital reference objects recovered the ground truth parameters with mean relative percent error of 1.07 × 10-7 and 5.60 × 10-4 respectively. Direct voxel-to-voxel Pearson's analysis showed statistically significant correlations between CT and MR which peaked at Day 7 for Ktrans (R = 0.74, p <= 0.0001). Statistically significant correlations were also present between ADC and Ve derived from both DCE-MRI and DCE-CT with highest median correlations found at Day 3 between median ADC and Ve,MRI values (R = 0.6, p < 0.01) The strongest correlation to DCE-CT measurements was found with DCE-MRI analysis using voxelwise T10 maps (R = 0.575, p < 0.001) instead of assigning a fixed T10 value. CONCLUSION:: The unified implementation of multiparametric transport modelling allowed for more robust and timely observer-independent data analytics. Utility of a common analysis platform has shown higher correlations between pharmacokinetic parameters obtained from different modalities than has previously been reported. ADVANCES IN KNOWLEDGE:: Utility of a common analysis platform has shown statistically higher correlations between pharmacokinetic parameters obtained from different modalities than has previously been reported.

Phantom Validation of DCE-MRI Magnitude and Phase-Based Vascular Input Function Measurements.

Accurate, patient-specific measurement of arterial input functions (AIF) may improve model-based analysis of vascular permeability. This study investigated factors affecting AIF measurements from magnetic resonance imaging (MRI) magnitude (AIFMAGN) and phase (AIFPHA) signals, and compared them against computed tomography (CT) (AIFCT), under controlled conditions relevant to clinical protocols using a multimodality flow phantom. The flow phantom was applied at flip angles of 20° and 30°, flow rates (3-7.5 mL/s), and peak bolus concentrations (0.5-10 mM), for in-plane and through-plane flow. Spatial 3D-FLASH signal and variable flip angle T1 profiles were measured to investigate in-flow and radiofrequency-related biases, and magnitude- and phase-derived Gd-DTPA concentrations were compared. MRI AIF performance was tested against AIFCT via Pearson correlation analysis. AIFMAGN was sensitive to imaging orientation, spatial location, flip angle, and flow rate, and it grossly underestimated AIFCT peak concentrations. Conversion to Gd-DTPA concentration using T1 taken at the same orientation and flow rate as the dynamic contrast-enhanced acquisition improved AIFMAGN accuracy; yet, AIFMAGN metrics remained variable and significantly reduced from AIFCT at concentrations above 2.5 mM. AIFPHA performed equivalently within 1 mM to AIFCT across all tested conditions. AIFPHA, but not AIFMAGN, reported equivalent measurements to AIFCT across the range of tested conditions. AIFPHA showed superior robustness.

Measurement of Tumor Hypoxia in Patients With Locally Advanced Cervical Cancer Using Positron Emission Tomography with 18F-Fluoroazomyin Arabinoside.

PURPOSE: To assess cervical tumor hypoxia using the hypoxia tracer 18F-fluoroazomycin arabinoside (18F-FAZA) and compare different reference tissues and thresholds for quantifying tumor hypoxia. METHODS AND MATERIALS: Twenty-seven patients with cervical cancer were studied prospectively by positron emission tomography (PET) imaging with 18F-FAZA before starting standard chemoradiation. The hypoxic volume was defined as all voxels within a tumor (T) with standardized uptake values (SUVs) greater than 3 standard deviations from the mean gluteus maximus muscle SUV value (M) or SUVs greater than 1 to 1.4 times the mean SUV value of the left ventricle, a blood (B) surrogate. The hypoxic fraction was defined as the ratio of the number of hypoxic voxels to the total number of tumor voxels. RESULTS: A 18F-FAZA-PET hypoxic volume could be identified in the majority of cervical tumors (89% when using T/M or T/B > 1.2 as threshold) on the 2-hour static scan. The hypoxic fraction ranged from 0% to 99% (median 31%) when defined using the T/M threshold and from 0% to 78% (median 32%) with the T/B > 1.2 threshold. Hypoxic volumes derived from the different thresholds were highly correlated (Spearman's correlation coefficient ρ between T/M and T/B > 1-1.4 were 0.82-0.91), as were hypoxic fractions (0.75-0.85). Compartmental analysis of the dynamic scans showed k3, the FAZA accumulation constant, to be strongly correlated with hypoxic fraction defined using the T/M (Spearman's ρ=0.72) and T/B > 1.2 thresholds (0.76). CONCLUSIONS: Hypoxia was detected in the majority of cervical tumors on 18F-FAZA-PET imaging. The extent of hypoxia varied markedly between tumors but not significantly with different reference tissues/thresholds.

Validation of a Multimodality Flow Phantom and Its Application for Assessment of Dynamic SPECT and PET Technologies.

Simple and robust techniques are lacking to assess performance of flow quantification using dynamic imaging. We therefore developed a method to qualify flow quantification technologies using a physical compartment exchange phantom and image analysis tool. We validate and demonstrate utility of this method using dynamic PET and SPECT. Dynamic image sequences were acquired on two PET/CT and a cardiac dedicated SPECT (with and without attenuation and scatter corrections) systems. A two-compartment exchange model was fit to image derived time-activity curves to quantify flow rates. Flowmeter measured flow rates (20-300 mL/min) were set prior to imaging and were used as reference truth to which image derived flow rates were compared. Both PET cameras had excellent agreement with truth ( [Formula: see text]). High-end PET had no significant bias (p > 0.05) while lower-end PET had minimal slope bias (wash-in and wash-out slopes were 1.02 and 1.01) but no significant reduction in precision relative to high-end PET (<15% vs. <14% limits of agreement, p > 0.3). SPECT (without scatter and attenuation corrections) slope biases were noted (0.85 and 1.32) and attributed to camera saturation in early time frames. Analysis of wash-out rates from non-saturated, late time frames resulted in excellent agreement with truth ( [Formula: see text], slope = 0.97). Attenuation and scatter corrections did not significantly impact SPECT performance. The proposed phantom, software and quality assurance paradigm can be used to qualify imaging instrumentation and protocols for quantification of kinetic rate parameters using dynamic imaging.

Comparison of Voxel-Wise Tumor Perfusion Changes Measured With Dynamic Contrast-Enhanced (DCE) MRI and Volumetric DCE CT in Patients With Metastatic Brain Cancer Treated with Radiosurgery.

Dynamic contrast-enhanced (DCE)-MRI metrics are evaluated against volumetric DCE-CT quantitative parameters as a standard for tracer-kinetic validation using a common 4-dimensional temporal dynamic analysis platform in tumor perfusion measurements following stereotactic radiosurgery (SRS) for brain metastases. Patients treated with SRS as part of Research Ethics Board-approved clinical trials underwent volumetric DCE-CT and DCE-MRI at baseline, then at 7 and 21 days after SRS. Temporal dynamic analysis was used to create 3-dimensional pharmacokinetic parameter maps for both modalities. Individual vascular input functions were selected for DCE-CT and a population function was used for DCE-MRI. Semiquantitative and pharmacokinetic DCE parameters were assessed using a modified Tofts model within each tumor at every time point for both modalities for characterization of perfusion and capillary permeability, as well as their dependency on precontrast relaxation times (TRs), T10, and input function. Direct voxel-to-voxel Pearson analysis showed statistically significant correlations between CT and magnetic resonance which peaked at day 7 for Ktrans (R = 0.74, P ≤ .0001). The strongest correlation to DCE-CT measurements was found with DCE-MRI analysis using voxel-wise T10 maps (R = 0.575, P < .001) instead of assigning a fixed T10 value. Comparison of histogram features showed statistically significant correlations between modalities over all tumors for median Ktrans (R = 0.42, P = .01), median area under the enhancement curve (iAUC90) (R = 0.55, P < .01), and median iAUC90 skewness (R = 0.34, P = .03). Statistically significant, strong correlations were found for voxel-wise Ktrans, iAUC90, and ve values between DCE-CT and DCE-MRI. For DCE-MRI, the implementation of voxel-wise T10 maps plays a key role in ensuring the accuracy of heterogeneous pharmacokinetic maps.

Feasibility of 4D perfusion CT imaging for the assessment of liver treatment response following SBRT and sorafenib.

OBJECTIVES: To evaluate the feasibility of 4-dimensional perfusion computed tomography (CT) as an imaging biomarker for patients with hepatocellular carcinoma and metastatic liver disease. METHODS AND MATERIALS: Patients underwent volumetric dynamic contrast-enhanced CT on a 320-slice scanner before and during stereotactic body radiation therapy and sorafenib, and at 1 and 3 months after treatment. Quiet free breathing was used in the CT acquisition and multiple techniques (rigid or deformable registration as well as outlier removal) were applied to account for residual liver motion. Kinetic modeling was performed on a voxel-by-voxel basis in the gross tumor volume and normal liver resulting in 3-dimensional parameter maps of blood perfusion, capillary permeability, blood volume, and mean transit time. Perfusion characteristics in the tumor and adjacent liver were correlated with radiation dose distributions to evaluate dose-response. Paired t tests assessed change in spatial and histogram parameters from baseline to different time points during and after treatment. Technique reproducibility as well as the impact of arterial and portal vein input functions was also investigated using intra- and inter-subject variance and Bland-Altman analysis. RESULTS: Quantitative perfusion parameters were reproducible (±5.7%; range, 2%-10%) depending on tumor/normal liver type and kinetic parameter. Statistically significant reductions in tumor perfusion were measurable over the course of treatment and as early as 1 week after sorafenib administration (P < .05). Marked liver parenchyma perfusion reduction was seen with a strong dose-response effect (R2 = 0.95) that increased significantly over the course treatment. CONCLUSIONS: The proposed methodology demonstrated feasibility of evaluating spatiotemporal changes in liver tumor perfusion and normal liver function following antiangiogenic therapy and radiation treatment warranting further evaluation of biomarker prognostication.

A prospective study of DWI, DCE-MRI and FDG PET imaging for target delineation in brachytherapy for cervical cancer.

BACKGROUND AND PURPOSE: We examined the utility of dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted MRI (DWI), and FDG-PET imaging for brachytherapy target delineation in patients with locally advanced cervical cancer. MATERIALS AND METHODS: Twenty-two patients had DWI, DCE-MRI, and FDG-PET/CT scans after brachytherapy applicator insertion, in addition to standard T2-weighted (T2w) 3T MRI. Gross tumor volume (GTVB) and high-risk clinical target volume (HRCTV) were contoured first on T2w images, and then modified if indicated upon review of DWI/DCE-MRI/FDG-PET images by two observers. The primary endpoint was utility, determined by the number of patients whose volumes were modified, and interobserver variability. RESULTS: Eleven patients' T2w-GTVB were modified based on DWI/DCE-MRI/FDG-PET by observer 1, due to clearer demarcation (7) and residual disease not well visualized on T2w MRI (4). GTVB was modified in 17 patients by observer 2 (11 and 6, respectively). Incorporation of functional imaging improved the conformity index (CI) for GTVB from 0.54 (T2w alone) to 0.65 (P=0.003). HRCTV was modified in 3 and 8 patients by observers 1 and 2, respectively, with a trend toward higher CI using functional imaging (0.71 to 0.76, P=0.06). CONCLUSIONS: DWI/DCE-MRI/FDG-PET imaging as a supplement to T2w MRI decreased interobserver variability in GTVB delineation.

Automated voxel-based analysis of volumetric dynamic contrast-enhanced CT data improves measurement of serial changes in tumor vascular biomarkers.

OBJECTIVES: Development of perfusion imaging as a biomarker requires more robust methodologies for quantification of tumor physiology that allow assessment of volumetric tumor heterogeneity over time. This study proposes a parametric method for automatically analyzing perfused tissue from volumetric dynamic contrast-enhanced (DCE) computed tomography (CT) scans and assesses whether this 4-dimensional (4D) DCE approach is more robust and accurate than conventional, region-of-interest (ROI)-based CT methods in quantifying tumor perfusion with preliminary evaluation in metastatic brain cancer. METHODS AND MATERIALS: Functional parameter reproducibility and analysis of sensitivity to imaging resolution and arterial input function were evaluated in image sets acquired from a 320-slice CT with a controlled flow phantom and patients with brain metastases, whose treatments were planned for stereotactic radiation surgery and who consented to a research ethics board-approved prospective imaging biomarker study. A voxel-based temporal dynamic analysis (TDA) methodology was used at baseline, at day 7, and at day 20 after treatment. The ability to detect changes in kinetic parameter maps in clinical data sets was investigated for both 4D TDA and conventional 2D ROI-based analysis methods. RESULTS: A total of 7 brain metastases in 3 patients were evaluated over the 3 time points. The 4D TDA method showed improved spatial efficacy and accuracy of perfusion parameters compared to ROI-based DCE analysis (P<.005), with a reproducibility error of less than 2% when tested with DCE phantom data. Clinically, changes in transfer constant from the blood plasma into the extracellular extravascular space (Ktrans) were seen when using TDA, with substantially smaller errors than the 2D method on both day 7 post radiation surgery (±13%; P<.05) and by day 20 (±12%; P<.04). Standard methods showed a decrease in Ktrans but with large uncertainty (111.6 ± 150.5) %. CONCLUSIONS: Parametric voxel-based analysis of 4D DCE CT data resulted in greater accuracy and reliability in measuring changes in perfusion CT-based kinetic metrics, which have the potential to be used as biomarkers in patients with metastatic brain cancer.

Multimodality functional imaging in radiation therapy planning: relationships between dynamic contrast-enhanced MRI, diffusion-weighted MRI, and 18F-FDG PET.

OBJECTIVES: Biologically guided radiotherapy needs an understanding of how different functional imaging techniques interact and link together. We analyse three functional imaging techniques that can be useful tools for achieving this objective. MATERIALS AND METHODS: The three different imaging modalities from one selected patient are ADC maps, DCE-MRI, and 18F-FDG PET/CT, because they are widely used and give a great amount of complementary information. We show the relationship between these three datasets and evaluate them as markers for tumour response or hypoxia marker. Thus, vascularization measured using DCE-MRI parameters can determine tumour hypoxia, and ADC maps can be used for evaluating tumour response. RESULTS: ADC and DCE-MRI include information from 18F-FDG, as glucose metabolism is associated with hypoxia and tumour cell density, although 18F-FDG includes more information about the malignancy of the tumour. The main disadvantage of ADC maps is the distortion, and we used only low distorted regions, and extracellular volume calculated from DCE-MRI can be considered equivalent to ADC in well-vascularized areas. CONCLUSION: A dataset for achieving the biologically guided radiotherapy must include a tumour density study and a hypoxia marker. This information can be achieved using only MRI data or only PET/CT studies or mixing both datasets.

A novel minimally invasive technique to create a rabbit VX2 lung tumor model for nano-sized image contrast and interventional studies.

BACKGROUND: The rabbit VX2 lung cancer model is a large animal model useful for preclinical lung cancer imaging and interventional studies. However, previously reported models had issues in terms of invasiveness of tumor inoculation, control of tumor aggressiveness and incidence of complications. PURPOSE: We aimed to develop a minimally invasive rabbit VX2 lung cancer model suitable for imaging and transbronchial interventional studies. METHODS: New Zealand white rabbits and VX2 tumors were used in the study. An ultra-thin bronchoscope was inserted through a miniature laryngeal mask airway into the bronchus. Different numbers of VX2 tumor cells were selectively inoculated into the lung parenchyma or subcarinal mediastinum to create a uniform tumor with low incidence of complications. The model was characterized by CT, FDG-PET, and endobronchial ultrasound (EBUS). Liposomal dual-modality contrast agent was used to evaluate liposome drug delivery system in this model. RESULTS: Both peripheral and mediastinal lung tumor models were created. The tumor making success rate was 75.8% (25/33) in the peripheral lung tumor model and 60% (3/5) in the mediastinal tumor model. The group of 1.0×10(6) of VX2 tumor cells inoculation showed a linear growth curve with less incidence of complications. Radial probe EBUS visualized the internal structure of the tumor and the size measurement correlated well with CT measurements (r(2) = 0.98). Over 7 days of continuous enhancement of the lung tumor by liposomal contrast in the lung tumor was confirmed both CT and fluorescence imaging. CONCLUSION: Our minimally invasive bronchoscopic rabbit VX2 lung cancer model is an ideal platform for lung cancer imaging and preclinical bronchoscopic interventional studies.

Pulmonary tumor measurements from x-ray computed tomography in one, two, and three dimensions.

RATIONALE AND OBJECTIVES: We evaluated the accuracy and reproducibility of three-dimensional (3D) measurements of lung phantoms and patient tumors from x-ray computed tomography (CT) and compared these to one-dimensional (1D) and two-dimensional (2D) measurements. MATERIALS AND METHODS: CT images of three spherical and three irregularly shaped tumor phantoms were evaluated by three observers who performed five repeated measurements. Additionally, three observers manually segmented 29 patient lung tumors five times each. Follow-up imaging was performed for 23 tumors and response criteria were compared. For a single subject, imaging was performed on nine occasions over 2 years to evaluate multidimensional tumor response. To evaluate measurement accuracy, we compared imaging measurements to ground truth using analysis of variance. For estimates of precision, intraobserver and interobserver coefficients of variation and intraclass correlations (ICC) were used. Linear regression and Pearson correlations were used to evaluate agreement and tumor response was descriptively compared. RESULTS: For spherical shaped phantoms, all measurements were highly accurate, but for irregularly shaped phantoms, only 3D measurements were in high agreement with ground truth measurements. All phantom and patient measurements showed high intra- and interobserver reproducibility (ICC >0.900). Over a 2-year period for a single patient, there was disagreement between tumor response classifications based on 3D measurements and those generated using 1D and 2D measurements. CONCLUSION: Tumor volume measurements were highly reproducible and accurate for irregular, spherical phantoms and patient tumors with nonuniform dimensions. Response classifications obtained from multidimensional measurements suggest that 3D measurements provide higher sensitivity to tumor response.

Idiopathic scoliosis in families of children with congenital scoliosis.

Although most cases of congenital scoliosis are thought to be of sporadic etiology, it is not known whether other types of spinal deformity occur in families of individuals with this type of scoliosis. Children with congenital scoliosis were identified through a review of health records and radiographic report databases. Of 237 children with congenital scoliosis investigated, 49 (20.7%) reported a family history of spinal deformity. Detailed pedigrees were done, which showed a history of idiopathic scoliosis in 17.3% of the 237 families. This is a higher than expected rate of spinal deformity in families of children with congenital scoliosis, and the strong association of idiopathic scoliosis in families of children with congenital scoliosis has not been reported previously. Although this finding could be related to the chance occurrence of multiple genetic abnormalities or sporadic events in these families, it does raise the possibility that one genetic defect at least predisposes these families to having different types of spinal deformity develop.