Radiation segmentectomy of hepatic metastases with Y-90 glass microspheres.

PURPOSE: To evaluate safety and efficacy of radiation segmentectomy (RS) with 90Y glass microspheres in patients with limited metastatic liver disease not amenable to resection or percutaneous ablation. METHODS: Patients with ≤ 3 tumors treated with RS from 6/2015 to 12/2017 were included. Target tumor radiation dose was > 190 Gy based on medical internal radiation dose (MIRD) dosimetry. Tumor response, local tumor progression (LTP), LTP-free survival (LTPFS) and disease progression rate in the treated segment were defined using Choi and RECIST 1.1 criteria. Toxicities were evaluated using modified SIR criteria. RESULTS: Ten patients with 14 tumors underwent 12 RS. Median tumor size was 3 cm (range 1.4-5.6). Median follow-up was 17.8 months (range 1.6-37.3). Response rates per Choi and RECIST 1.1 criteria were 8/8 (100%) and 4/9 (44%), respectively. Overall LTP rate was 3/14 (21%) during the study period. One-, two- and three-year LTPFS was 83%, 83% and 69%, respectively. Median LTPFS was not reached. Disease progression rate in the treated segment was 6/18 (33%). Median overall survival was 41.5 months (IQR 16.7-41.5). Median delivered tumor radiation dose was 293 Gy (range 163-1303). One major complication was recorded in a patient post-Whipple procedure who suffered anaphylactic reaction to prophylactic cefotetan and liver abscess in RS region 6.5 months post-RS. All patients were alive on last follow-up. CONCLUSION: RS of ≤ 3 hepatic segments can safely provide a 2-year local tumor control rate of 83% in selected patients with limited metastatic liver disease and limited treatment options. Optimal dosimetry methodology requires further investigation.

KRAS mutation effects on the 2-[18F]FDG PET uptake of colorectal adenocarcinoma metastases in the liver.

BACKGROUND: Deriving individual tumor genomic characteristics from patient imaging analysis is desirable. We explore the predictive value of 2-[18F]FDG uptake with regard to the KRAS mutational status of colorectal adenocarcinoma liver metastases (CLM). METHODS: 2-[18F]FDG PET/CT images, surgical pathology and molecular diagnostic reports of 37 patients who underwent PET/CT-guided biopsy of CLM were reviewed under an IRB-approved retrospective research protocol. Sixty CLM in 39 interventional PET scans of the 37 patients were segmented using two different auto-segmentation tools implemented in different commercially available software packages. PET standard uptake values (SUV) were corrected for: (1) partial volume effect (PVE) using cold wall-corrected contrast recovery coefficients derived from phantom spheres with variable diameter and (2) variability of arterial tracer supply and variability of uptake time after injection until start of PET scan derived from the tumor-to-blood standard uptake ratio (SUR) approach. The correlations between the KRAS mutational status and the mean, peak and maximum SUV were investigated using Student's t test, Wilcoxon rank sum test with continuity correction, logistic regression and receiver operation characteristic (ROC) analysis. These correlation analyses were also performed for the ratios of the mean, peak and maximum tumor uptake to the mean blood activity concentration at the time of scan: SURMEAN, SURPEAK and SURMAX, respectively. RESULTS: Fifteen patients harbored KRAS missense mutations (KRAS+), while another 3 harbored KRAS gene amplification. For 31 lesions, the mutational status was derived from the PET/CT-guided biopsy. The Student's t test p values for separating KRAS mutant cases decreased after applying PVE correction to all uptake metrics of each lesion and when applying correction for uptake time variability to the SUR metrics. The observed correlations were strongest when both corrections were applied to SURMAX and when the patients harboring gene amplification were grouped with the wild type: p ≤ 0.001; ROC area under the curve = 0.77 and 0.75 for the two different segmentations, respectively, with a mean specificity of 0.69 and sensitivity of 0.85. CONCLUSION: The correlations observed after applying the described corrections show potential for assigning probabilities for the KRAS missense mutation status in CLM using 2-[18F]FDG PET images.

Repeatability of SUV measurements in serial PET.

PURPOSE: The standardized uptake value (SUV) is a quantitative measure of FDG tumor uptake frequently used as a tool to monitor therapeutic response. This study aims to (i) assess the reproducibility and uncertainty of SUV max and SUV mean, due to purely statistical, i.e., nonbiological, effects and (ii) to establish the minimum uncertainty below which changes in SUV cannot be expected to be an indicator of physiological changes. METHODS: Three sets of measurements were made using a GE Discovery STE PET/CT Scanner in 3D mode: (1) A uniform 68Ge 20 cm diameter cylindrical phantom was imaged. Thirty serial frames were acquired for durations of 3, 6, 10, 15, and 30 min. (2) Esser flangeless phantom (Data Spectrum, approximately 6.1 L) with fillable thin-walled cylinders inserts (diameters: 8, 12, 16, and 25 mm; height: approximately 3.8 mm) was scanned for five consecutive 3 min runs. The cylinders were filled with 18FDG with a 37 kBq/cc concentration, and with a target-to-background ratio (T/BKG) of 3/1. (3) Eight cancer patients with healthy livers were scanned approximately 1.5 h post injection. Three sequential 3 min scans were performed for one bed position covering the liver, with the patient and bed remaining at the same position for the entire length of the scan. Volumes of interest were drawn on all images using the corresponding CT and then transferred to the PET images. For each study (1-3), the average percent change in SUV mean and SUV max were determined for each run pair. Moreover, the repeatability coefficient was calculated for both the SUV mean and SUV max for each pair of runs. Finally, the overall ROI repeatability coefficient was determined for each pair of runs. RESULTS: For the 68Ge phantom the average percent change in SUV max and SUV mean decrease as a function of increasing acquisition time from 4.7 +/- 3.1 to 1.1 +/- 0.6%, and from 0.14 +/- 0.09 to 0.04 +/- 0.03%, respectively. Similarly, the coefficients of repeatability also decrease between the 3 and 30 min acquisition scans, in the range of 10.9 +/- 3.9% - 2.6 +/- 0.9%, and 0.3 +/- 0.1% - 0.10 +/- 0.04%, for the SUV max and SUV mean, respectively. The overall ROI repeatability decreased from 18.9 +/- 0.2 to 6.0 +/- 0.1% between the 3 and 30 min acquisition scans. For the l8FDG phantom, the average percent change in SUV max and SUV mean decreases with target diameter from 3.6 +/- 2.0 to 1.5 +/- 0.8% and 1.5 +/- 1.3 to 0.26 +/- 0.15%, respectively, for targets from 8-25 mm in diameter and for a region in the background (BKG). The coefficients of repeatability for SUV max and SUV mean also decrease as a function of target diameter from 7.1 +/- 2.5 to 2.4 +/- 0.9 and 4.2 +/- 1.5 to 0.6 +/- 0.2, respectively, for targets from 8 mm to BKG in diameter. Finally, overall ROI repeatability decreased from 12.0 +/- 4.1 to 13.4 +/- 0.5 targets from 8 mm to BKG in diameter. Finally, for the measurements in healthy livers the average percent change in SUVmax and SUV mean were in the range of 0.5 +/- 0.2% - 6.2 +/- 3.9% and 0.4 +/- 0.1 and 1.6 +/- 1%, respectively. The coefficients of repeatability for SUV max and SUV men are in the range of 0.6 +/- 0.7% - 9.5 +/- 12% and 0.6 +/- 0.7% - 2.9 +/- 3.6%, respectively. The overall target repeatability varied between 27.9 +/- 0.5% and 41.1 +/- 1.0%. CONCLUSIONS: The statistical fluctuations of the SUV mean are half as large as those of the SUV max in the absence of biological or physiological effects. In addition, for clinically applicable scan durations (i.e., approximately 3 min) and FDG concentrations, the SUV max and SUV mean have similar amounts of statistical fluctuation for small regions. However, the statistical fluctuations of the SUVmean rapidly decrease with respect tothe SUVmax as the statistical power of the data grows either due to longer scanning times or as the target regions encompass a larger volume.

A novel respiratory tracking system for smart-gated PET acquisition.

PURPOSE: In this study, the authors validated a novel respiratory tracking device, the multidimensional respiratory tracking (MDRT) system, that was designed to assist in correcting for respiratory motion in PET/CT images. The authors also investigated a novel PET acquisition technique, smart gating (SG), that enables to acquire motion-free PET data prospectively, with minimum user interference and with no additional postprocessing of the PET data. METHODS: MDRT uses visual tracking techniques to track simultaneously the two-dimensional (in the vertical plane) motion of multiple fiducial markers using a standard video camera. A threshold window is set at the breathing amplitude of interest using the MDRT GUI. A trigger is generated at a rate of 250 Hz as long as the breathing signal is within the threshold window. The triggers are fed into the PET scanner to initialize one single bin of a gated acquisition every 4 ms. No triggers are delivered as the breathing signal drifts outside the threshold window. Consequently, PET data are acquired only whenever the breathing signal is confined within the amplitude threshold window, thus resulting into a motion-free image set. The accuracy of MDRT in tracking the breathing signal was assessed (1) by comparing the period of an oscillating phantom, as measured by MDRT, to that measured with a photogate timer and (2) by comparing the MDRT output to that of the real-time position management (RPM) in ten patients. The SG PET/CT acquisition was validated in phantoms and in two stereotactic body radiosurgery (SBRS) lung DIBH-PET/CT patients. RESULTS: MDRT was in agreement with the photogate timer in determining the period of motion to less than 2%. The percent errors between MDRT and RPM in the positions of the peaks and troughs of the ten patients' breathing signals were within 10%. In phantoms, SG technique enables to correct for motion-induced artifacts in the PET images and improve the accuracy of PET quantitation. For the SBRS application, in one patient, the patient's CT lesion was not detected in the corresponding clinical PET images, while it exhibited an SUV of 1.8 in the DIBH image set. In the second patient, DIBH-PET images showed an improved PET-to-CT spatial matching and a 52% increase in the lesion SUV. CONCLUSIONS: MDRT has been shown to be accurate in tracking breathing motion and assisted in implementing a smart-gating PET acquisition technique that allowed to acquire prospectively motion-free PET images.

Renal uptake of bismuth-213 and its contribution to kidney radiation dose following administration of actinium-225-labeled antibody.

Clinical therapeutic studies using (225)Ac-labeled antibodies have begun. Of major concern is renal toxicity that may result from the three alpha-emitting progeny generated following the decay of (225)Ac. The purpose of this study was to determine the amount of (225)Ac and non-equilibrium progeny in the mouse kidney after the injection of (225)Ac-huM195 antibody and examine the dosimetric consequences. Groups of mice were sacrificed at 24, 96 and 144 h after injection with (225)Ac-huM195 antibody and kidneys excised. One kidney was used for gamma ray spectroscopic measurements by a high-purity germanium (HPGe) detector. The second kidney was used to generate frozen tissue sections which were examined by digital autoradiography (DAR). Two measurements were performed on each kidney specimen: (1) immediately post-resection and (2) after sufficient time for any non-equilibrium excess (213)Bi to decay completely. Comparison of these measurements enabled estimation of the amount of excess (213)Bi reaching the kidney (γ-ray spectroscopy) and its sub-regional distribution (DAR). The average absorbed dose to whole kidney, determined by spectroscopy, was 0.77 (SD 0.21) Gy kBq(-1), of which 0.46 (SD 0.16) Gy kBq(-1) (i.e. 60%) was due to non-equilibrium excess (213)Bi. The relative contributions to renal cortex and medulla were determined by DAR. The estimated dose to the cortex from non-equilibrium excess (213)Bi (0.31 (SD 0.11) Gy kBq(-1)) represented ∼46% of the total. For the medulla the dose contribution from excess (213)Bi (0.81 (SD 0.28) Gy kBq(-1)) was ∼80% of the total. Based on these estimates, for human patients we project a kidney-absorbed dose of 0.28 Gy MBq(-1) following administration of (225)Ac-huM195 with non-equilibrium excess (213)Bi responsible for approximately 60% of the total. Methods to reduce renal accumulation of radioactive progeny appear to be necessary for the success of (225)Ac radioimmunotherapy.

Using an external gating signal to estimate noise in PET with an emphasis on tracer avid tumors.

The purpose of this study is to establish and validate a methodology for estimating the standard deviation of voxels with large activity concentrations within a PET image using replicate imaging that is immediately available for use in the clinic. To do this, ensembles of voxels in the averaged replicate images were compared to the corresponding ensembles in images derived from summed sinograms. In addition, the replicate imaging noise estimate was compared to a noise estimate based on an ensemble of voxels within a region. To make this comparison two phantoms were used. The first phantom was a seven-chamber phantom constructed of 1 liter plastic bottles. Each chamber of this phantom was filled with a different activity concentration relative to the lowest activity concentration with ratios of 1:1, 1:1, 2:1, 2:1, 4:1, 8:1 and 16:1. The second phantom was a GE Well-Counter phantom. These phantoms were imaged and reconstructed on a GE DSTE PET/CT scanner with 2D and 3D reprojection filtered backprojection (FBP), and with 2D- and 3D-ordered subset expectation maximization (OSEM). A series of tests were applied to the resulting images that showed that the region and replicate imaging methods for estimating standard deviation were equivalent for backprojection reconstructions. Furthermore, the noise properties of the FBP algorithms allowed scaling the replicate estimates of the standard deviation by a factor of 1/square root N, where N is the number of replicate images, to obtain the standard deviation of the full data image. This was not the case for OSEM image reconstruction. Due to nonlinearity of the OSEM algorithm, the noise is shown to be both position and activity concentration dependent in such a way that no simple scaling factor can be used to extrapolate noise as a function of counts. The use of the Well-Counter phantom contributed to the development of a heuristic extrapolation of the noise as a function of radius in FBP. In addition, the signal-to-noise ratio for high uptake objects was confirmed to be higher with backprojection image reconstruction methods. These techniques were applied to several patient data sets acquired in either 2D or 3D mode, with (18)F (FLT and FDG). Images of the standard deviation and signal-to-noise ratios were constructed and the standard deviations of the tumors' uptake were determined. Finally, a radial noise extrapolation relationship deduced in this paper was applied to patient data.

An iterative technique to segment PET lesions using a Monte Carlo based mathematical model.

PURPOSE: The need for an accurate lesion segmentation tool in 18FDG PET is a prerequisite for the estimation of lesion response to therapy, for radionuclide dosimetry, and for the application of 18FDG PET to radiotherapy planning. In this work, the authors have developed an iterative method based on a mathematical fit deduced from Monte Carlo simulations to estimate tumor segmentation thresholds. METHODS: The GATE software, a GEANT4 based Monte Carlo tool, was used to model the GE Advance PET scanner geometry. Spheres ranging between 1 and 6 cm in diameters were simulated in a 10 cm high and 11 cm in diameter cylinder. The spheres were filled with water-equivalent density and simulated in both water and lung equivalent background. The simulations were performed with an infinite, 8/1, and 4/1 target-to-background ratio (T/B). A mathematical fit describing the correlation between the lesion volume and the corresponding optimum threshold value was then deduced through analysis of the reconstructed images. An iterative method, based on this mathematical fit, was developed to determine the optimum threshold value. The effects of the lesion volume and T/B on the threshold value were investigated. This method was evaluated experimentally using the NEMA NU2-2001 IEC phantom, the ACNP cardiac phantom, a randomly deformed aluminum can, and a spheroidal shape phantom implemented artificially in the lung, liver, and brain of patient PET images. Clinically, the algorithm was evaluated in six lesions from five patients. Clinical results were compared to CT volumes. RESULTS: This mathematical fit predicts an existing relationship between the PET lesion size and the percent of maximum activity concentration within the target volume (or threshold). It also showed a dependence of the threshold value on the T/B, which could be eliminated by background subtraction. In the phantom studies, the volumes of the segmented PET targets in the PET images were within 10% of the nominal ones. Clinically, the PET target volumes were also within 10% of those measured from CT images. CONCLUSIONS: This iterative algorithm enabled accurately segment PET lesions, independently of their contrast value.

Phase and amplitude binning for 4D-CT imaging.

We compare the consistency and accuracy of two image binning approaches used in 4D-CT imaging. One approach, phase binning (PB), assigns each breathing cycle 2pi rad, within which the images are grouped. In amplitude binning (AB), the images are assigned bins according to the breathing signal's full amplitude. To quantitate both approaches we used a NEMA NU2-2001 IEC phantom oscillating in the axial direction and at random frequencies and amplitudes, approximately simulating a patient's breathing. 4D-CT images were obtained using a four-slice GE Lightspeed CT scanner operating in cine mode. We define consistency error as a measure of ability to correctly bin over repeated cycles in the same field of view. Average consistency error mue+/-sigmae in PB ranged from 18%+/-20% to 30%+/-35%, while in AB the error ranged from 11%+/-14% to 20%+/-24%. In PB nearly all bins contained sphere slices. AB was more accurate, revealing empty bins where no sphere slices existed. As a proof of principle, we present examples of two non-small cell lung carcinoma patients' 4D-CT lung images binned by both approaches. While AB can lead to gaps in the coronal images, depending on the patient's breathing pattern, PB exhibits no gaps but suffers visible artifacts due to misbinning, yielding images that cover a relatively large amplitude range. AB was more consistent, though often resulted in gaps when no data existed due to patients' breathing pattern. We conclude AB is more accurate than PB. This has important consequences to treatment planning and diagnosis.

Evaluation of an automated deformable image matching method for quantifying lung motion in respiration-correlated CT images.

We have evaluated an automated registration procedure for predicting tumor and lung deformation based on CT images of the thorax obtained at different respiration phases. The method uses a viscous fluid model of tissue deformation to map voxels from one CT dataset to another. To validate the deformable matching algorithm we used a respiration-correlated CT protocol to acquire images at different phases of the respiratory cycle for six patients with nonsmall cell lung carcinoma. The position and shape of the deformable gross tumor volumes (GTV) at the end-inhale (EI) phase predicted by the algorithm was compared to those drawn by four observers. To minimize interobserver differences, all observers used the contours drawn by a single observer at end-exhale (EE) phase as a guideline to outline GTV contours at EI. The differences between model-predicted and observer-drawn GTV surfaces at EI, as well as differences between structures delineated by observers at EI (interobserver variations) were evaluated using a contour comparison algorithm written for this purpose, which determined the distance between the two surfaces along different directions. The mean and 90% confidence interval for model-predicted versus observer-drawn GTV surface differences over all patients and all directions were 2.6 and 5.1 mm, respectively, whereas the mean and 90% confidence interval for interobserver differences were 2.1 and 3.7 mm. We have also evaluated the algorithm's ability to predict normal tissue deformations by examining the three-dimensional (3-D) vector displacement of 41 landmarks placed by each observer at bronchial and vascular branch points in the lung between the EE and EI image sets (mean and 90% confidence interval displacements of 11.7 and 25.1 mm, respectively). The mean and 90% confidence interval discrepancy between model-predicted and observer-determined landmark displacements over all patients were 2.9 and 7.3 mm, whereas interobserver discrepancies were 2.8 and 6.0 mm. Paired t tests indicate no significant statistical differences between model predicted and observer drawn structures. We conclude that the accuracy of the algorithm to map lung anatomy in CT images at different respiratory phases is comparable to the variability in manual delineation. This method has therefore the potential for predicting and quantifying respiration-induced tumor motion in the lung.

Quantitation of respiratory motion during 4D-PET/CT acquisition.

We report on the variability of the respiratory motion during 4D-PET/CT acquisition. The respiratory motion for five lung cancer patients was monitored by tracking external markers placed on the abdomen. CT data were acquired over an entire respiratory cycle at each couch position. The x-ray tube status was recorded by the tracking system, for retrospective sorting of the CT data as a function of respiration phase. Each respiratory cycle was sampled in ten equal bins. 4D-PET data were acquired in gated mode, where each breathing cycle was divided into ten 500 ms bins. For both CT and PET acquisition, patients received audio prompting to regularize breathing. The 4D-CT and 4D-PET data were then correlated according to their respiratory phases. The respiratory periods, and average amplitude within each phase bin, acquired in both modality sessions were then analyzed. The average respiratory motion period during 4D-CT was within 18% from that in the 4D-PET sessions. This would reflect up to 1.8% fluctuation in the duration of each 4D-CT bin. This small uncertainty enabled good correlation between CT and PET data, on a phase-to-phase basis. Comparison of the average-amplitude within the respiration trace, between 4D-CT and 4D- PET, on a bin-by-bin basis show a maximum deviation of approximately 15%. This study has proved the feasibility of performing 4D-PET/CT acquisition. Respiratory motion was in most cases consistent between PET and CT sessions, thereby improving both the attenuation correction of PET images, and co-registration of PET and CT images. On the other hand, in two patients, there was an increased partial irregularity in their breathing motion, which would prevent accurately correlating the corresponding PET and CT images.

Four-dimensional (4D) PET/CT imaging of the thorax.

We have reported in our previous studies on the methodology, and feasibility of 4D-PET (Gated PET) acquisition, to reduce respiratory motion artifact in PET imaging of the thorax. In this study, we expand our investigation to address the problem of respiration motion in PET/CT imaging. The respiratory motion of four lung cancer patients were monitored by tracking external markers placed on the thorax. A 4D-CT acquisition was performed using a "step-and-shoot" technique, in which computed tomography (CT) projection data were acquired over a complete respiratory cycle at each couch position. The period of each CT acquisition segment was time stamped with an "x-ray ON" signal, which was recorded by the tracking system. 4D-CT data were then sorted into 10 groups, according to their corresponding phase of the breathing cycle. 4D-PET data were acquired in the gated mode, where each breathing cycle was divided into ten 0.5 s bins. For both CT and PET acquisitions, patients received audio prompting to regularize breathing. The 4D-CT and 4D-PET data were then correlated according to respiratory phase. The effect of 4D acquisition on improving the co-registration of PET and CT images, reducing motion smearing, and consequently increase the quantitation of the SUV, were investigated. Also, quantitation of the tumor motions in PET, and CT, were studied and compared. 4D-PET with matching phase 4D-CTAC showed an improved accuracy in PET-CT image co-registration of up to 41%, compared to measurements from 4D-PET with clinical-CTAC. Gating PET data in correlation with respiratory motion reduced motion-induced smearing, thereby decreasing the observed tumor volume, by as much as 43%. 4D-PET lesions volumes showed a maximum deviation of 19% between clinical CT and phase- matched 4D-CT attenuation corrected PET images. In CT, 4D acquisition resulted in increasing the tumor volume in two patients by up to 79%, and decreasing it in the other two by up to 35%. Consequently, these corrections have yielded an increase in the measured SUV by up to 16% over the clinical measured SUV, and 36% over SUV's measured in 4D-PET with clinical-CT Attenuation Correction (CTAC) SUV's. Quantitation of the maximum tumor motion amplitude, using 4D-PET and 4D-CT, showed up to 30% discrepancy between the two modalities. We have shown that 4D PET/CT is clinically a feasible method, to correct for respiratory motion artifacts in PET/CT imaging of the thorax. 4D PET/CT acquisition can reduce smearing, improve the accuracy in PET-CT co-registration, and increase the measured SUV. This should result in an improved tumor assessment for patients with lung malignancies.

A stereotactic method for the three-dimensional registration of multi-modality biologic images in animals: NMR, PET, histology, and autoradiography.

The objective of this work was to develop and then validate a stereotactic fiduciary marker system for tumor xenografts in rodents which could be used to co-register magnetic resonance imaging (MRI), PET, tissue histology, autoradiography, and measurements from physiologic probes. A Teflon fiduciary template has been designed which allows the precise insertion of small hollow Teflon rods (0.71 mm diameter) into a tumor. These rods can be visualized by MRI and PET as well as by histology and autoradiography on tissue sections. The methodology has been applied and tested on a rigid phantom, on tissue phantom material, and finally on tumor bearing mice. Image registration has been performed between the MRI and PET images for the rigid Teflon phantom and among MRI, digitized microscopy images of tissue histology, and autoradiograms for both tissue phantom and tumor-bearing mice. A registration accuracy, expressed as the average Euclidean distance between the centers of three fiduciary markers among the registered image sets, of 0.2 +/- 0.06 mm was achieved between MRI and microPET image sets of a rigid Teflon phantom. The fiduciary template allows digitized tissue sections to be co-registered with three-dimensional MRI images with an average accuracy of 0.21 and 0.25 mm for the tissue phantoms and tumor xenografts, respectively. Between histology and autoradiograms, it was 0.19 and 0.21 mm for tissue phantoms and tumor xenografts, respectively. The fiduciary marker system provides a coordinate system with which to correlate information from multiple image types, on a voxel-by-voxel basis, with sub-millimeter accuracy--even among imaging modalities with widely disparate spatial resolution and in the absence of identifiable anatomic landmarks.

Effect of respiratory gating on reducing lung motion artifacts in PET imaging of lung cancer.

Positron emission tomography (PET) has shown an increase in both sensitivity and specificity over computed tomography (CT) in lung cancer. However, motion artifacts in the 18F fluorodioxydoglucose (FDG) PET images caused by respiration persists to be an important factor in degrading PET image quality and quantification. Motion artifacts lead to two major effects: First, it affects the accuracy of quantitation, producing a reduction of the measured standard uptake value (SUV). Second, the apparent lesion volume is overestimated. Both impact upon the usage of PET images for radiation treatment planning. The first affects the visibility, or contrast, of the lesion. The second results in an increase in the planning target volume, and consequently a greater radiation dose to the normal tissues. One way to compensate for this effect is by applying a multiple-frame capture technique. The PET data are then acquired in synchronization with the respiratory motion. Reduction in smearing due to gating was investigated in both phantoms and patient studies. Phantom studies showed a dependence of the reduction in smearing on the lesion size, the motion amplitude, and the number of bins used for data acquisition. These studies also showed an improvement in the target-to-background ratio, and a more accurate measurement of the SUV. When applied to one patient, respiratory gating showed a 28% reduction in the total lesion volume, and a 56.5% increase in the SUV. This study was conducted as a proof of principle that a gating technique can effectively reduce motion artifacts in PET image acquisition.

Relative therapeutic efficacy of (125)I- and (131)I-labeled monoclonal antibody A33 in a human colon cancer xenograft.

UNLABELLED: A33, a monoclonal antibody that targets colon carcinomas, was labeled with (125)I or (131)I and the relative therapeutic efficacy of the 2 radiolabeled species was compared in a human colon cancer xenograft system. METHODS: Nude mice bearing human SW1222 colon carcinoma xenografts were administered escalating activities of (125)I-A33 (9.25-148 MBq) or (131)I-A33 (0.925-18.5 MBq), (125)I- and (131)I-labeled control antibodies, unlabeled antibody, or no antibody. The effects of treatment were assessed using the endpoints of tumor growth delay and cure. RESULTS: Tumor growth delay increased with administered activity for all radiolabeled antibodies. Approximately 4.5 times more activity was required for (125)I-A33 to produce therapeutic effects that were equivalent to those of (131)I-A33. This ratio was approximately 7 for a nonspecific, noninternalizing isotype-matched, radiolabeled control antibody. Unlabeled A33 antibody had no effect on tumor growth. Approximately 10 times more activity of (125)I-A33 produced toxicity similar to that of (131)I-A33, and this ratio fell to approximately 6 for radiolabeled control antibody. CONCLUSION: Treatment with (125)I-A33 resulted in a relative therapeutic gain of approximately 2 compared with (131)I-A33 in this experimental system.

PET imaging of (86)Y-labeled anti-Lewis Y monoclonal antibodies in a nude mouse model: comparison between (86)Y and (111)In radiolabels.

UNLABELLED: Absorbed doses in (90)Y radioimmunotherapy are usually estimated by extrapolating from (111)In imaging data. PET using (86)Y (beta(+) 33%; half-life, 14.7 h) as a surrogate radiolabel could be a more accurate alternative. The aim of this study was to evaluate an (86)Y-labeled monoclonal antibody (mAb) as a PET imaging agent and to compare the biodistribution of (86)Y- and (111)In-labeled mAb. METHODS: The humanized anti-Lewis Y mAb hu3S193 was labeled with (111)In or (86)Y through CHX-A"-diethylenetriaminepentaacetic acid chelation. In vitro cell binding and cellular retention of radiolabeled hu3S193 were evaluated using HCT-15 colon carcinoma cells, a cell line expressing Lewis Y. Nude mice bearing HCT-15 xenografts were injected with (86)Y-hu3S193 or (111)In-hu3S193. The biodistribution was studied by measurements of dissected tissues as well as by PET and planar imaging. RESULTS: The overall radiochemical yield in hu3S193 labeling and purification was 42% +/- 2% (n = 2) and 76% +/- 3% (n = 6) for (86)Y and (111)In, respectively. Both radioimmunoconjugates specifically bound to HCT-15 cells. When cellular retention of hu3S193 was studied using (111)In-hu3S193, 80% of initially cell-bound (111)In activity was released into the medium as high-molecular-weight compounds within 8 h. When coadministered, in vivo tumor uptake of (86)Y-hu3S193 and (111)In-hu3S193 reached maximum values of 30 +/- 6 and 29 +/- 6 percentage injected dose per gram and tumor sites were easily identifiable by PET and planar imaging, respectively. CONCLUSION: At 2 d after injection of (111)In-hu3S193 and (86)Y-hu3S193 radioimmunoconjugates, the uptake of (111)In and (86)Y activity was generally similar in most tissues. After 4 d, however, the concentration of (86)Y activity was significantly higher in several tissues, including tumor and bone tissue. Accordingly, the quantitative information offered by PET, combined with the presumably identical biodistribution of (86)Y and (90)Y radiolabels, should enable more accurate absorbed dose estimates in (90)Y radioimmunotherapy.

Using positron emission tomography with [(18)F]FDG to predict tumor behavior in experimental colorectal cancer.

This study investigates the relationship between FDG uptake as determined by positron emission tomography (PET) imaging and rates of tumor growth, cellular GLUT1 transporter density, and the activities of hexokinase and glucose-6-phosphatase in a solid tumor implant model. Five different human colorectal xenografts of different growth properties were implanted in athymic rats and evaluated by dynamic (18)F-FDG-PET. The phosphorylating and dephosphorylating activities of the key glycolytic enzymes, hexokinase and glucose-6-phosphatase, were measured in these tumor types by spectrophotometric assays and the expression of GLUT1 glucose transporter protein was determined by immunohistochemistry. Correlations among FDG accumulation, hexokinase activity, and tumor doubling time are reported in these colon xenografts. The results indicate that the activity of tumor hexokinase may be a marker of tumor growth rate that can be determined by (18)F-FDG-PET imaging. PET scanning may not only be a useful tool for staging patients for extent of disease, but may provide important prognostic information concerning the proliferative rates of malignancies.

Estimate of absorbed dose based on two-dimensional autoradiographic information in internal radionuclide therapy.

In radiation therapies using radionuclides emitting short-range particles, such as radioimmunotherapy or boron neutron capture therapy, the biological effects are strongly affected by the heterogeneity of the absorbed dose distribution delivered to tumor cells. The three-dimensional (3D) information of the source distribution at the cellular level is required to accurately determine the absorbed dose distribution to the individual tumor cells. Two-dimensional distribution of cell and nuclide with a resolution of 1 microm can be obtained from individual tissue sections by microautoradiography. To obtain such information in 3D, an ideal approach would be to align the serial tissue sections from a block and analyze all of them. This is straightforward in theory, but extremely difficult in practice. Furthermore, every section in the block has to be processed and analyzed, and the usage of the data from this laborious work is very inefficient. An approach presented here is to estimate the absorbed dose based on individual sections without 3D reconstruction. It is realistically workable since it avoids the most difficult task of alignment for the serial tissue sections. In addition, the absorbed dose can be estimated based on a limited number of noncontiguous sections. The validity of this approach has been tested by a Monte Carlo simulation for two representative radionuclide configurations: (a) a uniform distribution of sources and (b) a cell membrane bound source distribution. With only a limited number of sampling sections, the uncertainties in the dose estimation were estimated to approximately 15% for short-range particles.

Hypoxia-Induced increase in FDG uptake in MCF7 cells.

UNLABELLED: Recent clinical data indicate that tumor hypoxia negatively affects the treatment outcome of both radiotherapy and surgery in various cancers, emphasizing the need for noninvasive detection of tumor hypoxia. Several studies have shown an increased uptake of FDG in hypoxic regions of xenografts, suggesting the use of PET with FDG as a potential technique. In this study, we examine the mechanism underlying the hypoxia-induced increase of FDG uptake in the human breast carcinoma cell line MCF7. METHODS: The uptake of 3H-FDG into MCF7 cells was determined after incubation under hypoxic (0% oxygen) or normoxic conditions, with or without redox agents, for varying time periods. In addition, the effects of the redox agents on the glucose transporter activity and the hexokinase activity were determined independently, and the effects of hypoxia on glucose transporter protein and hexokinase levels were assessed. RESULTS: A more than twofold increase (2.53 +/- 0.79; P < 0.005) in 3H-FDG uptake was observed under hypoxic conditions, but no changes in the cellular levels of glucose transporter proteins or hexokinase were observed. A reducing agent, dithiothreitol (DTT), also caused an increase in 3H-FDG uptake but failed to affect uptake under hypoxic conditions. This indicates that the mechanisms by which hypoxia and DTT affect 3H-FDG uptake might be the same. The oxidizing agent p-chloromercuribenzenesulfonic acid (pCMBS) had no effect on 3H-FDG uptake under normoxic conditions but counteracted the effect of hypoxia. DTT caused an increase in glucose transporter activity, whereas it had no effect on hexokinase activity. pCMBS had no effect on either glucose transporter activity or hexokinase activity. CONCLUSION: The hypoxia-induced increase in 3H-FDG uptake in MCF7 cells is the result, in part, of an increase in glucose transporter activity resulting from the modification (reduction) of thiol group(s) in the glucose transport protein(s). Modulation of hexokinase activity is probably not involved in the hypoxia-induced increase in 3H-FDG uptake in these cells.

Targeted radioimmunotherapy for leptomeningeal cancer using (131)I-3F8.

BACKGROUND: Intrathecal antibody-based targeted therapies may have clinical potential for patients with leptomeningeal (LM) cancer. PROCEDURE: Five patients with GD2-positive LM tumors were injected with 1-2 mCi intra-Ommaya (131)I-3F8, a murine IgG3 antibody specific for GD2. Serial cerebrospinal fluid (CSF) and serum samples and SPECT imagings (4, 24, and 48 hr) were performed to predict radiation doses to the tumor and normal brain and blood prior to the administration of larger therapeutic doses. RESULTS: Side effects included self-limited fever, headache, and vomiting. Focal (131)I-3F8 uptake consistent with tumors was seen along the craniospinal axis in four patients. Calculated radiation dose to the CSF was 14.9-56 cGy/mCi and to blood and other organs outside the CNS less than 2 cGy/mCi. CONCLUSIONS: Intraventricular (131)I-3F8 successfully detected LM disease and resulted in a large favorable CSF/blood ratio. Intraventricular (131)I-3F8 may have clinical utility in the diagnosis and radioimmunotherapy of GD2-positive LM cancers. Med. Pediatr. Oncol. 35:716-718. 2000.

Optimizing the sequence of combination therapy with radiolabeled antibodies and fractionated external beam.

UNLABELLED: The purpose of this study was to determine the optimum sequence for combined modality therapy with radiolabeled antibodies and fractionated external beam radiation. METHODS: The uptake and distribution of a nontherapeutic activity of 125I-labeled tumor-associated A33 monoclonal antibody was determined in SW1222 human colon carcinoma xenografts in nude mice for 4 study groups: group 1, radiolabeled antibody alone; group 2, radiolabeled antibody administered (day 0) immediately before the first of 5 daily fractions of 2-Gy, 320-kilovolt peak x-rays; group 3, radiolabeled antibody administered after the fifth radiation fraction (day 5); and group 4, radiolabeled antibody administered 5 d after irradiation (day 10). Tumors were excised 5 d after antibody administration. Tumors were frozen and sectioned for histology and phosphor plate autoradiography. The percentage of A33 antigen-expressing cells was estimated by immunohistochemical staining. RESULTS: The average tumor uptake values relative to control group 1 were 1.47 (group 2), 0.78 (group 3), and 0.21 (group 4), which illustrates that tumor uptake is increased by almost 50% when the antibody is present in the blood at the start of irradiation. Five days into a fractionated irradiation protocol, antibody uptake was reduced, falling more significantly on day 10. Phosphor plate autoradiographs showed decreased uptake uniformity for groups 3 and 4. Immunohistochemical data showed a reduction in A33 antigen-positive cells from 85%, 64%, 50%, to 41% for groups 1-4, respectively. CONCLUSION: Maximum radiolabeled antibody tumor uptake was achieved when the antibody was administered just before radiation therapy. This might be explained by a transient increase in capillary leakage to macromolecules, followed by a reduction at later times, possibly the result of capillary damage and occlusion.