Interreader agreement and variability of FDG PET volumetric parameters in human solid tumors.

OBJECTIVE: The purpose of this article is to evaluate the interreader agreement and variability of two (18)F-FDG PET parameters, metabolic tumor volume and total lesion glycolysis, in human solid tumors. MATERIALS AND METHODS: One hundred eleven patients (mean [± SD] age, 61.9 ± 12.5 years) with baseline staging FDG PET/CT scans were included. Two readers independently read the scans and segmented metabolic tumor volume and total lesion glycolysis using two fixed thresholds, 40% and 50% of the lesion's maximum standardized uptake value (SUVmax). The impact of the lesion's FDG avidity and location on reader agreement and variability was established. Intraclass correlation coefficient (ICC), precision, and Bland-Altman analysis were used to evaluate agreement and variability. RESULTS: The ICCs for 40% and 50% SUVmax segmentations of metabolic tumor volume between the readers were 0.987 and 0.995, and the corresponding values for 40% and 50% SUVmax segmentations of total lesion glycolysis were 0.987 and 0.986, respectively (p = 0.0001). The corresponding precisions were 0.5%, 0.2%, 0.5%, and 0.5%, respectively. The mean biases between the readers for 40% and 50% SUVmax segmentations of metabolic tumor volume were -1.78 ± 8.42 mL and -0.46 ± 2.1 mL and for 40% and 50% SUVmax segmentations of total lesion glycolysis were -7.3 ± 31.6 g and -2.97 ± 12.86 g, respectively. Subgroup analysis showed better precision and lesser variability for 50% SUVmax segmentations of metabolic tumor volume and total lesion glycolysis in patients with the highest and lowest FDG-avid primary tumors. The precision was highest and variability was lowest for lung tumors. CONCLUSION: There is excellent interreader agreement for measurement of metabolic tumor volume and total lesion glycolysis with 40% and 50% SUVmax threshold segmentations in human solid tumors.

Novel Quantitative Techniques in Hybrid (PET-MR) Imaging of Brain Tumors.

Brain tumors are a collection of heterogeneous intracranial neoplasms. Molecular PET and anatomic MR imaging together can provide reliable quantitative information on tumor characterization, and help in treatment planning and monitoring therapeutic evaluation, noninvasively. Coregistration of MRI and PET images have been successfully used to improve diagnostic accuracy and in evaluating treatment response. Whole-body PET-MR scanners capable of assessing morphologic, metabolic, and functional information simultaneously are now commercially available. Early clinical studies speculate that PET-MR will be useful in several clinical specialties. In this report, we highlight the advances and applications of hybrid PET-MR in quantitative brain tumor imaging.

Biodistribution, tumor detection, and radiation dosimetry of 18F-DCFBC, a low-molecular-weight inhibitor of prostate-specific membrane antigen, in patients with metastatic prostate cancer.

UNLABELLED: Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein expressed on the surface of prostate cancer (PCa) cells, particularly in androgen-independent, advanced, and metastatic disease. Previously, we demonstrated that N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-(18)F-fluorobenzyl-L-cysteine ((18)F-DCFBC) could image an experimental model of PSMA-positive PCa using PET. Here, we describe the initial clinical experience and radiation dosimetry of (18)F-DCFBC in men with metastatic PCa. METHODS: Five patients with radiologic evidence of metastatic PCa were studied after the intravenous administration of 370 MBq (10 mCi) of (18)F-DCFBC. Serial PET was performed until 2 h after administration. Time-activity curves were generated for selected normal tissues and metastatic foci. Radiation dose estimates were calculated using OLINDA/EXM 1.1. RESULTS: Most vascular organs demonstrated a slow decrease in radioactivity concentration over time consistent with clearance from the blood pool, with primarily urinary radiotracer excretion. Thirty-two PET-positive suspected metastatic sites were identified, with 21 concordant on both PET and conventional imaging for abnormal findings compatible with metastatic disease. Of the 11 PET-positive sites not identified on conventional imaging, most were within the bone and could be considered suggestive for the detection of early bone metastases, although further validation is needed. The highest mean absorbed dose per unit administered radioactivity (µGy/MBq) was in the bladder wall (32.4), and the resultant effective dose was 19.9 ± 1.34 µSv/MBq (mean ± SD). CONCLUSION: Although further studies are needed for validation, our findings demonstrate the potential of (18)F-DCFBC as a new positron-emitting imaging agent for the detection of metastatic PCa. This study also provides dose estimates for (18)F-DCFBC that are comparable to those of other PET radiopharmaceuticals such as (18)F-FDG.

[32P]ATP inhibits the growth of xenografted tumors in nude mice.

The search for new therapeutic agents that are effective against cancer has been difficult and expensive. The activity of anticancer candidate agents against human cancer-derived cell lines in immunocompromised mice is an important tool in this search. Because ATP is a naturally occurring small molecule, its radiolabeled form poses many advantages as a potential anticancer therapeutic agent. We previously found that a single, low-dose intravenous injection of [ ( 32) P]ATP inhibited the growth of xenografted tumors in nude mice for up to several weeks. The current study describes the biodistribution and the results and advantages of multi-dose administration of this potential drug. Future studies should investigate the mechanism involved in the possible use of [ ( 32) P]ATP as a cytotoxic agent that homes naturally to the tumor microenvironment.

Tumor dosimetry and response for 153Sm-ethylenediamine tetramethylene phosphonic acid therapy of high-risk osteosarcoma.

UNLABELLED: (153)Sm-ethylenediamine tetramethylene phosphonic acid ((153)Sm-EDTMP) therapy for osteosarcoma is being investigated. In this study, we analyzed the influence of (153)Sm-EDTMP administered activity (AA), osteosarcoma tumor density, mass, and the shape of the tumor on absorbed dose (AD). We also studied the biologic implication of the nonuniform tumor AD distribution using radiobiologic modeling and examined the relationship between tumor AD and response. METHODS: Nineteen tumors in 6 patients with recurrent, refractory osteosarcoma enrolled in a phase I or II clinical trial of (153)Sm-EDTMP were analyzed using the 3-dimensional radiobiologic dosimetry (3D-RD) software package. Patients received a low dose of (153)Sm-EDTMP (37.0-51.8 MBq/kg), followed on hematologic recovery by a second, high dose (222 MBq/kg). Treatment response was evaluated using either CT or MRI after each therapy. SPECT/CT of the tumor regions were obtained at 4 and 48 h or 72 h after (153)Sm-EDTMP therapy for 3D-RD analysis. Mean tumor AD was also calculated using the OLINDA/EXM unit-density sphere model and was compared with the 3D-RD estimates. RESULTS: On average, a 5-fold increase in the AA led to a 4-fold increase in the mean tumor AD over the high- versus low-dose-treated patients. The range of mean tumor AD and equivalent uniform dose (EUD) for low-dose therapy were 1.48-14.6 and 0.98-3.90 Gy, respectively. Corresponding values for high-dose therapy were 2.93-59.3 and 1.89-12.3 Gy, respectively. Mean tumor AD estimates obtained from OLINDA/EXM were within 5% of the mean AD values obtained using 3D-RD. On an individual tumor basis, both mean AD and EUD were positively related to percentage tumor volume reduction (P = 0.031 and 0.023, respectively). CONCLUSION: The variations in tumor density, mass, and shape seen in these tumors did not affect the mean tumor AD estimation significantly. The tumor EUD was approximately 2- and 3-fold lower than the mean AD for low- and high-dose therapy, respectively. A dose-response relationship was observed for transient tumor volume shrinkage.

2-(3-{1-Carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid, [18F]DCFPyL, a PSMA-based PET imaging agent for prostate cancer.

PURPOSE: We have synthesized and evaluated in vivo 2-(3-{1-carboxy-5-[(6-[(18)F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid, [(18)F]DCFPyL, as a potential imaging agent for the prostate-specific membrane antigen (PSMA). PSMA is upregulated in prostate cancer epithelia and in the neovasculature of most solid tumors. EXPERIMENTAL DESIGN: [(18)F]DCFPyL was synthesized in two steps from the p-methoxybenzyl (PMB) protected lys-C(O)-glu urea precursor using 6-[(18)F]fluoronicotinic acid tetrafluorophenyl ester ([(18)F]F-Py-TFP) for introduction of (18)F. Radiochemical synthesis was followed by biodistribution and imaging with PET in immunocompromised mice using isogenic PSMA PC3 PIP and PSMA- PC3 flu xenograft models. Human radiation dosimetry estimates were calculated using OLINDA/EXM 1.0. RESULTS: DCFPyL displays a K(i) value of 1.1 ± 0.1 nmol/L for PSMA. [(18)F]DCFPyL was produced in radiochemical yields of 36%-53% (decay corrected) and specific radioactivities of 340-480 Ci/mmol (12.6-17.8 GBq/µmol, n = 3). In an immunocompromised mouse model [(18)F]DCFPyL clearly delineated PSMA+ PC3 PIP prostate tumor xenografts on imaging with PET. At 2 hours postinjection, 39.4 ± 5.4 percent injected dose per gram of tissue (%ID/g) was evident within the PSMA+ PC3 PIP tumor, with a ratio of 358:1 of uptake within PSMA+ PC3 PIP to PSMA- PC3 flu tumor placed in the opposite flank. At or after 1 hour postinjection, minimal nontarget tissue uptake of [(18)F]DCFPyL was observed. The bladder wall is the dose-limiting organ. CONCLUSIONS: These data suggest [(18)F]DCFPyL as a viable, new positron-emitting imaging agent for PSMA-expressing tissues.

Radiation dosimetry of 82Rb in humans under pharmacologic stress.

UNLABELLED: (82)Rb is used with PET for cardiac perfusion studies. Using human biokinetic measurements, in vivo, we recently reported on the resting-state dosimetry of this agent. The objective of this study was to obtain (82)Rb dose estimates under stress. METHODS: (82)Rb biokinetics were obtained in 10 healthy volunteers (5 male, 5 female; mean age ± SD, 33 ± 10 y; age range, 18-50 y) using whole-body PET/CT. The 76-s half-life of (82)Rb and the corresponding need for pharmacologic vasodilation require that all imaging be completed within 10 min. To accommodate these constraints, while acquiring the data needed for dosimetry we used the following protocol. First, a whole-body attenuation correction CT scan was obtained. Then, a series of 3 whole-body PET scans was acquired after a single infusion of 1.53 ± 0.12 GBq of (82)Rb at rest. Four minutes after the infusion of a 0.56 mg/kg dose of the vasodilator, dipyridamole, 3 serial whole-body PET scans were acquired after a single infusion of 1.50 ± 0.16 GBq of (82)Rb under stress. The time-integrated activity coefficient (TIAC) for stress was obtained by scaling the mean rest TIAC obtained from our previous rest study by the stress-to-rest TIAC ratio obtained from the rest-stress measurements described in this report. RESULTS: The highest mean organ-absorbed doses under stress were as follows: heart wall, 5.1, kidneys, 5.0, lungs, 2.8, and pancreas, 2.4 µGy/MBq (19, 19, 10.4, and 8.9 mrad/mCi, respectively). The mean effective doses under stress were 1.14 ± 0.10 and 1.28 ± 0.10 µSv/MBq using the tissue-weighting factors of the International Commission on Radiological Protection, publications 60 and 103, respectively. CONCLUSION: Appreciable differences in source-organ biokinetics were observed for heart wall and kidneys during stress when compared with the previously reported rest study. The organ receiving the highest dose during stress was the heart wall. The mean effective dose calculated during stress was not significantly different from that obtained at rest.

Human biodistribution and radiation dosimetry of 82Rb.

UNLABELLED: Prior estimates of radiation-absorbed doses from (82)Rb, a frequently used PET perfusion tracer, yielded discrepant results. We reevaluated (82)Rb dosimetry using human in vivo biokinetic measurements. METHODS: Ten healthy volunteers underwent dynamic PET/CT (6 contiguous table positions, each with separate (82)Rb infusion). Source organ volumes of interest were delineated on the CT images and transferred to the PET images to obtain time-integrated activity coefficients. Radiation doses were estimated using OLINDA/EXM 1.0. RESULTS: The highest mean absorbed organ doses (µGy/MBq) were observed for the kidneys (5.81), heart wall (3.86), and lungs (2.96). Mean effective doses were 1.11 ± 0.22 and 1.26 ± 0.20 µSv/MBq using the tissue-weighting factors of the International Commission on Radiological Protection (ICRP), publications 60 and 103, respectively. CONCLUSION: Our current (82)Rb dosimetry suggests reasonably low radiation exposure. On the basis of this study, a clinical (82)Rb injection of 2 × 1,480 MBq (80 mCi) would result in a mean effective dose of 3.7 mSv using the weighting factors of the ICRP 103-only slightly above the average annual natural background exposure in the United States (3.1 mSv).

A gamma camera count rate saturation correction method for whole-body planar imaging.

Whole-body (WB) planar imaging has long been one of the staple methods of dosimetry, and its quantification has been formalized by the MIRD Committee in pamphlet no 16. One of the issues not specifically addressed in the formalism occurs when the count rates reaching the detector are sufficiently high to result in camera count saturation. Camera dead-time effects have been extensively studied, but all of the developed correction methods assume static acquisitions. However, during WB planar (sweep) imaging, a variable amount of imaged activity exists in the detector's field of view as a function of time and therefore the camera saturation is time dependent. A new time-dependent algorithm was developed to correct for dead-time effects during WB planar acquisitions that accounts for relative motion between detector heads and imaged object. Static camera dead-time parameters were acquired by imaging decaying activity in a phantom and obtaining a saturation curve. Using these parameters, an iterative algorithm akin to Newton's method was developed, which takes into account the variable count rate seen by the detector as a function of time. The algorithm was tested on simulated data as well as on a whole-body scan of high activity Samarium-153 in an ellipsoid phantom. A complete set of parameters from unsaturated phantom data necessary for count rate to activity conversion was also obtained, including build-up and attenuation coefficients, in order to convert corrected count rate values to activity. The algorithm proved successful in accounting for motion- and time-dependent saturation effects in both the simulated and measured data and converged to any desired degree of precision. The clearance half-life calculated from the ellipsoid phantom data was calculated to be 45.1 h after dead-time correction and 51.4 h with no correction; the physical decay half-life of Samarium-153 is 46.3 h. Accurate WB planar dosimetry of high activities relies on successfully compensating for camera saturation which takes into account the variable activity in the field of view, i.e. time-dependent dead-time effects. The algorithm presented here accomplishes this task.

18F-fluorocholine PET-guided target volume delineation techniques for partial prostate re-irradiation in local recurrent prostate cancer.

BACKGROUND AND PURPOSE: We evaluate the contribution of (18)F-choline PET/CT in the delineation of gross tumour volume (GTV) in local recurrent prostate cancer after initial irradiation using various PET image segmentation techniques. MATERIALS AND METHODS: Seventeen patients with local-only recurrent prostate cancer (median=5.7 years) after initial irradiation were included in the study. Rebiopsies were performed in 10 patients that confirmed the local recurrence. Following injection of 300 MBq of (18)F-fluorocholine, dynamic PET frames (3 min each) were reconstructed from the list-mode acquisition. Five PET image segmentation techniques were used to delineate the (18)F-choline-based GTVs. These included manual delineation of contours (GTV(man)) by two teams consisting of a radiation oncologist and a nuclear medicine physician each, a fixed threshold of 40% and 50% of the maximum signal intensity (GTV(40%) and GTV(50%)), signal-to-background ratio-based adaptive thresholding (GTV(SBR)), and a region growing (GTV(RG)) algorithm. Geographic mismatches between the GTVs were also assessed using overlap analysis. RESULTS: Inter-observer variability for manual delineation of GTVs was high but not statistically significant (p=0.459). In addition, the volumes and shapes of GTVs delineated using semi-automated techniques were significantly higher than those of GTVs defined manually. CONCLUSIONS: Semi-automated segmentation techniques for (18)F-choline PET-guided GTV delineation resulted in substantially higher GTVs compared to manual delineation and might replace the latter for determination of recurrent prostate cancer for partial prostate re-irradiation. The selection of the most appropriate segmentation algorithm still needs to be determined.

Where should surgeons place the graft on the left anterior descending coronary artery? A theoretical basis for change.

Grafts to the left anterior descending coronary artery (LAD) are generally placed in the distal, most accessible part of the vessel. As a result, there is a segment of variable length between the site of stenosis on the LAD and the site of graft placement. This segment is perfused in a retrograde unphysiological manner and is prone to the development of atherosclerosis and rapid progression of preexisting atherosclerosis. Placing the graft close to the site of stenosis has the potential to reduce the length of the arterial segment, which can become occluded or severely diseased. This holds important implications for the performance of percutaneous interventions in the event of graft failure, and possibly also for perfusion to the myocardium supplied by this segment even when the graft is patent. However, because of the tendency for rupture-prone plaques to segregate in the proximal portions of coronary arteries, a strategy of proximal graft placement might not provide the same protection from the effects of plaque rupture as the traditional distal graft placement. Despite their obvious clinical implications, these factors do not influence the site of graft placement in current practice. In this review, we attempt to quantify these opposing influences and present a theoretical framework for choosing the site of graft placement on the LAD.

Biodosimetry using micronucleus assay in acute partial body therapeutic irradiation.

Biological dosimetry provides information on the absorbed dose and its distribution in the body for an early assessment of irradiation consequences in exposed individuals. In this study, an effort has been made to see the applicability of biological dosimetry using micronuclei assay for dose estimation in therapeutic irradiation of cancer patients in acute high dose partial body irradiation. Dose estimation in partial body irradiations was done on the basis of Dolphin's contaminated Poisson method, using the in vitro dose response calibration curve. The equivalent whole body dose and the dose to the irradiated part of the body were estimated to be 1.8+/-0.1 Gy and 6.4+/-0.3 Gy, respectively. The estimated percentage of irradiated blood and the fraction of cells exposed were 41.5+/-1.6% and 10.4+/-0.8%, respectively. The estimated fraction of irradiated cells was comparable with the actual volume of irradiation.

Assessment of various strategies for 18F-FET PET-guided delineation of target volumes in high-grade glioma patients.

PURPOSE: The purpose of the study is to assess the contribution of (18)F-fluoro-ethyl-tyrosine ((18)F-FET) positron emission tomography (PET) in the delineation of gross tumor volume (GTV) in patients with high-grade gliomas compared with magnetic resonance imaging (MRI) alone. MATERIALS AND METHODS: The study population consisted of 18 patients with high-grade gliomas. Seven image segmentation techniques were used to delineate (18)F-FET PET GTVs, and the results were compared to the manual MRI-derived GTV (GTV(MRI)). PET image segmentation techniques included manual delineation of contours (GTV(man)), a 2.5 standardized uptake value (SUV) cutoff (GTV(2.5)), a fixed threshold of 40% and 50% of the maximum signal intensity (GTV(40%) and GTV(50%)), signal-to-background ratio (SBR)-based adaptive thresholding (GTV(SBR)), gradient find (GTV(GF)), and region growing (GTV(RG)). Overlap analysis was also conducted to assess geographic mismatch between the GTVs delineated using the different techniques. RESULTS: Contours defined using GTV(2.5) failed to provide successful delineation technically in three patients (18% of cases) as SUV(max) < 2.5 and clinically in 14 patients (78% of cases). Overall, the majority of GTVs defined on PET-based techniques were usually smaller than GTV(MRI) (67% of cases). Yet, PET detected frequently tumors that are not visible on MRI and added substantially tumor extension outside the GTV(MRI) in six patients (33% of cases). CONCLUSIONS: The selection of the most appropriate (18)F-FET PET-based segmentation algorithm is crucial, since it impacts both the volume and shape of the resulting GTV. The 2.5 SUV isocontour and GF segmentation techniques performed poorly and should not be used for GTV delineation. With adequate setting, the SBR-based PET technique may add considerably to conventional MRI-guided GTV delineation.