A threshold-based method to predict thyroid nodules on scintigraphy scans.

Nuclear Medicine imaging is an important modality to follow up abnormalities of thyroid function tests and to uncover and characterize thyroid nodules either de novo or as previously seen on other imaging modalities, namely ultrasound. In general, the hypofunctioning 'cold' nodules pose a higher malignancy potential than hyperfunctioning 'hot' nodules, for which the risk is <1%. Hot nodules are detected by the radiologist as a region of focal increased radiotracer uptake, which appears as a density of pixels that is higher than surrounding normal thyroid parenchyma. Similarly, cold nodules show decreased density of pixels, corresponding to their decreased uptake of radiotracer, and are photopenic. Partly because Nuclear Medicine images have poor resolution, these density variations can sometimes be subtle, and a second reader computer-aided detection (CAD) scheme that can highlight hot/cold nodules has the potential to reduce false negatives by bringing the radiologists' attention to the occasional overlooked nodules. Our approach subdivides thyroid images into small regions and employs a set of pixel density cutoffs, marking regions that fulfill density criteria. Thresholding is a fundamental tool in image processing. In nuclear medicine, scroll bars to adjust standardized uptake value cutoffs are already in wide commercial use in PET/CT display systems. A similar system could be used for planar thyroid images, whereby the user varies threshold and highlights suspect regions after an initial reader survey of the images. We hypothesized that a thresholding approach would accurately detect both hot and cold thyroid nodules relative to expert readers. Analyzing 22 nodules, half of them hot and the other half cold, we found good agreement between highlighted candidate nodules and the consensus selections of two expert readers, with nonzero overlap between expert and CAD selections in all cases.

Estimating radiation doses to the skin from interventional radiology procedures for a patient population with cancer.

PURPOSE: To estimate the peak radiation skin doses for interventional radiology cases performed at a cancer center, identify procedure types likely to result in skin doses exceeding the American College of Radiology's 3 Gy follow-up level, and determine a kerma area product (P(KA)) for use in monitoring. MATERIALS AND METHODS: A single-center retrospective study was performed to estimate doses from consecutive procedures performed during 2006. Of 6,598 procedures, 3,925 (60%) had P(KA) recorded and were included. Forty-three procedure types are represented. RESULTS: The median estimated peak skin dose was 39 mGy (third quartile, 205 mGy). In 2.6% of the cases, the estimated skin dose exceeded 3 Gy. No procedures resulted in skin doses greater than 15 Gy, and 94% of the cases resulted in skin doses less than 1 Gy. Procedure types with instances of skin doses greater than 1 Gy included hepatic, portal, and other arterial embolizations; diagnostic arteriography; biliary drainages; stent placements and catheter exchanges; nephrostomy/nephroureterostomy; urinary catheter exchanges; inferior vena cava filters; foreign body retrieval; abscess drainage; catheter exchange; and fistulography. Hepatic embolizations, nonhepatic arterial embolizations, and biliary drain/stent procedures were most likely to result in skin doses greater than 1 Gy. Significant variations in skin dose were noted within the same procedure type. No patients were noted to have developed any sequelae from radiation. CONCLUSIONS: It is unlikely that typical cases in an oncologic interventional radiology practice would exceed the Joint Commission's "reviewable sentinel event" skin dose level of 15 Gy. A P(KA) trigger of 300 Gy cm(2) could be used in the authors' clinic to identify follow-up requirements.

Possible axonal regrowth in late recovery from the minimally conscious state.

We used diffusion tensor imaging (DTI) to study 2 patients with traumatic brain injury. The first patient recovered reliable expressive language after 19 years in a minimally conscious state (MCS); the second had remained in MCS for 6 years. Comparison of white matter integrity in the patients and 20 normal subjects using histograms of apparent diffusion constants and diffusion anisotropy identified widespread altered diffusivity and decreased anisotropy in the damaged white matter. These findings remained unchanged over an 18-month interval between 2 studies in the first patient. In addition, in this patient, we identified large, bilateral regions of posterior white matter with significantly increased anisotropy that reduced over 18 months. In contrast, notable increases in anisotropy within the midline cerebellar white matter in the second study correlated with marked clinical improvements in motor functions. This finding was further correlated with an increase in resting metabolism measured by PET in this subregion. Aberrant white matter structures were evident in the second patient's DTI images but were not clinically correlated. We propose that axonal regrowth may underlie these findings and provide a biological mechanism for late recovery. Our results are discussed in the context of recent experimental studies that support this inference.

Validation of GATE Monte Carlo simulations of the GE Advance/Discovery LS PET scanners.

The recently developed GATE (GEANT4 application for tomographic emission) Monte Carlo package, designed to simulate positron emission tomography (PET) and single photon emission computed tomography (SPECT) scanners, provides the ability to model and account for the effects of photon noncollinearity, off-axis detector penetration, detector size and response, positron range, photon scatter, and patient motion on the resolution and quality of PET images. The objective of this study is to validate a model within GATE of the General Electric (GE) Advance/Discovery Light Speed (LS) PET scanner. Our three-dimensional PET simulation model of the scanner consists of 12 096 detectors grouped into blocks, which are grouped into modules as per the vendor's specifications. The GATE results are compared to experimental data obtained in accordance with the National Electrical Manufactures Association/Society of Nuclear Medicine (NEMA/SNM), NEMA NU 2-1994, and NEMA NU 2-2001 protocols. The respective phantoms are also accurately modeled thus allowing us to simulate the sensitivity, scatter fraction, count rate performance, and spatial resolution. In-house software was developed to produce and analyze sinograms from the simulated data. With our model of the GE Advance/Discovery LS PET scanner, the ratio of the sensitivities with sources radially offset 0 and 10 cm from the scanner's main axis are reproduced to within 1% of measurements. Similarly, the simulated scatter fraction for the NEMA NU 2-2001 phantom agrees to within less than 3% of measured values (the measured scatter fractions are 44.8% and 40.9 +/- 1.4% and the simulated scatter fraction is 43.5 +/- 0.3%). The simulated count rate curves were made to match the experimental curves by using deadtimes as fit parameters. This resulted in deadtime values of 625 and 332 ns at the Block and Coincidence levels, respectively. The experimental peak true count rate of 139.0 kcps and the peak activity concentration of 21.5 kBq/cc were matched by the simulated results to within 0.5% and 0.1% respectively. The simulated count rate curves also resulted in a peak NECR of 35.2 kcps at 10.8 kBq/cc compared to 37.6 kcps at 10.0 kBq/cc from averaged experimental values. The spatial resolution of the simulated scanner matched the experimental results to within 0.2 mm.

Prediction of myelotoxicity based on bone marrow radiation-absorbed dose: radioimmunotherapy studies using 90Y- and 177Lu-labeled J591 antibodies specific for prostate-specific membrane antigen.

UNLABELLED: In radioimmunotherapy, myelotoxicity due to bone marrow radiation-absorbed dose is the predominant factor and frequently is the dose-limiting factor that determines the maximum tolerated dose (MTD). With (90)Y- and (131)I-labeled monoclonal antibodies, it has been reported that myelotoxicity cannot be predicted on the basis of the amount of radioactive dose administered or the bone marrow radiation-absorbed dose (BMrad), estimated using blood radioactivity concentration. As part of a phase I dose-escalation study in patients with prostate cancer with (90)Y-DOTA-J591 (DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) ((90)Y-J591) and (177)Lu-DOTA-J591 ((177)Lu-J591), we evaluated the potential value of several factors in predicting myelotoxicity. METHODS: Seven groups of patients (n = 28) received 370-2,775 MBq/m(2) (10-75 mCi/m(2)) of (177)Lu-J591 and 5 groups of patients (n = 27) received 185-740 MBq (5-20 mCi/m(2)) of (90)Y-J591. Pharmacokinetics and imaging studies were performed for 1-2 wk after (177)Lu treatment, whereas patients receiving (90)Y had these studies performed with (111)In-DOTA-J591 ((111)In-J591) as a surrogate. The BMrad was estimated based on blood radioactivity concentration. Myelotoxicity consisting of thrombocytopenia or neutropenia was graded 1-4 based on criteria of the National Cancer Institute. RESULTS: Blood pharmacokinetics are similar for both tracers. The radiation dose (mGy/MBq) to the bone marrow was 3 times higher with (90)Y (0.91 +/- 0.43) compared with that with (177)Lu (0.32 +/- 0.10). The MTD was 647.5 MBq/m(2) with (90)Y-J591 and 2,590 MBq/m(2) with (177)Lu-J591. The percentage of patients with myelotoxicity (grade 3-4) increased with increasing doses of (90)Y (r = 0.91) or (177)Lu (r = 0.92). There was a better correlation between the radioactive dose administered and the BMrad with (177)Lu (r = 0.91) compared with that with (90)Y (r = 0.75). In addition, with (177)Lu, the fractional decrease in platelets (FDP) correlates well with both the radioactive dose administered (r = 0.88) and the BMrad (r = 0.86). In contrast, with (90)Y, there was poor correlation between the FDP and the radioactive dose administered (r = 0.20) or the BMrad (r = 0.26). Similar results were also observed with white blood cell toxicity. CONCLUSION: In patients with prostate cancer, myelotoxicity after treatment with (177)Lu-J591 can be predicted on the basis of the amount of radioactive dose administered or the BMrad. The lack of correlation between myelotoxicity and (90)Y-J591 BMrad may be due to several factors. (90)Y-J591 may be less stable in vivo and, as a result, higher amounts of free (90)Y may be localized in the bone. In addition, the cross-fire effect of high-energy beta(-)-particles within the bone and the marrow may deliver radiation dose nonuniformly within the marrow.

Pharmacokinetics and biodistribution of 111In- and 177Lu-labeled J591 antibody specific for prostate-specific membrane antigen: prediction of 90Y-J591 radiation dosimetry based on 111In or 177Lu?

UNLABELLED: 111In-Labeled antibodies and peptides have been routinely used as chemical and biologic surrogates for 90Y-labeled therapeutic agents. However, recent studies have shown that there are significant differences in biodistribution between 111In- and 90Y-labeled agents. Yttrium and lutetium metals favor the +3 oxidation state, similar to indium, but there are minor differences in the solution and coordination chemistries among these metals. These 3 metals, however, form strong complexes with the macrocyclic chelator, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA). We, therefore, compared the pharmacokinetics and biodistribution of 111In- and 177Lu-labeled J591 antibody. The radiation dosimetry of 90Y-J591 was estimated based on both 111In and 177Lu data to validate the usage of 111In as a chemical and biologic surrogate for 90Y. METHODS: J591 is a deimmunized monoclonal antibody with specificity for the extracellular domain of prostate-specific membrane antigen. In patients with prostate cancer, phase I dose-escalation studies were conducted with 90Y-J591 (n = 29) and 177Lu-J591 (n = 25). Each patient had pharmacokinetics and imaging studies with 111In-J591 (185 MBq/20 mg) over a period of 1 wk and before treatment with 90Y-J591 antibody. In the 177Lu trial, the pharmacokinetics and imaging studies were performed after treatment with the 177Lu-J591 dose (370-2,590 MBq/m2/10 mg/m2) over a 2-wk period after treatment. RESULTS: Blood and urinary pharmacokinetics were similar for both tracers. Based on biexponential decay, the terminal half-life was 44 +/- 15 h for both tracers. In addition, the total-body retention of radioactivity over a 7-d period was also similar between the 2 isotopes. The percentage uptake in liver was about 20% greater with 111In than with 177Lu. Radiation dosimetry estimates for 90Y-J591 calculated on the basis of 111In or 177Lu data were mostly similar and showed that liver is the critical organ, followed by spleen and kidney. Based on blood radioactivity, the radiation dose (mGy/MBq) to the bone marrow was 3 times higher with 90Y (0.91 +/- 0.43) compared with that with 177Lu (0.32 +/- 0.10). CONCLUSION: 111In- and 177Lu-labeled J591 antibodies have similar plasma and whole-body clearance kinetics. The net retention of 111In activity by lung, liver, and spleen is slightly higher compared with that with 177Lu. These results justify using 111In as a chemical and biologic surrogate for 90Y. However, the radiation dose to the liver may be overestimated by about 25% based on 111In data. In addition, the data also suggest that 177Lu may be a potential alternative for estimating the pharmacokinetics and biodistribution of 90Y-labeled radiopharmaceuticals.

Determination of immunoreactive fraction of radiolabeled monoclonal antibodies: what is an appropriate method?

Determination of the immunoreactive fraction (IF) of radiolabeled monoclonal antibodies (MAb) is essential to the understanding of the effects of radiolabeling and subsequent target-specific tumor localization. There has been generally no accepted method of determining the IF of MAbs. The conventional method is based on a radioimmunoassay technique in which the fraction of radiolabeled MAb bound to antigen under conditions of "antigen excess" is determined. Lindmo et al. introduced a modified method in which the IF is determined by extrapolation to conditions representing "infinite antigen excess." Although the Lindmo method, in principle, is insensitive to experimental parameters, it does not always provide a reliable estimate of IF. We, therefore, evaluated an alternate method in which percent cell bound fraction is measured under conditions of fixed antigen concentration and various dilutions of radiolabeled MAb. We developed a mathematical equation to estimate immunoreactivity. J591 MAb specific for prostate-specific membrane antigen was radiolabeled with (111)In, (90)Y and (177)Lu to specific activities of 1-20 mCi/mg. We compared the effect of several experimental conditions on the determination of IF using all three different methods. The Lindmo method requires careful optimization of experimental conditions for each radiolabeled MAb. The alternate method, based on a fixed antigen concentration, appears to be practical and may provide a more reliable measure of immunoreactivity.

Targeted alpha particle immunotherapy for myeloid leukemia.

Unlike beta particle-emitting isotopes, alpha emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets myeloid leukemia cells and has activity against minimal disease. When labeled with the beta-emitters (131)I and (90)Y, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses. To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of beta-emitting constructs, the alpha-emitting isotope (213)Bi was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg (213)Bi-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the (213)Bi-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with beta-emitting constructs in this antigen system and patient population. Fourteen (93%) of 15 evaluable patients had reductions in circulating blasts, and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of (213)Bi-HuM195, and it is the first proof-of-concept for systemic targeted alpha particle immunotherapy in humans.