Evaluation of a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated bombesin-based radioantagonist for the labeling with single-photon emission computed tomography, positron emission tomography, and therapeutic radionuclides

PURPOSE: G protein-coupled receptor agonists are being used as radiolabeled vectors for in vivo localization and therapy of tumors. Recently, somatostatin-based antagonists were shown to be superior to agonists. Here, we compare the new [111In/68Ga]-labeled bombesin-based antagonist RM1 with the agonist [111In]-AMBA for targeting the gastrin-releasing peptide receptor (GRPR). EXPERIMENTAL DESIGN: IC50, Kd values, and antagonist potency were determined using PC-3 and HEK-GRPR cells. Biodistribution and imaging studies were done in nude mice transplanted with the PC-3 tumor. The antagonist potency was assessed by evaluating the effects on calcium release and on receptor internalization monitored by immunofluorescence microscopy. RESULTS: The IC50 value of [(nat)In]-RM1 was 14 +/- 3.4 nmol/L. [(nat/111)In]-RM1 was found to bind to the GRPR with a Kd of 8.5 +/- 2.7 nmol/L compared with a Kd of 0.6 +/- 0.3 nmol/L of [111In]-AMBA. A higher maximum number of binding site value was observed for [111In]-RM1 (2.4 +/- 0.2 nmol/L) compared with [111In]-AMBA (0.7 +/- 0.1 nmol/L). [(nat)Lu]-AMBA is a potent agonist in the immunofluorescence-based internalization assay, whereas [(nat)In]-RM1 is inactive alone but efficiently antagonizes the bombesin effect. These data are confirmed by the calcium release assay. The pharmacokinetics showed a superiority of the radioantagonist with regard to the high tumor uptake (13.4 +/- 0.8% IA/g versus 3.69 +/- 0.75% IA/g at 4 hours after injection. as well as to all tumor-to-normal tissue ratios. CONCLUSION: Despite their relatively low GRPR affinity, the antagonists [111In/68Ga]-RM1 showed superior targeting properties compared with [111In]-AMBA. As found for somatostatin receptor-targeting radiopeptides, GRP-based radioantagonists seem to be superior to radioagonists for in vivo imaging and potentially also for targeted radiotherapy of GRPR-positive tumors.

How well do radiographic absorptiometry and quantitative ultrasound predict osteoporosis at spine or hip? A cost-effectiveness analysis

Dual energy X-ray absorptiometry (DXA) is widely accepted as the reference method for diagnosis and monitoring of osteoporosis and for assessment of fracture risk, especially at hip. However, axial-DXA is not suitable for mass screening, because it is usually confined to specialized centers. We propose a two-step diagnostic approach to postmenopausal osteoporosis: the first step, using an inexpensive, widely available screening technique, aims at risk stratification in postmenopausal women; the second step, DXA of spine and hip is applied only to potentially osteoporotic women preselected on the basis of the screening measurement. In a group of 110 healthy postmenopausal woman, the capability of various peripheral bone measurement techniques to predict osteoporosis at spine and/or hip (T-score < -2.5SD using DXA) was tested using receiver operating characteristic (ROC) curves: radiographic absorptiometry of phalanges (RA), ultrasonometry at calcaneus (QUS. CALC), tibia (SOS.TIB), and phalanges (SOS.PHAL). Thirty-three women had osteoporosis at spine and/or hip with DXA. Areas under the ROC curves were 0.84 for RA, 0.83 for QUS.CALC, 0.77 for SOS.PHAL (p < 0.04 vs RA) and 0.74 for SOS.TIB (p < 0.02 vs RA and p = 0.05 vs QUS.CALC). For levels of sensitivity of 90%, the respective specificities were 67% (RA), 64% (QUS.CALC), 48% (SOS.PHAL), and 39% (SOS.TIB). In a cost-effective two-step, the price of the first step should not exceed 54% (RA), 51% (QUS.CALC), 42% (SOS.PHAL), and 25% (SOS.TIB). In conclusion, RA, QUS.CALC, SOS.PHAL, and SOS.TIB may be useful to preselect postmenopausal women in whom axial DXA is indicated to confirm/exclude osteoporosis at spine or hip.

Differences between dual X-ray absorptiometry using pencil beam and fan beam modes and their determinants in vivo and in vitro

The aim of this study was to determine the influence of individual factors on differences in bone mineral density (BMD) using dual X-ray absorptiometry pencil beam (PB) and fan beam (FB) modes in vivo and in vitro. PB.BMD and FB.BMD of 63 normal Caucasian females ages 21-80 yr were measured at the lumbar spine and hip. Residuals of the FB/PB regression were used to assess the impact of height, weight, adiposity index (AI) (= weight/height(3/2)), back tissue thickness, and PB.BMD, respectively, on FB/PB difference. The Hologic Anthropomorphic Spine Phantom (ASP) was measured using the PB and FB modes at two different levels to assess the impact of scanning mode and focus distance. The European Spine Phantom (ESP) prototype, a geometrically well-defined phantom with known vertebral densities, was measured using PB and FB modes and analyzed manually to determine the impact of bone density on FB/PB difference and automatically to determine the impact of edge detection on FB/PB difference. Population BMD results were perfectly correlated, but significantly overestimated by 1.5% at the lumbar spine and underestimated by 0.7% at the neck, 1.8% at the trochanter, and 2.0% at the total hip, respectively, when using the FB compared with PB mode. At the lumbar spine, the FB/PB residual correlated negatively with height (r = 0.34, p < 0.01) and PB.BMD (r = 0.48, p <: 0. 0001) and positively with AI (r = 0.26, p < 0.05). At the hip, residual of trochanter correlated positively with weight (r = 0.36, p < 0.01) and AI (r = 0.36, p < 0.01). The FB mode significantly increased ASP BMD by 0.7% compared with PB. Using the FB mode, increasing focus distance significantly (p < 0.001) decreased area and bone mineral content, but not BMD. By contrast, increasing focus distance significantly decreased PB.BMD by 0.7%. With the ESP, the PB mode supplied accurate projected are of the bone (AREA) results but significant underestimation of specified BMD in the manual analysis. The FB mode significantly underestimated PB. AREA by 2.9% but fitted specified BMD quite well. FB/PB overestimation was larger for the low-density (+8.7%) than for the high-density vertebra (+4. 9%). The automated analysis resulted in more than 14% underestimation of PB. AREA (low-density vertebra) and an almost 13% overestimation of PB.BMD (high-density vertebra) using FB. In conclusion, FB and PB measurements are highly correlated at the lumbar spine and hip with small but significant BMD differences related to height, adiposity, and BMD. In clinical practice, it can be erroneous to switch from one method to another, especially in women with low bone density.

Bone mineral density at distal tibia using dual-energy X-ray absorptiometry in normal women and in patients with vertebral osteoporosis or primary hyperparathyroidism

To assess the effect of age and disease on mineral distribution at the distal third of the tibia, bone mineral content (BMC) and bone mineral density (BMD) were measured at lumbar spine (spine), femoral neck (neck), and diaphysis (Dia) and distal epiphysis (Epi) of the tibia in 89 healthy control women of different age groups (20-29, n = 12; 30-39, n = 11; 40-44, n = 12; 45-49, n = 12; 50-54, n = 12; 55-59, n = 10; 60-69, n = 11; 70-79, n = 9), in 25 women with untreated vertebral osteoporosis (VOP), and in 19 women with primary hyperparathyroidism (PHPT) using dual-energy x-ray absorptiometry (DXA; Hologic QDR 1000 and standard spine software). A soft tissue simulator was used to compensate for heterogeneity of soft tissue thickness around the leg. Tibia was scanned over a length of 130 mm from the ankle joint, fibula being excluded from analysis. For BMC and BMD, 10 sections 13 mm each were analyzed separately and then pooled to define the epiphysis (Epi 13-52 mm) and diaphysis area (Dia 91-130 mm). Precision after repositioning was 1.9 and 2.1% for Epi and Dia, respectively. In the control group, at any site there was no significant difference between age groups 20-29 and 30-39, which thus were pooled to define the peak bone mass (PBM).(ABSTRACT TRUNCATED AT 250 WORDS)

Dual-energy X-ray absorptiometry for measuring total bone mineral content in the rat: study of accuracy and precision

Sequential studies of osteopenic bone disease in small animals require the availability of non-invasive, accurate and precise methods to assess bone mineral content (BMC) and bone mineral density (BMD). Dual-energy X-ray absorptiometry (DXA), which is currently used in humans for this purpose, can also be applied to small animals by means of adapted software. Precision and accuracy of DXA was evaluated in 10 rats weighing 50-265 g. The rats were anesthetized with a mixture of ketamine-xylazine administrated intraperitoneally. Each rat was scanned six times consecutively in the antero-posterior incidence after repositioning using the rat whole-body software for determination of whole-body BMC and BMD (Hologic QDR 1000, software version 5.52). Scan duration was 10-20 min depending on rat size. After the last measurement, rats were sacrificed and soft tissues were removed by dermestid beetles. Skeletons were then scanned in vitro (ultra high resolution software, version 4.47). Bones were subsequently ashed and dissolved in hydrochloric acid and total body calcium directly assayed by atomic absorption spectrophotometry (TBCa[chem]). Total body calcium was also calculated from the DXA whole-body in vivo measurement (TBCa[DXA]) and from the ultra high resolution measurement (TBCa[UH]) under the assumption that calcium accounts for 40.5% of the BMC expressed as hydroxyapatite. Precision error for whole-body BMC and BMD (mean +/- S.D.) was 1.3% and 1.5%, respectively. Simple regression analysis between TBCa[DXA] or TBCa[UH] and TBCa[chem] revealed tight correlations (n = 0.991 and 0.996, respectively), with slopes and intercepts which were significantly different from 1 and 0, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of Optically Stimulated Luminescent Detectors in Photon & Proton Beams for Use in Anthropomorphic Phantoms

This study investigated characteristics of optically stimulated luminescent detectors (OSLDs) in protons, allowing comparison to thermoluminescent detectors, and to be implemented into the Radiological Physics Center’s (RPC) remote audit quality assurance program for protons, and for remote anthropomorphic phantom irradiations. The OSLDs used were aluminum oxide (Al2O3:C) nanoDots from Landauer, Inc. (Glenwood, Ill.) measuring 10x10x2 mm3. A square, 20(L)x20(W)x0.5(H) cm3 piece of solid water was fabricated with pockets to allow OSLDs and TLDs to be irradiated simultaneously and perpendicular to the beam. Irradiations were performed at 5cm depth in photons, and in the center of a 10 cm SOBP in a 200MeV proton beam. Additionally, the Radiological Physics Center’s anthropomorphic pelvic phantom was used to test the angular dependence of OSLDs in photons and protons. A cylindrical insert in the phantom allows the dosimeters to be rotated to any angle with a fixed gantry angle. OSLDs were irradiated at 12 angles between 0 and 360 degrees. The OSLDs were read out with a MicroStar reader from Landauer, Inc. Dose response indicates that at angles where the dosimeter is near parallel with the radiation beam response is reduced slightly. Measurements in proton beams do not show significant angular dependence. Post-irradiation fading of OSLDs was studied in proton beams to determine if the fading was different than that of photons. The fading results showed no significant difference from results in photon beams. OSLDs and TLDs are comparable within 3% in photon beams and a correction factor can be posited for proton beams. With angular dependence characteristics defined, OSLDs can be implemented into multiple-field treatment plans in photons and protons and used in the RPC’s quality assurance program.

Dynamics of isolated-photon plus jet production in pp collisions at with the ATLAS detector

The dynamics of isolated-photon plus jet production in pp collisions at a centre-of-mass energy of 7 TeV has been studied with the ATLAS detector at the LHC using an integrated luminosity of 37 pb^-^1. Measurements of isolated-photon plus jet bin-averaged cross sections are presented as functions of photon transverse energy, jet transverse momentum and jet rapidity. In addition, the bin-averaged cross sections as functions of the difference between the azimuthal angles of the photon and the jet, the photon-jet invariant mass and the scattering angle in the photon-jet centre-of-mass frame have been measured. Next-to-leading-order QCD calculations are compared to the measurements and provide a good description of the data, except for the case of the azimuthal opening angle.

Search for new phenomena in photon+jet events collected in proton–proton collisions at √s = 8 TeV with the ATLAS detector

This Letter describes a model-independent search for the production of new resonances in photon + jet events using 20 inverse fb of proton--proton LHC data recorded with the ATLAS detector at a centre-of-mass energy of s√ = 8 TeV. The photon + jet mass distribution is compared to a background model fit from data; no significant deviation from the background-only hypothesis is found. Limits are set at 95% credibility level on generic Gaussian-shaped signals and two benchmark phenomena beyond the Standard Model: non-thermal quantum black holes and excited quarks. Non-thermal quantum black holes are excluded below masses of 4.6 TeV and excited quarks are excluded below masses of 3.5 TeV.

Measurement of isolated-photon pair production in pp collisions at sqrts=7 TeV with the ATLAS detector

The ATLAS experiment at the LHC has measured the production cross section of events with two isolated photons in the final state, in proton-proton collisions at root s = 7 TeV. The full data set collected in 2011, corresponding to an integrated luminosity of 4.9 fb(-1), is used. The amount of background, from hadronic jets and isolated electrons, is estimated with data-driven techniques and subtracted. The total cross section, for two isolated photons with transverse energies above 25 GeV and 22 GeV respectively, in the acceptance of the electromagnetic calorimeter (vertical bar eta vertical bar < 1.37 and 1.52 < vertical bar eta vertical bar 2.37) and with an angular separation Delta R > 0.4, is 44.0(-4.2)(+3.2) pb. The differential cross sections as a function of the di-photon invariant mass, transverse momentum, azimuthal separation, and cosine of the polar angle of the largest transverse energy photon in the Collins-Soper di-photon rest frame are also measured. The results are compared to the prediction of leading-order parton-shower and next-to-leading-order and next-to-next-to-leading-order parton-level generators.