An international multi-center investigation on the accuracy of radionuclide calibrators in nuclear medicine theragnostics.

BACKGROUND: Personalized molecular radiotherapy based on theragnostics requires accurate quantification of the amount of radiopharmaceutical activity administered to patients both in diagnostic and therapeutic applications. This international multi-center study aims to investigate the clinical measurement accuracy of radionuclide calibrators for 7 radionuclides used in theragnostics: 99mTc, 111In, 123I, 124I, 131I, 177Lu, and 90Y. METHODS: In total, 32 radionuclide calibrators from 8 hospitals located in the Netherlands, Belgium, and Germany were tested. For each radionuclide, a set of four samples comprising two clinical containers (10-mL glass vial and 3-mL syringe) with two filling volumes were measured. The reference value of each sample was determined by two certified radioactivity calibration centers (SCK CEN and JRC) using two secondary standard ionization chambers. The deviation in measured activity with respect to the reference value was determined for each radionuclide and each measurement geometry. In addition, the combined systematic deviation of activity measurements in a theragnostic setting was evaluated for 5 clinically relevant theragnostic pairs: 131I/123I, 131I/124I, 177Lu/111In, 90Y/99mTc, and 90Y/111In. RESULTS: For 99mTc, 131I, and 177Lu, a small minority of measurements were not within ± 5% range from the reference activity (percentage of measurements not within range: 99mTc, 6%; 131I, 14%; 177Lu, 24%) and almost none were outside ± 10% range. However, for 111In, 123I, 124I, and 90Y, more than half of all measurements were not accurate within ± 5% range (111In, 51%; 123I, 83%; 124I, 63%; 90Y, 61%) and not all were within ± 10% margin (111In, 22%; 123I, 35%; 124I, 15%; 90Y, 25%). A large variability in measurement accuracy was observed between radionuclide calibrator systems, type of sample container (vial vs syringe), and source-geometry calibration/correction settings used. Consequently, we observed large combined deviations (percentage deviation > ± 10%) for the investigated theragnostic pairs, in particular for 90Y/111In, 131I/123I, and 90Y/99mTc. CONCLUSIONS: Our study shows that substantial over- or underestimation of therapeutic patient doses is likely to occur in a theragnostic setting due to errors in the assessment of radioactivity with radionuclide calibrators. These findings underline the importance of thorough validation of radionuclide calibrator systems for each clinically relevant radionuclide and sample geometry.

Characterization of BAT activity in rats using invasive and non-invasive techniques.

INTRODUCTION: Brown adipose tissue (BAT) is considered as a potential target for combating obesity in humans where active BAT metabolizes glucose and fatty acids as fuel resulting in heat production. Prospective studies in humans have been set up to further study the presence and metabolic activity of BAT mostly using Positron Emission Tomography (PET) imaging in cold-stimulated conditions with the radiolabeled glucose derivative [18F]FDG. However, radiotracers beyond [18F]FDG have been proposed to investigate BAT activity, targeting various aspects of BAT metabolism. It remains questionable which tracer is best suited to detect metabolic BAT activity and to what extent those results correlate with ex vivo metabolic BAT activity. METHODS: PET and Single Photon Emission Computed Tomography (SPECT) imaging, targeting different aspects of BAT activation such as glucose metabolism, fatty acid metabolism, noradrenergic stimulation, blood perfusion and amino acid transport system, was performed immediately after injection of the tracer in rats under different temperatures: room temperature, acute cold (4 °C for 4 h) or acclimated to cold (4 °C for 6 h per day during 28 days). Furthermore, Magnetic Resonance Spectroscopy (MRS)-derived BAT temperature was measured in control and cold-acclimated rats. RESULTS: At room temperature, only [18F]FDG visualized BAT. Glucose metabolism, fatty acid metabolism, noradrenergic stimulation and blood perfusion showed a clear tracer-dependent twofold increase in BAT uptake upon cold exposure. Only the tracer for the amino acid transport system did not show BAT specific uptake under any of the experimental conditions. MRS demonstrated that cold-acclimated animals had BAT with a stronger heat-production compared to control animals. CONCLUSION: BAT activity following cold exposure in rats was visualized by several tracers, while only [18F]FDG was also able to show BAT activity under non-stimulated conditions (room temperature). The variances in uptake of the different tracers should be taken into account when developing future clinical applications in humans.

A comparison of four radionuclide dose calibrators using various radionuclides and measurement geometries clinically used in nuclear medicine.

PURPOSE: Reliable quantification of radioactivity in nuclear medicine is becoming increasingly important in various therapeutic applications requiring a high accuracy of nuclear medicine measuring equipment, such as radionuclide calibrators. In this study the accuracy of four different radionuclide calibrators was assessed for 99mTc, 111In, 68Ga and 18F for measurement geometries clinically used. METHODS: Syringes and vials were prepared with a reference activity using a stock solution of which the activity concentration was determined using gamma-ray spectroscopy. The accuracy of four different radionuclide calibrator systems, ISOMED 2000, ISOMED 2010, VIK-202 and Capintec CRC-25R, was assessed by comparing the measured activity to the reference activity. RESULTS: Deviations in measured activity from reference values were found up to 12.5%, 32.0%, 29.0% and 12.6% for 99mTc, 111In, 68Ga and 18F, respectively. For 68Ga all radionuclide calibrators systematically overestimated the activity by 10-20%. For 111In, large differences in activity measurements were observed between different source geometries, in particular between syringes and vials. Deviations between radionuclide calibrator systems were found up to 11.8%, 44.4%, 14.4% and 8.7% for 99mTc, 111In, 68Ga and 18F, respectively. When comparing similar syringe types of different brands filled with identical stock solution volume, deviations up to 1.8%, 5.8%, 10.2% and 3.2% were found for 99mTc, 111In, 68Ga and 18F. CONCLUSION: Substantial deviations in measured activity were found for all radionuclides and radionuclide calibrators, which may result in erroneous activity dosing and image quantification. This underlines the importance of thorough validation of radionuclide calibrators for all measurement geometries and radionuclides clinically used.

Comparison of Intraoperative γ-Probe Imaging and Postoperative SPECT/CT in Detection of Sentinel Nodes Related to the Ovary.

Tracer injection into ovarian ligaments has been shown to detect sentinel nodes (SNs) in patients with ovarian cancer. To determine the possibility that SNs are missed, this feasibility study compared their detection during surgery with their detection on postoperative SPECT/CT. METHODS: In 8 patients (with either ovarian or endometrial cancer), after a staging lymphadenectomy including resection of SNs related to the ovary, SPECT/CT was performed within 24 h. RESULTS: SPECT/CT identified hotspots in 4 patients at sites where SNs were resected. In 6 patients, additional sites were found, mainly in the pelvic region. CONCLUSION: Discrepancies between the γ-probe and SPECT/CT may be due to missed SNs during surgery, but with respect to pelvic hotspots, in most cases they are more probably related to remnants of tracer at injection sites. With respect to sites where SNs were resected, remaining hotspots may have been caused by residual lymphatic flow after resection.

Synthesis and in Vivo Biological Evaluation of (68)Ga-Labeled Carbonic Anhydrase IX Targeting Small Molecules for Positron Emission Tomography.

Tumor hypoxia contributes resistance to chemo- and radiotherapy, while oxygenated tumors are sensitive to these treatments. The indirect detection of hypoxic tumors is possible by targeting carbonic anhydrase IX (CA IX), an enzyme overexpressed in hypoxic tumors, with sulfonamide-based imaging agents. In this study, we present the design and synthesis of novel gallium-radiolabeled small-molecule sulfonamides targeting CA IX. The compounds display favorable in vivo pharmacokinetics and stability. We demonstrate that our lead compound, [(68)Ga]-2, discriminates CA IX-expressing tumors in vivo in a mouse xenograft model using positron emission tomography (PET). This compound shows specific tumor accumulation and low uptake in blood and clears intact to the urine. These findings were reproduced in a second study using PET/computed tomography. Small molecules investigated to date utilizing (68)Ga for preclinical CA IX imaging are scarce, and this is one of the first effective (68)Ga compounds reported for PET imaging of CA IX.

Molecular imaging of angiogenesis after myocardial infarction by (111)In-DTPA-cNGR and (99m)Tc-sestamibi dual-isotope myocardial SPECT.

BACKGROUND: CD13 is selectively upregulated in angiogenic active endothelium and can serve as a target for molecular imaging tracers to non-invasively visualise angiogenesis in vivo. Non-invasive determination of CD13 expression can potentially be used to monitor treatment response to pro-angiogenic drugs in ischemic heart disease. CD13 binds peptides and proteins through binding to tripeptide asparagine-glycine-arginine (NGR) amino acid residues. Previous studies using in vivo fluorescence microscopy and magnetic resonance imaging indicated that cNGR tripeptide-based tracers specifically bind to CD13 in angiogenic vasculature at the border zone of the infarcted myocardium. In this study, the CD13-binding characteristics of an (111)In-labelled cyclic NGR peptide (cNGR) were determined. To increase sensitivity, we visualised (111)In-DTPA-cNGR in combination with (99m)Tc-sestamibi using dual-isotope SPECT to localise CD13 expression in perfusion-deficient regions. METHODS: Myocardial infarction (MI) was induced in Swiss mice by ligation of the left anterior descending coronary artery (LAD). (111)In-DTPA-cNGR and (99m)Tc-sestamibi dual-isotope SPECT imaging was performed 7 days post-ligation in MI mice and in control mice. In addition, ex vivo SPECT imaging on excised hearts was performed, and biodistribution of (111)In-DTPA-cNGR was determined using gamma counting. Binding specificity of (111)In-DTPA-cNGR to angiogenic active endothelium was determined using the Matrigel model. RESULTS: Labelling yield of (111)In-DTPA-cNGR was 95% to 98% and did not require further purification. In vivo, (111)In-DTPA-cNGR imaging showed a rapid clearance from non-infarcted tissue and a urinary excretion of 82% of the injected dose (I.D.) 2 h after intravenous injection in the MI mice. Specific binding of (111)In-DTPA-cNGR was confirmed in the Matrigel model and, moreover, binding was demonstrated in the infarcted myocardium and infarct border zone. CONCLUSIONS: Our newly designed and developed angiogenesis imaging probe (111)In-DTPA-cNGR allows simultaneous imaging of CD13 expression and perfusion in the infarcted myocardium and the infarct border zone by dual-isotope micro-SPECT imaging.

The detection of sentinel nodes in ovarian cancer: a feasibility study.

UNLABELLED: Few sentinel node (SN) studies in ovarian cancer have been reported, mainly because of the risk of tumor dissemination associated with the injection of tracers into the ovarian cortex. To our knowledge, the injection of tracers into the ovarian ligaments has not been explored. The aim of this study was to determine the feasibility of the SN procedure in ovarian cancer with tracer injection into the ovarian ligaments and to establish whether the procedure is safe for the healthcare workers. METHODS: The study included patients who were at high risk of ovarian malignancy. Blue dye and radioactive colloid were injected into the proper ovarian ligament and suspensory ligament of the ovary. To measure professional radiation exposure, ring dose meters were worn by the surgeon, theater nurse, and pathologist during 3 procedures. RESULTS: An SN procedure was performed in 21 patients, and at least 1 SN location was identified in all patients using the γ probe before retroperitoneal exploration. SNs were located in the paraaortic and paracaval regions only in 67% of the patients, in the pelvic region only in 9%, and in both the paraaortic/paracaval and the pelvic regions in 24%. All but 2 SNs were found on the ipsilateral side. In 6 patients who underwent retroperitoneal exploration, 1-4 SNs were identified using the γ probe and resected. Blue-stained SNs were detected in 2 patients. Positive SNs were detected in 1 patient with lymph node metastases. The amount of radiation exposure to the surgeon, theater nurse, and pathologist did not exceed the safe limit. CONCLUSION: The identification of SNs in all cases suggests that the SN procedure performed by injection of tracers in the ovarian ligaments is feasible and promising. The procedure is safe for the involved personnel. Further investigation is necessary to determine the clinical application of this new technique.

Retention of 99mTc-DMSA(III) and 99mTc-nanocolloid in different syringes affects imaging quality.

(99m)Tc-dimercaptosuccinic acid [DMSA(III)] and colloidal human serum albumin ((99m)Tc-nanocolloid) are widely used radiopharmaceuticals. Recently, in our institution we encountered image quality problems in DMSA scans after changing the brand of syringes we were using, which triggered us to look into the adsorption properties of syringes from different brands for (99m)Tc-DMSA(III) and (99m)Tc-nanocolloid. We also describe a clinical case in which adsorption of (99m)Tc-DMSA(III) caused inferior imaging quality. DMSA and nanocolloid were labeled with (99m)Tc following manufacturer guidelines. After synthesis, syringes with (99m)Tc-DMSA(III) and (99m)Tc-nanocolloid were stored for 15, 30, 60, and 120 min. We evaluated Luer Lock syringes manufactured by different brands such as Artsana, Henke-Sass-Wolf, B. Braun Medical N.V., CODAN Medizinische Geräte GmbH & Co KG, Becton Dickinson and Company, and Terumo Europe. Adsorption of (99m)Tc-DMSA(III) and (99m)Tc-nanocolloid was acceptably low for all syringes (<13%), except for two brands with (99m)Tc-DMSA(III) adsorption rates of 36 and 30%, respectively, and for one brand with a (99m)Tc-nanocolloid adsorption rate of 27%. Adsorption of (99m)Tc-DMSA(III) and (99m)Tc-nanocolloid reaches critical levels in syringes produced by two brands, potentially causing poor image quality--for example, in DMSA scans using pediatric radiopharmaceutical doses. It is advised to check the compatibility of any radiopharmaceutical with syringes as an integral part of the quality assurance program.

Sentinel node in ovarian cancer: study protocol for a phase 1 study.

BACKGROUND: The concept of sentinel lymph node surgery is to determine whether the cancer has spread to the very first lymph node or sentinel node. If the sentinel node does not contain cancer, then there is a high likelihood that the cancer has not spread to other lymph nodes. The sentinel node technique has been proven to be effective in different types of cancer. In this study we want to determine whether a sentinel node procedure in patients with ovarian cancer is feasible when the tracers are injected into the ovarian ligaments. METHODS/DESIGN: Patients with a high likelihood of having an ovarian malignancy in whom a median laparotomy and a frozen section analysis is planned and patients with endometrial cancer in whom a staging laparotomy is planned will be included.Before starting the surgical staging procedure, blue dye and radioactive colloid will be injected into the ligamentum ovarii proprium and the ligamentum infundibulo-pelvicum. In the analysis we calculate the percentage of patients in whom it is feasible to identify sentinel nodes. Other study parameters are the anatomical localization of the sentinel node(s) and the incidence of false negative lymph nodes. TRIAL REGISTRATION: Approval number: NL40323.068.12Name: Medical Ethical Committee Maastricht University Hospital, University of MaastrichtAffiliation: Maastricht University HospitalBoard Chair Name: Medisch Ethische Commissie azM/UM.

An HPLC-based assay of adenylosuccinate lyase in erythrocytes.

ADSL deficiency is a disorder of purine metabolism with a broad clinical spectrum. A rapid and simple HPLC-based assay to measure ADSL activity in erythrocytes was developed. The suitability of DBSs was assessed. ADSL activity was measured in erythrocyte lysates and DBS using succinyl-AMP as the substrate. Detection and quantification were performed using isocratic ion-pairing reversed-phase HPLC with UV-detection. Reference values in erythrocyte lysates were established. The intra- and interassay variations were 2% and 8%, respectively. ADSL deficiency was easily recognized. ADSL activity in DBS was highly unstable, disqualifying DBS for diagnostic procedures.