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PubMed2005

Melanoma therapy via peptide-targeted {alpha}-radiation.

PURPOSE: The therapeutic efficacy of a unique melanoma-targeting peptide conjugated with an in vivo generated alpha-particle-emitting radionuclide was evaluated in the B16/F1 mouse melanoma animal model. alpha-Radiation is densely ionizing, resulting in high concentrations of destructive radicals and irreparable DNA double-strand breaks. This high linear energy transfer overcomes radiation-resistant tumor cells and oxygen effects resulting in potentially high therapeutic indices in tumors such as melanoma. EXPERIMENTAL DESIGN: The melanoma targeting peptide, 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA)-Re(Arg(11))CCMSH, was radiolabeled with (212)Pb, the parent of (212)Bi, which decays via alpha and beta decay. Biodistribution and therapy studies were done in the B16/F1 melanoma-bearing C57 mouse flank tumor model. RESULTS: (212)Pb[DOTA]-Re(Arg(11))CCMSH exhibited rapid tumor uptake and extended retention coupled with rapid whole body disappearance. Radiation dose delivered to the tumor was estimated to be 61 cGy/muCi (212)Pb administered. Treatment of melanoma-bearing mice with 50, 100, and 200 muCi of (212)Pb[DOTA]-Re(Arg(11))CCMSH extended their mean survival to 22, 28, and 49.8 days, respectively, compared with the 14.6-day mean survival of the placebo control group. Forty-five percent of the mice receiving 200 muCi doses survived the study disease-free. CONCLUSIONS: Treatment of B16/F1 murine melanoma-bearing mice with (212)Pb[DOTA]-Re(Arg(11))CCMSH significantly decreased tumor growth rates resulting in extended mean survival times, and in many cases, complete remission of disease. (212)Pb-DOTA-Re(Arg(11))CCMSH seems to be a very promising radiopharmaceutical for targeted radionuclide therapy of melanoma.

Alpha Particles↗
PubMed1984

A clinical evaluation of a prototype positron camera for longitudinal emission tomography.

A multiwire proportional-chamber positron camera, developed at the Rutherford Laboratory, has been evaluated at The Royal Marsden Hospital. The prototype camera consists of two opposing 30 X 30 cm2 chambers. Longitudinal tomograms of a positron-emitting radioactive distribution placed between the detectors are obtained via back-projection and 2D-deconvolution. Due to the limited stereoscopic angle achieved with stationary detectors, only five planes parallel to the detector faces are reconstructed. A selection of images is presented of phantoms using 68Ga and of patients using 18F, 18F fluorodeoxyglucose and Na124I, to illustrate the tomographic performance of the positron camera. A comparison between back-projected and deconvoluted images shows that the 2D-deconvolution process, which includes filtration of image noise, successfully removes the background due to scattered photons. The spatial resolution achieved depends on the half-height frequency cut-off used in the filtering process, and this parameter was chosen according to the count density in the back-projected images. A qualitative visual comparison was made between the positron images and equivalent single photon studies on the same patient. The results justify further development of this new detector, especially for use with generator-produced positron-emitting radionuclides. Three-dimensional deconvolution resulted in improved tomographic performance for phantom data, but was less successful for patient data. These problems associated with limited-angle tomography will be overcome by multi-view acquisition. This study has shown that a relatively low-cost positron imaging system can be used for routine organ imaging. Further developments in hardware and software should yield images which are superior to those from single-photon planar or tomographic studies.

Bone Marrow↗
PubMed1989

Nuclear medicine in the 1990s: a quantitative physiological approach.

This paper describes the potential advantages to medical diagnosis and treatment that might be obtained from the wider application of positron emission tomography as a clinical tool. Developments along the lines suggested here will require a radical change in thinking from both clinicians and the medically related scientific community in the UK and some enlightened and resourceful funding from a mixture of charitable, industrial and government sources. If these ideas are to be pursued successfully, then the work must start now on a much wider scale than is presently perceived in the UK, and close collaboration between physicists, engineers, chemists, biochemists, clinicians and industrialists is needed. Furthermore, it is imperative that the scientific developments now underway in silicon technology, parallel data processors, biochemical and pharmacological processes and even high-temperature superconductors be kept under close and constant review by those associated with the technological advancements of medicine, so that the value of such developments is rapidly transferred to applications to medicine. This must include closer relationships between academic medicine and science than is the general rule in the UK at present. In conclusion, the scenario presented here includes the installation of regional cyclotron facilities to provide a large number of institutions in the UK with positron-emitter labelled radiopharmaceuticals. Additionally, agents labelled with radionuclides from in-house generators and other already existing higher-energy cyclotrons will provide a versatile and valuable range of radiopharmaceuticals for the study of human disease. These developments must be supported by the manufacture of lower-cost positron camera systems, as suggested here, connected to high-data-rate parallel processors to provide images of body function and to determine the effects brought about by disease. These images may then be processed using algorithms based on kinetic models of the body systems to provide information about the basic biochemical and physiological processes of the body. Such a development could have a profound effect on our knowledge of human disease and on our ability to control and treat it successfully.

Forecasting↗
PubMed2002

Preliminary studies with 188rhenium-tin colloid for radiation synovectomy: preparation, size determination, in-vivo distribution, effect and dosimetry studies.

BACKGROUND: Generator-produced beta-emitting radionuclides such as (188)Re are gaining in importance for radiosynoviorthesis because of their availability on a regular basis. MATERIAL AND METHODS: We prepared a (188)Re-tin colloid in a reaction carried out either at 100 degrees C or at room temperature (RT). The size of the colloid particles was measured with a laser lightscattering method, and their biodistribution, dosimetric aspects and therapeutic effects were studied in an antigen-induced arthritis (AIA) model in rabbits. (188)Re-tin colloid solution was injected intra-articularly into the knee joints of rabbits with AIA and imaging studies were performed. Blood samples were collected post injection for estimation of the blood residence time. We also injected 2 intact rabbits in the same manner with (188)Re perrhenate solution in order to observe its effects and distribution in the body. All the treated rabbit knees were subjected to histopathology. RESULTS: The colloid particle size distribution was different after preparation at the different reaction temperatures, with a more suitable mean of 4.53 micro m in the RT preparation. The dose delivered to the synovial surface was between 3.51 and 4.21 Gy and that to the bone surface was between 0.70 and 0.84 Gy. Histopathologic examination revealed the development of fibrous connective tissue in the AIA knees 4 weeks after treatment, but not in the control group. CONCLUSIONS: The (188)Re-tin colloid preparation used in this study was suitable for radiation synovectomy application. It requires modifications in the preparation protocol so as to increase the labeling efficiency in correlation with an appropriate particle size.

Journal Article↗
PubMed1990

[Radiolabeling and biodistribution of 62Cu-dithiocarbamate--an application for the new 62Zn/62Cu generator].

The newly developed 62Zn/62Cu generator system has made available the production of the short-lived 62Cu (T1/2 = 9.8 min) positron radionuclide, eluted as 62Cu-glycine. In the search for 62Cu labeled radiopharmaceuticals for positron CT (PET) brain diagnostic studies, two ligands N,N-diethyl- and N,N-dimethyl-dithiocarbamic acid (DDC and DmDC) were selected, based on their Cu chelating abilities and the neutral lipophilic character of their copper chelates. In the present work, an in vitro study with non-radioactive Cu-glycine showed that both ligands easily formed the stable, neutral Cu-DDC and Cu-DmDC chelates (1:2 metal-ligand complexes) based on the ligand exchange reaction. Then the 62Zn/62Cu generator eluate, the 62Cu-glycine was used for the radiolabeling of DDC and DmDC. The following HPLC analysis revealed that the ligand exchange reaction proceeded rapidly; the radiochemical purities of 62Cu-DDC and 62Cu-DmDC were extremely high (non-detectable 62Cu-glycine) and both chelates were more lipophilic than 62Cu-glycine. The mouse biodistribution of both radiolabeled compounds, 62Cu-DDC and 62Cu-DmDC indicated a brain accumulation of 2.8 and 5.3 times higher than 62Cu-glycine, 15 min post injection, respectively. The brain accumulation observed with both 62Cu-DDC and 62Cu-DmDC might be due to their stable, neutral and lipophylic character; the latter enhanced by the presence of the methylated side chains. The gathered results indicated the applicability of dithiocarbamic acid derivatives in the production of new 62Cu-labeled compounds using the 62Zn/62Cu generator system based on the ligand exchange reaction with 62Cu-glycine eluate. Further studies with Cu-dithiocarbamic acid derivatives for development of new generator-produced 62Cu positron radiopharmaceuticals can be recalled.

Animals↗
PubMed1998

Reactor-produced radioisotopes from ORNL for bone pain palliation.

The treatment of painful skeletal metastases is a common clinical problem, and the use of therapeutic radionuclides which localize at metastatic sites has been found to be an effective method for treatment of pain, especially for multiple sites for which the use of external beam irradiation is impractical. There are currently several metastatic-targeted agents radiolabeled with various therapeutic radionuclides which are in various stages of clinical investigation. Since neutron-rich radionuclides are produced in research reactors and often decay by emission of beta- particles, most radionuclides used for bone pain palliation are reactor-produced. Key examples of radionuclides produced by single neutron capture of enriched targets include rhenium-186 and samarium-153. In addition, generator systems are also of interest which provide therapeutic daughter radionuclides from the decay of reactor-produced parent radionuclides. One important example is rhenium-188, available from generators via decay of reactor-produced tungsten-188. Tin-117m is an example of a reactor-produced radionuclide which decays with the emission of low-energy conversion electrons rather than by beta- decay. Each of these agents and/or radionuclides has specific advantages and disadvantages, however, the ideal agent for bone pain palliation has not yet been identified. The goal of this paper is to briefly review the production and use of several reactor-produced radionuclides for bone pain palliation, and to discuss the role of the ORNL High Flux Isotope Reactor (HFIR) for the production of many of these radionuclides.

Bone Neoplasms↗
PubMed1996

[Radionuclide purity of 99mTC eluate for use in nuclear medicine].

The radionuclide purity of 99mTc eluates obtained by the elution on the commercially available 99Mo/99mTc generators based of fission-produced 99Mo was determined by gamma spectrometry. The following parameters were determined: the content of radionuclide impurities and their distribution in the eluates during the 10 days elution of the generator. The main radiocontaminant is 99Mo. In all eluates three long-living gamma emitters 103Ru, 106Ru and 131I were found. 125Sb appears only in the first three eluates. After that its activity falls under the detection limit. These four radioisotopes are fission products. They are formed in the fission of 235U and follow 99Mo during the separation and purification steps. It was found that the highest activity in eluates is due to the presence of 103Ru. By comparison of the obtained results and the prescribed criteria of the radio-nuclide purity of 99mTc eluates it could be concluded that all the found radionuclide impurities are under the permitted levels. Therefore 99mTc eluates fulfill the criteria for the nuclear-medical applications.

Humans↗
PubMedDate not supplied

Multi-method of standardization of radionuclides with "triangular scheme" of disintegration.

The new system of absolute methods of measurement of activity is presented in the paper. This system could be named a new generation of methods particularly for standardization of radionuclides with "triangular-scheme" of disintegration. The system is based on multi-parametric coincidence and anti-coincidence 4pi(LS)-gamma methods. Theoretical considerations and experimental data of 51Cr-activity measurement using the above methods are presented. Finally, determination of the uncertainty for all the components in the multi-method system and the overall uncertainty for the system is presented.

Journal Article↗
PubMedDate not supplied

3D simulation of PET brain images using segmented MRI data and positron tomograph characteristics.

A 3D simulation procedure has been developed to generate simulated PET brain images from MRI data. MRI slices were segmented into gray matter, white matter, CSF structures, and assigned with radionuclide distributions. Projections through these regions were generated according to physical characteristics of a positron tomograph, including 3D sampling and resolution, attenuation, scatter, randoms, and counting statistics. The projection data were then reconstructed by filtered backprojection. The procedure was validated with a cold spot phantom. Simulated PET images for cerebral blood flow or metabolism are presented, along with a brief discussion of some applications and limitations.

Brain↗
PubMed1995

The role of multiple regression and exploratory data analysis in the development of leukemia incidence risk models for comparison of radionuclide air stack emissions from nuclear and coal power industries.

Risks associated with power generation must be identified to make intelligent choices between alternate power technologies. Radionuclide air stack emissions for a single coal plant and a single nuclear plant are used to compute the single plant leukemia incidence risk and total industry leukemia incidence risk. Leukemia incidence is the response variable as a function of radionuclide bone dose for the six proposed dose response curves considered. During normal operation a coal plant has higher radionuclide emissions than a nuclear plant and the coal industry has a higher leukaemia incidence risk than the nuclear industry, unless a nuclear accident occurs. Variation of nuclear accident size allows quantification of the impact of accidents on the total industry leukemia incidence risk comparison. The leukemia incidence risk is quantified as the number of accidents of a given size for the nuclear industry leukemia incidence risk to equal the coal industry leukemia incidence risk. The general linear model is used to develop equations that relate the accident frequency required for equal industry risks to the magnitude of the nuclear emission. Exploratory data analysis revealed that the relationship between the natural log of accident number versus the natural log of accident size is linear.

Journal Article↗
PubMed2006

Quality assurance methods and procedures used to verify consistency in calculating dose coefficients.

The development of a spallation neutron source with a mercury target will lead to the production of rare radionuclides. The dose coefficients for many of these radionuclides have not yet been published. A collaboration of universities and national labs has taken on the task of calculating dose coefficients for the rare radionuclides using the software package DCAL. The working group developed a procedure for calculating dose coefficients and a quality assurance (QA) program to verify the calculations completed. The first portion of this QA program was to verify that each participating group could independently reproduce the dose coefficients for a known set of radionuclides. The second effort was to divide the group of rare radionuclides among the independent participants in a manner that assured that each radionuclide would be redundantly and independently calculated, and the results subsequently be submitted for publication in a separate manuscript. The final aspect of this program was to resolve any discrepancies arising among the participants as a group. The output of the various software programs for six QA radionuclides, 144Nd, 201Au, 50V, 61Co, 41Ar, and 38S were compared among all members of the working group. Initially, a few differences in outputs were identified. This exercise identified weaknesses in the procedure, which has since been revised. After the revisions, dose coefficients were calculated and compared to published dose coefficients with good agreement. The present efforts involve generating dose coefficients for the rare radionuclides anticipated to be produced from the spallation neutron source should a mercury target be employed.

Databases as Topic↗
PubMed1989

Assessment of the intracardiac left to right shunts with a single scintillation probe.

In order to assess the accuracy of pulmonary time-activity curves obtained at bedside with a single scintillation probe and Technetium-99m-labelled erythrocytes, pulmonary to systemic flow ratio (Qp:Qs) was calculated for radionuclide and hemodynamic investigations in 104 patients with suspected intracardiac left to right shunts. Cardiac catheterization confirmed the presence of shunts in 76 patients. Pulmonary time-activity curve was 100% sensitive, 88% specific, and 96% accurate in detecting the shunt. Correlation between the radionuclide and hemodynamic Qp:Qs was excellent (r = 0.93). Results were classified in four quantitative categories according to the Qp:Qs values. In 76 patients (73%) radionuclide and hemodynamic data fell in the same category. We conclude that radionuclide pulmonary time-activity curves generated with a scintillation probe is a reliable method in quantitative assessment of intracardiac left to right shunts.

Adolescent↗
PubMed1977

[Trial preparation and evaluation of a 81mKr-generator for medical use].

A prototype 81mKr-generator consisting of an ion exchange column and some attachments for handling was prepared on trial. Parent nuclide 81Rb obtained by the reaction of 82Kr(p, 2n)81Rb was absorbed on the resin, and radionuclidic purity, sterility and apyrogenicity of the generator eluate were examined. Analysis of gamma-ray spectrum obtained with a Ge(Li) detector and a multichannel pulse height analyzer revealed that the nuclidic purity of the 81mKr in the eluate was 99.997-99.999% with 0.001-0.003% of 79Kr at the start of the elution. Sterility and apyrogenicity of the eluate were proved by J.P. sterility test and limulus test respectively. All results obtained show that the 81mKr-generator is very suitable for medical application.

Evaluation Studies as Topic↗
PubMed1999

Semi-quantitative assessment of tibial blood flow and distribution in response to surgical intervention using first pass radionuclide angiography and intravascular vital dye.

The acute vascular response in bone to surgical trauma was investigated utilizing a sheep model. Blood flow and distribution were determined using two methods; perfusion of the vasculature with an intravascular vital dye (Disulphine blue) prior to euthanasia and by radionuclide angiography (RNA) before and after each surgical intervention. The pattern of Disulphine blue distribution provided a good indication of local perfusion and response to surgical trauma (drilling holes). Radionuclide angiography provided a dynamic image of the vascular response to surgical trauma. The generation of time activity curves of the first pass of radionuclide bolus enabled calculation of the relative blood flow through selected regions. For both techniques areas of ischaemia were apparent which were directly related to the location of screw holes. We conclude that factors other than bone plate contact influence the ischaemia that develops in bone subsequent to the application of bone plates.

Animals↗
PubMed2003

Comparison of biodistribution, dosimetry, and outcome from clinical trials of radionuclide-CC49 antibody therapy.

CC49 is a second-generation murine antibody with anti-TAG-72 (tumor-associated antigen) reactivity. For cancer therapy, it has the advantage of being expressed on adenocarcinomas but not on most normal tissues. CC49 has been utilized in phase I and II clinical trials at multiple institutions. Therapeutic applications to date have included (131)I-, (90)Y-, and (177)Lu-CC49, with tracer amounts of (111)In-CC49 as a dosimetry surrogate for (90)Y-CC49 therapy. Dosimetry methods and details of their description vary between studies. Biodistribution to normal organs and the effective plasma T(1/2) for various radionuclides were relatively consistent among patients with different diseases and treatment at several institutions. As expected with marrow suppression being the dose-limiting toxicity, higher doses of (177)Lu-CC49 were tolerated via intraperitoneal than IV administration. The biologic response modifier interferon enhanced TAG-72 expression and resulted in a trend of increased uptake of (131)I-CC49 by tumors. Tumor dose estimates were more variable than that of normal organs. Standardization and improved dosimetry may be helpful for comparison among patients in various studies and for establishing dose/toxicity relationships that are useful for predicting safe levels of radioimmunoconjugates.

Antibodies, Monoclonal↗
PubMed2004

Numerical and experimental results of the operational neutron dosemeter 'Saphydose-N'.

Since 1993, the Institute for Radiological Protection and Nuclear Safety (IRSN) has lead, in association with Electricité de France (EDF), a R&D study of a neutron personal electronic dosemeter. This dosemeter, called 'Saphydose-N', is manufactured by the SAPHYMO company. This paper presents first the optimisation of some detector components using Monte Carlo calculations, and second the test of the manufactured Saphydose-N under radiation following the IEC 1323 standard's recommendations for active personal neutron dosemeters. The measurements with the manufactured dosemeter were performed on the one hand at PTB (Physikalisch-Technische Bundesanstalt) in mono-energetic neutron fields and, on the other hand at IRSN in neutron fields generated by a thermal facility (SIGMA), radionuclide ISO sources and a realistic spectrum (CANEL/T400). The manufactured dosemeter Saphydose-N was also tested during measurement campaigns of the European programme EVIDOS ('Evaluation of Individual Dosimetry in Mixed Neutron and Photon Radiation Fields') at different nuclear workplaces. The study showed that Saphydose-N complies with the recommendations of standard IEC 1323 and can be used at any workplace with no previous knowledge of the neutron field characteristics.

Algorithms↗
PubMed2006

Performance of the electronic personal dosemeter for neutron 'Saphydose-N' at different workplaces of nuclear facilities.

This paper mainly aims at presenting the measurements and the results obtained with the electronic personal neutron dosemeter Saphydose-N at different facilities. Three campaigns were led in the frame of the European contract EVIDOS ('Evaluation of Individual Dosimetry in Mixed Neutron and Photon Radiation Fields'). The first one consisted in the measurements at the IRSN French research laboratory in reference neutron fields generated by a thermal facility (SIGMA), radionuclide ISO sources ((241)AmBe; (252)Cf; (252)Cf(D(2)O)\Cd) and a realistic spectrum (CANEL/T400). The second one was performed at the Krümmel Nuclear Power Plant (Germany) close to the boiling water reactor and to a spent fuel transport cask. The third one was realised at Mol (Belgium), at the VENUS Research Reactor and at Belgonucléaire, a fuel processing factory.

Dose-Response Relationship, Radiation↗
PubMed2000

188Re-ethylene dicysteine: a novel agent for possible use in endovascular radiation therapy.

Several agents, such as 188ReO4-, 188Re-MAG3 and 188Re-DTPA are currently under investigation as radiation sources in liquid-filled balloons for prevention of restenosis following coronary angioplasty. Bearing in mind the risk factor associated with leakage of radioactivity in the event of balloon rupture, the criteria sought in selecting suitable agents for endovascular radiation therapy (EVRT) are rapid clearance and low dose to vital organs. Since 99Tcm labelled ethylene dicysteine (EC) is a well established agent for renal tubular function imaging, the use of 186Re-ethylene dicysteine as a potential agent for prevention of restenosis after angioplasty has been evaluated previously. Therefore, it was of interest to evaluate the applicability of the more potential isotope of rhenium, 188Re, a high energy beta-emitter (Ebetamax = 2.12 MeV) with a suitable T 1/2 = 16.9 h, obtainable carrier-free from the 188W-188Re generator, as an attractive and alternative radionuclide for labelling with L,L-EC. In this paper, the preparation and pharmacological behaviour of the 188Re complex of ethylene dicysteine are reported. The complex can be prepared in high yields (99.5%) under optimized conditions of pH 2-3, at a ligand concentration of 15 mM, 50 microg (0.18 mM) carrier rhenium and using 2 mg x mL(-1) stannous chloride. On storage at 4 degrees C, the RC purity was more than 97% after 48 h when prepared under optimum conditions. Biodistribution studies in Wistar rats showed the desired characteristics of fast blood clearance and low retention of activity in the vital organs (< 2% in intestine, < 1% in stomach, < 0.5% in liver) with a high renal excretion (90.65+/-0.6%) at 3 h post-injection. These results confirm the advantages of using the 188Re-EC complex compared with perrhenate and other rhenium radiopharmaceuticals currently being used in balloons for EVRT.

Angioplasty, Balloon, Coronary↗