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Recent advances in radionuclide therapy.

A variety of radionuclides continue to be investigated and/or clinically used for different therapeutic applications in nuclear medicine. The choice of a particular radionuclide with regard to appropriate emissions, linear energy transfer, and physical half-life is dictated to a large extent by the character of the disease (eg, solid tumor or metastatic disease) and by the carrier used to selectively transport the radionuclide to the desired site. An impressive body of information has appeared in the recent literature that addresses many of these considerations. This article summarizes and discusses the many recent advances and the progress in the clinical applications of therapeutic radionuclides in relatively new and developing areas, such as radioimmunotherapy, peptide therapy, intravascular therapy to prevent restenosis, radiation synovectomy, and bone malignancy therapy. Projections are made as to the future directions and progress in these areas. The crucial issue of a reliable, year-round supply of new and emerging therapeutic radionuclides in quantities sufficient initially for research, and then for routine clinical use, is a very worthy goal which, in the United States, remains to be achieved.

Angioplasty, Balloon, Coronary↗

Neutron beams from protons on beryllium.

Measurements of dose rate and penetration in water have been made for neutron beams produced by 30--75 MeV protons on beryllium. The effects of Polythene filters added on the target side of the collimator have also been studied. A neutron beam comparable with a photon beam from a 4--8 MeV linear accelerator can be produced with p/Be neutrons plus 5 cm Polythene filtrations, with protons in the range 50--75 MeV. This is a more economical method than use of the d/Be reaction.

Beryllium↗

Radiotoxicity of iodine-125 and other auger-electron-emitting radionuclides: background to therapy.

Auger-electron cascades with their ability to deposit energy in extremely small volumes, typically in the range of cubic nanometers, have served as valuable probes of radiobiologic phenomena. Results from their experimental use form part of the evidence that nuclear DNA is the most radiosensitive cell element; that chromosomal aberrations and large scale double-strand breaks are correlated with reproductive survival; that neoplastic transformation and also mutagenesis are greatest at low doses with high specific ionization; and that, like high linear-energy-transfer radiation, Auger-electron cascades can lead to bystander effects. We have also learned that radiobiologic responses to Auger-electron emission are particularly sensitive to the site of decay, not only within the cell but also in the nucleus within the fine structure of chromatin.

DNA↗

Abnormal ventricular contraction patterns in patients with arrhythmogenic substrates using three-dimensional phase analysis.

Arrhythmogenic substrate diagnosis has been achieved by electrophysiological studies and best localized by successful radiofrequency ablation. Pre-invasive localization procedures have been based on surface ECGs and more recently on biomagnetism, but in addition to these electric and magnetic signals a mechanical signal may be utilized: the initial site of contraction may be detected by phase analysis during radionuclide ventriculography. Generation of three-dimensional data set of phases is achieved by incorporating the new emission tomography technique. The performance of this modified phase analysis has been investigated for the detection of the normal contraction pattern during sinus rhythm, the arrhythmogenic substrate of the WPW syndrome and ventricular tachycardia, and further, to define the limitations of the method in experimental studies on pigs. In 30 out of 44 patients with normal sinus rhythm and no ventricular lesion, a characteristic phase pattern was found. Physiologically, the initial site of contraction appeared to be paraseptal and in the anterior wall of the right ventricle close to the apex. In 13 patients with WPW syndrome and in seven with ventricular tachycardia, the phase data were compared to the electrophysiological study. In 14 of 20 there was a complete match, in 3 of 20 a mechanical focus was found in the area adjacent to the electric focus. From experimental pig studies with simulated stimulation, a spatial precision of at least 20 mm was found at a pre-excitation of 20 ms.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Radioiodine speciation in the hot cell effluent gases of a radiopharmaceutical production facility.

In order to characterize the various chemical forms of airborne radioiodine species, grab-sampling measurements were conducted at the hot cell laboratory of a radiopharmaceutical production facility, using a selective-adsorbent-iodine filter system. Volatile radioiodine species were produced in the hot cell process which extracted the fission product 99Mo from the irradiated uranium target. The effluent gases were then released through the hot cell filter bank and the main filter bank. Two samplings were made, one at the inlet and one at the outlet of the hot cell filter bank. In comparison with other radioiodine isotopes detected, higher than expected concentrations of 132I were found, primarily in the form of organic iodide--an observation that could be explained by the beta decay of 132Te, the precursor of 132I, in the hot cell waste solution. The relative distribution of airborne 132I was considerably different from that of other iodine radioisotopes. An unexpected component of these distributions was radioiodine penetrating the silver zeolite filter and adsorbed on a triethylenediamine (TEDA) impregnated charcoal filter.

Air Pollutants, Radioactive↗

Feasibility of fractionating MAG3 cold kit for cost reduction.

99Tcm-MAG3 is the first 99Tcm-labelled radiopharmaceutical with a renal clearance similar to that of 131I-OIH. The cost of a unit dose of 99Tcm-MAG3 is comparatively less expensive than the cost of a combined 99Tcm-DTPA and 131I-OIH study dose. However, this cost-saving is dramatically reduced when only a few doses are withdrawn from a 99Tcm-MAG3 kit. Our goal in this study was to subdivide the MAG3 kit into fractions to reduce expense. By dissolving the lyophilized ingredients of MAG3 kits with either 5 or 10 ml N2-purged normal saline, the resultant liquid was divided into 1-ml aliquot vials filled with N2. The MAG3 aliquot vials were then frozen at -70 degrees C for future use. The radiochemical purity (RCP) of each vial was evaluated using the recommended Sep-Pak C18 column chromatography at different time periods. Over the entire 28-day evaluation period, the average RCP of the 5:1 dilution MAG3 vials after reconstitution with 3.7 GBq 99Tcm was maintained at 95.6 +/- 2.7% (n = 100) for 6 h, whereas the 10:1 fractionation MAG3 kits after labelling with 740 MBq 99Tcm showed an average RCP value of 98.4 +/- 2.1% (n = 100) for 6 h. Based upon these results, it is concluded that the fractionation of MAG3 kits and frozen storage in an N2 atmosphere not only maintains the stability of MAG3 but also provides a cost-effective method for using 99Tcm-MAG3.

Costs and Cost Analysis↗

Monte Carlo calculation of the wall correction factors for ionization chambers and Aeq for 60Co gamma rays.

The application of cavity-ionization chambers to the standadization of 60Co gamma-ray beams, in terms of exposure, requires that the specific ionization of air Jg, be corrected for the attenuation and scatter of the incident rays by the wall, central electrode, and supporting stem of the chamber. A Monte Carlo photon-electron transport code has been developed for the purpose of calculating this correction for spherical and cylindrical chambers. The code has been applied to a spherical graphite chamber having dimensions typical of the chambers used by the NBS, the calculated wall-correction factor is in close agreement with the average of the NBS factors which were determined experimentally. The code was also used to calculate Aeq, which is central to the determination of tissue-air ratios. The calculated value, 0.989 +/- 0.003, is very close to the generally accepted value, 0.985.

Cobalt Radioisotopes↗

The Compton backscattering process and radiotherapy.

Radiotherapy utilizes photons for treating cancer. Historically these photons have been produced by the bremsstrahlung process. In this paper we introduce Compton backscattering as an alternate method of photon production for cancer treatment. Compton backscattering is a well-established method to produce high-energy photons (gamma rays) for nuclear physics experiments. Compton backscattering involves the collision of a low-energy (eV) photon with a high-energy (hundreds of MeV) electron. It is shown that the photons scattered in the direction opposite to the direction of the initial photon (backscattered) will have the energy desired for photon beam therapy. The output of Compton backscattering is a high-energy photon beam (gamma-ray beam), which is well collimated and has minimal low-energy components. Such gamma beams may be used for conventional high-energy photon treatments, production of radionuclides, and generation of positrons and neutrons. The theoretical basis for this process is reviewed and Monte Carlo calculations of dose profiles for peak energies of 7, 15, and 30 MeV are presented. The potential advantages of the Compton process and its future role in radiotherapy will be discussed.

Biophysical Phenomena↗

Method for determining photonuclear production of radioisotopes using high-energy electron beams.

Linear accelerators can produce electrons at high power and energy. These electrons can be targeted at materials to produce radionuclides. Monte Carlo simulation is used to follow the path of the linac electrons (15-35 MeV) through materials. The production of photons and their passage through the material is modeled. The method of using this Monte Carlo information to calculate activation in the materials is presented. It is found that kilowatt power levels can produce mCi amounts of radioactivity in minutes. This work permits systematic evaluation of the potential for designing linear accelerators for in-house production of radionuclides.

Computer Simulation↗

Genotypes associated with virulence in environmental isolates of Vibrio cholerae.

Vibrio cholerae is an autochthonous inhabitant of riverine and estuarine environments and also is a facultative pathogen for humans. Genotyping can be useful in assessing the risk of contracting cholera, intestinal, or extraintestinal infections via drinking water and/or seafood. In this study, environmental isolates of V. cholerae were examined for the presence of ctxA, hlyA, ompU, stn/sto, tcpA, tcpI, toxR, and zot genes, using multiplex PCR. Based on tcpA and hlyA gene comparisons, the strains could be grouped into Classical and El Tor biotypes. The toxR, hlyA, and ompU genes were present in 100, 98.6, and 87.0% of the V. cholerae isolates, respectively. The CTX genetic element and toxin-coregulated pilus El Tor (tcpA ET) gene were present in all toxigenic V. cholerae O1 and V. cholerae O139 strains examined in this study. Three of four nontoxigenic V. cholerae O1 strains contained tcpA ET. Interestingly, among the isolates of V. cholerae non-O1/non-O139, two had tcpA Classical, nine contained tcpA El Tor, three showed homology with both biotype genes, and four carried the ctxA gene. The stn/sto genes were present in 28.2% of the non-O1/non-O139 strains, in 10.5% of the toxigenic V. cholerae O1, and in 14.3% of the O139 serogroups. Except for stn/sto genes, all of the other genes studied occurred with high frequency in toxigenic V. cholerae O1 and O139 strains. Based on results of this study, surveillance of non-O1/non-O139 V. cholerae in the aquatic environment, combined with genotype monitoring using ctxA, stn/sto, and tcpA ET genes, could be valuable in human health risk assessment.

Biomarkers↗

Biophysical aspects of Auger processes--A review.

Radionuclide decay by electron capture and/or internal conversion is accompanied by complex atomic vacancy cascades and emission of low-energy electrons, resulting in a highly charged daughter atom and a high density of electron irradiation in the immediate vicinity of the decay site. The molecular and cellular consequences of such decay events include DNA strand breaks, mutations, chromosome aberrations, malignant transformation, division delay, and cell death. Damage to cells depends largely on the intracellular location of the radionuclide. Decays outside the cell nucleus produce low-LET-type radiation effects (RBE approximately 1). In contrast, decays in DNA cause pronounced high-LET-type effects (RBE approximately 7-9). However, recent studies suggest that even for DNA-associated Auger emitters cell damage can be modified to resemble the pattern observed with low-LET radiations. These findings indicate that the molecular and cellular mechanism(s) responsible for the cytotoxic effects of Auger emitters remain obscure.

Biophysical Phenomena↗

[Production of 52Fe by the 55Mn(p,4n)52Fe reaction and milking of 52mMn from 52Fe].

The excitation functions were measured for the nuclear reactions of 55Mn(p,4n)52Fe and 55Mn(p,n)55Fe by using thin manganese disks, specially prepared under a pressure of 200-250 kg/cm2 at 400-500 degrees C for 0.5-1 hour. The maximum cross section in the excitation function for the 55Mn(p,4n)52Fe reaction was found to be 1.4mb at Ep = 54 MeV. From the yield curve, 24.8 MBq/microA h (670 muCi/microA h) of 52Fe was estimated to be produced with 0.45% 55Fe contamination in the energy region between 73 and 39 MeV. Iron-52 was produced in the yield of 85-93% to the expected value from the yield curve in the energy region of 44-60 MeV. For the separation of 52Fe, the radiochemical yield of 52FeCl3 was 70-92% and its radionuclidic purity was higher than 99%. Manganese-52m was obtained repeatedly by eluting the anion exchange column adsorbing 52Fe with 6N-HC1 in 99.9% radionuclidic purity and 86% yield to the expected value. The amount of 55Fe in a large quantity of 52Fe could be determined in 1-2 days from end of bambardment (EOB) by analyzing decay curve of Mn-Ka-X ray from 52Fe and 55Fe.

Drug Contamination↗

[Clinical experience with rhenium-188 HEDP therapy for metastatic bone pain].

Rhenium-188 hydroxyethylidene diphosphonate (Re-188 HEDP) is a new radiopharmaceutical for treatment of metastatic bone pain. Re-188 is a generator-produced radionuclide emitting high energy beta and gamma rays and having a relative short physical half-life makes it of especially interesting for therapeutic purpose. Seven patients (pts) with multiple painful bone metastases were treated with Re-188 HEDP. Five pts with prostate cancer and 2 pts with breast cancer received a fixed activity of 3000 MBq of Re-188 HEDP intravenously in two steps. Complete blood counts were determined, blood chemistry examinations and urine-analysis were performed before and 1, 2, 3, 4, 6, 8, 12 weeks following the treatment. A visual analogue score, a verbal rating scale, the Spitzer index and the Karnofsky score were used to assess pain and performance status. Three hours after Re-188 HEDP administration at 1 m from the anterior mid-trunk of the pts gamma and at the patient body surface beta-radiation dose measurements were made, together with urine radioactivity measurements. Three pts become pain-free, 2 pts exhibited partial pain improvement and 1 patient gave no response to the Re-188 HEDP therapy. In 1 patient due to central nervous system metastasis the modification of the pain intensity could not be evaluated. Three pts displayed a flare reaction within 1 week after the treatment. Transient decreases in platelet and white blood cell counts were observed. There were no significant changes in the liver and renal functions. Radiation dose rate values of 6.3 +/- 1.0 microSv/h for gamma, and of 183 +/- 40 s-1 for beta-radiation were found. 25-32% of the administered dose was eliminated via the urinary tract in the first three hours. The preliminary data suggests that Re-188 HEDP is an effective radiopharmaceutical in treatment for metastatic bone pain. An administered activity of 3000 MBq can bring about a pain reduction without causing any clinically significant bone marrow toxicity.

Alkaline Phosphatase↗