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Marked survival prolongation of mice bearing a transplantable colon adenocarcinoma by treatment with radioactive platinum-[125I]histamine complex. Preliminary report.

BACKGROUND: Recently, a new PtCl2-histamine complex, and its radioactive analogues labelled with I-131 and I-125 have been synthesised and investigated both in vitro and in vivo. In this preliminary report the survival rate of radioactive platinum-[125I] histamine therapy in tumour-bearing mice is demonstrated. MATERIAL AND METHODS: A murine model of transplantable colon adenocarcinoma (C38) in C57BL/6 mice (15 days postimplantation) was used for the experiment. Three groups of animals were treated every 2-3 days with five intraperitoneal injections of the following preparations: PtCl2Hist (total dose of Pt--125 micromol/kg), PtCl2[125I]Hist (total dose of I-125--4.2 MBq; Pt--13 micromol/kg), and "Active/Cold"--PtCl2[125I]Hist/PtCl2Hist (I-125--4.2 MBq; Pt--125 micromol/kg). A solution of 15% dimethylformamide in saline was applied to the control group. A survival analysis with the Kaplan-Meier estimation of survival curves and a statistical comparison by a log-rank test was applied to evaluate the anticancer activity of the tested preparations. RESULTS: Treatment of the animals with platinum-histamine preparations resulted in a significant prolongation of survivals, especially if the radioactive complex with carrier-added PtCl2Hist (p < 0.005) was applied. The highest, almost a 60% prolongation of survival was observed in the Active/Cold group (MStr/MScon ratio = 1.58, 95% CI 1.22-1.93). For this group there was the lowest risk of death (hazard ratio HR = 0.29), whereas HR = 0.45 and 0.47 were found in the animals treated with unattended PtCl2Hist and 125I-labelled complex, respectively. CONCLUSION: The significant enhancement of in vivo anti-cancer activity by a concomitant combination of the therapeutic factors, i.e. cytotoxic/cytostatic activity of the platinum(II)-histamine and the Auger electrons effects generated by the attached I-125 radionuclide, was found on the murine model of transplantable colon adenocarcinoma.

Adenocarcinoma↗

Steps towards cancer therapy with radionuclides--a review including radiation biophysical aspects.

Though great advantages will be connected with endoradiotherapy, a lot of problems has still to be overcome, the greatest of them being without doubt the problem of selectivity of the carrier compounds. Some few of them have proved to be able to accumulate in certain cancers by reason of their incorporation as metabolites, especially in melanomas. The other great hope are the monoclonal antibodies or their fragments, and in this field much endeavour has been spent in the last years. Especially the two-step method of loading the radioactive nuclide to the antibodies when their binding to the cancer cells is complete appears very promising. Some other, unspecific vehicles may also prove suitable for accumulation in certain tumor types. For the selection of the nuclides it has to be considered that radiation biophysical experiments demonstrated that the critical targets for radiation action are with high probability the DNA superstructure units, and that the distribution of ionizations within them is decisive for the inactivation of a cell. With sparsely ionizing radiation (e.g. beta-radiation) rather high doses are required for reaching an adequate concentration of ionizations in these DNA units. Densely ionizing radiation with an LET of about 150 keV/microns exhibits the maximum relative biological effectiveness (12-16 referred to X-radiation). Therefore emitters of alpha-particles the LET of which lies actually somewhat lower, near 100 keV/microns, seem to be very suitable for endoradiotherapy. Moreover the short ranges of these particles (about 60 microns in tissue) render an extensive sparing of the surrounding normal tissue possible. The second group of effective nuclides is that of Auger electron emitters. The low-energy proportion of Auger electrons leads to a high ionization density in small volumes. The very short ranges of these electrons (in the nanometer range), however, require an incorporation of the nuclide into the cell nucleus if an effective cell inactivation is to occur. 211At (alpha-emitter) and 125I (Auger electron emitter) already proved their high inactivating effectiveness in cell cultures and their curative action in animal experiments, and studies of binding 211At to monoclonal antibodies are encouraging. Some other approaches proposed for the transport of radionuclides into tumor cells or for generating them within tumor tissue are also aimed in essential at the release of densely ionizing alpha-particles or of Auger electrons.

Animals↗

Kr-81m for determination of right ventricular ejection fraction (RVEF).

A 10--12 mCi 81Rb leads to 81mKr generator was connected to a specially designed short-period infusion set, to produce an equilibrium activity distribution in the right heart. This procedure was tested in 25 individuals to calculate the right ventricular ejection fraction (RVEF). On average 30 heart cycles were analyzed per study. No background activity from the left heart was visualized because of the radionuclide exhalation. The background from the lungs could be neglected, which is partially due to the ultra-short half-life of the nuclide (t 1/2 = 13 S). Thus, an easy automatic procedure can be applied to delineate the ventricle and to calculate the RVEF. The data showed excellent reproducibility, when investigations were repeated. The method would benefit from use of higher activity generators.

Adult↗

[Production and therapeutic use of rhenium-186, 188--the future of radionuclides].

INTRODUCTION: In contemporary nuclear medicine, alpha, pure beta or beta-gamma emitters are used for targeted therapy. Use of pure and combined alpha/beta emitters in oncology, endocrinology, rheumatology and, a short while ago, interventional cardiology, has refined as an important alternative to more common therapeutic regimens. Two radioisotopes of rhenium, rhenium-186 and rhenium-188, are of particular interest. PRODUCTION OF RHENIUM-186 AND RHENIUM-188: Rhenium-186 is routinely produced in nuclear reactors by direct neutron activation of metallic rhenium enriched with 185Re via 185Re(n,) 186Re nuclear reaction. For production of 188Re the target is 186W. 188W is produced by double neutron capture which gives 188Re due to beta decay. Separation of 188Re is performed in generators by column chromatography, extraction or by gel technology. The best results are obtained using chromatographic 188W/188Re generator in which 188W is adsorbed on aluminium. Rhenium-188 is eluted in saline solution. RADIOPHARMACEUTICALS LABELED WITH RHENIUM RADIOISOTOPES AND THEIR CLINICAL APPLICATIONS: There are several fields of applications of radiopharmaceuticals labeled with 186,188Re. For bone pain palliation the most often used are 186Re-HEDP and 188Re-DMSA. For synovectomy, 186Re-sulphide in kit form is already commercially available. Endovascular radiation therapy is performed by using 188Re-perrhenate or 188Re-MAG3. Labeling of peptides and antibodies with 188Re is also reported. Application of rhenium radiosotopes depends on their specific activity. Rhenium-186,188 of low specific activity can be used only for labeling of particles or diphosphonates. However, labeling of peptides or antibodies can be performed only by using 188Re of high specific activity. CONCLUSION: 188Re is expected to have wide applications after development of a chromatographic 188W/188Re generator. One of the advantages of rhenium is tis chemical similarity with technetium. So technetium analogues labeled with 186,188Re can be developed for several specific applications.

Humans↗

An automated technique for SPECT marker-based image registration in radionuclide therapy.

An automated technique for marker-based image registration in radionuclide therapy is described. This technique is based on localization of the centroids of external markers and on establishing correspondence between the individual markers of the two studies to be registered. Localization of the centroids of markers relies on segmenting the markers using iterative thresholding. Thresholding is locally adaptive in order to account for study-dependent conditions (e.g. crossover between adjacent markers and markers with varying radioactive concentrations). Following marker segmentation, the centroids of the markers are computed based on an intensity-weighted method. Finally, prior to the least-squares fit registration, the markers of the two sets are matched to achieve one-to-one correspondence. The technique was applied to both simulated and patient studies resulting in mean residual three-dimensional registration errors (+/- 1SD) of 1.7 +/- 0.1 mm and 3.5 +/- 0.3 mm respectively. The technique was compared with a semi-automated approach and no significant difference was found between the mean residual three-dimensional registration errors (t = 0.281. p = 0.8). This automated marker-based image registration technique provides robust and accurate registration. Although it was developed as part of a programme to generate three-dimensional dose distributions for radionuclide therapy, it could be useful for other clinical applications.

Algorithms↗

Measurement of normal left atrial function with gated radionuclide angiography.

A method is described for measuring relative left atrial volume changes with gated radionuclide angiography, using an approximate computer-generated functional image to locate the atrial region of interest. M mode echocardiographic measurements of left atrial and left ventricular distances from the chest wall allowed calculation of a correction factor for the differential attenuation of atrial and ventricular photons. Background-corrected left atrial time-activity curves obtained from normal subjects exhibited excellent temporal resolution and were used to identify and quantitate the reservoir and contractile phases of left atrial volume change. In 20 normal subjects, the mean (+/- standard deviation) value for left atrial fractional emptying was 0.39 +/- 0.07. Expressed as fractions of the left ventricular stroke volume, mean values of the specific phases of atrial volume change were (1) reservoir volume 0.25 +/- 0.09, (2) contractile volume 0.29 +/- 0.10, and (3) conduit volume 0.46 +/- 0.12.

Adult↗

Efficient evaluation of thyroid nodules by primary care providers and thyroid specialists.

OBJECTIVE: To determine whether primary care providers and thyroid specialists at Gundersen Lutheran Medical Center are evaluating thyroid nodules efficiently by following recently published clinical guidelines. STUDY DESIGN: One-year retrospective chart review. PATIENTS AND METHODS: We reviewed patient records from 1996 and tabulated the use of fine-needle aspiration cytology, radionuclide scanning, and thyroid ultrasonography by 49 primary care physicians evaluating 81 thyroid nodules and by 5 thyroid specialists evaluating 29 thyroid nodules. The results were compared with our previous findings and those recently reported by others. RESULTS: Fine-needle aspiration cytology was widely used by both groups of Gundersen Lutheran healthcare providers. Primary care physicians used imaging studies modestly and generated $106 per patient in unnecessary costs. Thyroid specialists occasionally used radionuclide scanning but did not use thyroid ultrasonography; they generated $41 per patient in unnecessary costs. Overall, the introduction of fine-needle aspiration cytology at our institution has reduced the use of radionuclide scanning from 90% to 12% and the use of thyroid ultrasonography from 30% to 10%. We also found that the frequency of surgery in patients with thyroid nodules fell substantially, yet detection of thyroid cancer in the operative specimens increased from 16% to 43% while the cost of removing a thyroid carcinoma decreased from $64,000 to $25,000. CONCLUSIONS: Fine-needle aspiration cytology, adopted as the initial test for diagnosing thyroid nodules by most of our healthcare providers, has reduced the use of imaging studies far below the frequency reported by others and has substantially decreased the cost of thyroid nodule management.

Adolescent↗

Double antibody immunoradiometric assay of hGH employing a terminal labeling technique.

A method is described, and validated for hGH, using a double antibody immunoradiometric assay and a universal antibody coupled to a chelating moiety that can be labeled as the terminal step in the assay procedure. This technique, usable for any antigen, precludes the need for radiolabeled specific antibodies, and because of the short-lived radionuclide used in the terminal labeling step, generates no radioactive waste. The assay itself uses a specific first antibody coupled to a solid support (paper disc) to which the antigen binds. A specific second antibody from a second species is then attached to the solid phase retained antigen. Now a third antibody is attached, which has been generated from a third species against the second antibody acting as an antigen, and which carries transferrin as a chelating moiety. This final complex is labeled with 113mIn and the plot of the percentage of the total activity bound against the hGH concentration provides the derived values for the antigen levels present in the assay solution.

Antibodies↗

The ICRP working party on bioassay interpretation.

In recent years there have been many developments in modelling the behaviour of radionuclides in the human body. The current generation of models is designed to be more 'realistic' than the previous generation of simple compartment models. The International Commission on Radiological Protection (ICRP) uses these models to produce dose coefficients and recognises that there is a need to give more guidance on how these models can be used to interpret bioassay data. A working party has been set up to address the issue. This paper describes some of the problems, some approaches to solving the problems and the progress of the ICRP working party.

Advisory Committees↗

The accuracy of functional parameters extracted from ventricular time-activity curves by Fourier curve fitting: a simulation study.

The accuracy of functional parameters derived from multiple harmonic Fourier curve fitting of left ventricular time-activity curves (TACs) was assessed in simulated curves of exactly known characteristics. Curves were generated to represent TACs of equilibrium gated radionuclide ventriculography (ERNV) sampling at 16 frames cycle-1. Curves of varying shape and noise characteristics were studied. The number of harmonics used in the fitting process was variable, the number being determined by an automated 'goodness of fit' test based on the chi-squared test. The accuracy of measured peak ejection rate (PER) and peak filling rate (PFR) was independent of the shape of the curve, but the accuracy of the time to these slopes (TPER, TPFR) was dependent on the steepness of the slope. The accuracy of the measured parameters improved as the influence of noise decreased allowing more harmonics to be added. The values of PER and PFR in control subjects varied between individuals, and with heart rate. There was less variation in the ratio (PER/PFR) of the slopes between individuals, and the accuracy of the ratio was better than that of the individual values of PER and PFR. Functional parameters of predictable accuracy may be determined by Fourier curve fitting at the statistical quality of global or regional ventricular TACs derived from ERNV sampling at 16 frames cycle-1.

Fourier Analysis↗

Tantalum-178--a short-lived nuclide for nuclear medicine: development of a potential generator system.

We describe a chemical separation that may form the basis of a generator system for the short-lived radionuclide Ta-178 (T 1/2 = 9 min). The parent nuclide W-178 (T 1/2 = 21.7 days) is loaded on an anion-exchange column and the daughter eluted with a mixture of dilute hydrochloric acid and hydrogen peroxide. The yields of tantalum and the breakthrough of the tungsten parent as a function of the eluting conditions are discussed, and preliminary animal distribution data are presented for various treatments of the eluant solution.

Animals↗

The medical use of gallium radionuclides: a brief history with some comments.

The use of gallium radionuclides in nuclear medicine dates back to the late 1940s, following the observation in toxicologic studies that gallium tended to localize to a high degree at sites of osteogenic activity. Initial attempts in the early 1950s to use 72Ga for clinical diagnosis and therapy of malignant bone lesions were unproductive. However, the basic information gained then in the preclinical and clinical investigations was quite instrumental in generating the present-day use of gallium radionuclides as effective radiopharmaceutical agents. Although initial clinical trials of 72Ga were unproductive, subsequent studies with 68Ga and 67Ga, together with advances in nuclear medical instrumentation, resulted in the identification of gallium radionuclides as effective tumor- and abscess-localizing agents. A major factor in the recognition of the peculiar biologic properties of gallium radionuclides was the existence of a carrier (stable isotope) effect. Also, it appears from basic studies of the mechanism(s) of the uptake of gallium in tumor tissue that the biodistribution of gallium involves many essential biologic processes. The future use of gallium radionuclides may, therefore, actually very well fall more into the field of basic biologic investigations rather than into the field of nuclear medical diagnosis.

Animals↗

Adsorption of radionuclides on silica and their uptake by rice plants from silica-multitracer solutions: the effects of pH.

We investigated the effect of solution pH on the adsorption on silica of a mixture radionuclides 83Rb, 85Sr, 54Mn, 65Zn, 88Y, and 75Se generated from irradiation of Ag in a 135-MeV/nucleon 12C beam accelerated by the RIKEN Ring Cyclotron and 137Cs obtained commercially. Then, we related these findings to their uptake by a rice plant (Oryza sativa L. cv. Koshihikari) from a silica-multitracer solution at pH 4.3 +/- 0.2 and at 5.3 +/- 0.2. To evaluate both adsorption and uptake, precisely we used a multitracer technique that simultaneously tracked the movements of all of the radionuclides. There was an increase in the uptake of Rb, Cs, Sr, Mn, and Zn by the rice plants with the increase in pH from 4.3 to 5.3. By contrast, the uptake of Y and Se was less at the higher pH. Our findings suggest that the uptake of these elements is governed by their transport systems on the plasma membrane and by their affinity to silica, both of which are regulated by H+ concentration.

Adsorption↗

Dynamic variable background subtraction: a simple means of displaying radiolabeled monoclonal antibody scintigrams.

Subtraction of a nonspecific radionuclide is frequently used to enhance visualization of tumors imaged by radiolabeled monoclonal antibodies. Determining the optimal amount of the nonspecific radionuclide image to subtract can be difficult. We have developed a computer program that generates a closed-loop cinematic display in which a continuously varying amount of the nonspecific radionuclide image is subtracted from the specific antibody image. Through examination of this dynamic display, a broad range of background-subtracted images can be viewed expeditiously in an effort to select the optimal level of background subtraction. This method may be useful in routinely displaying such background-subtracted studies.

Antibodies, Monoclonal↗

A method for the estimation of right ventricular volume by equilibrium radionuclide angiography.

To develop a method for estimating right ventricular volume and to assess right ventricular volume at rest, we studied 45 persons with equilibrium radionuclide angiography. The study group comprised 15 normal control subjects (5 with atypical chest pain and normal coronary angiograms) and 30 patients with coronary heart disease (CHD). Each coronary patient and 5/15 control subjects had both right and left heart catheterization studies with intracardiac pressure measurements within 24 hours of the radionuclide study. Using a previously described method for generating right ventricular volume curves, we used the counts at end-diastole, corrected for frame time, the total number of processed heart beats, and blood radioactivity to derive right ventricular end-diastolic volume units. All normal controls (group 1) had a right ventricular ejection fraction greater than or equal to 0.40, with a right ventricular volume index less than or equal to 5.8. The CHD patients consisted of two subgroups: group 2 (N = 20) and group 3 (N = 10), with right ventricular end-diastolic pressures less than 10 mm Hg and greater than or equal to 10 mm Hg, respectively. In group 2, 19/20 had a normal right ventricular ejection fraction, and 18 had a normal end-diastolic volume. In group 3, 4/10 patients had a depressed ejection fraction (less than .40) and 9/10 an increased end-diastolic volume. We conclude that right ventricular volume can be estimated with radionuclide angiography, and that dilation may precede depression of the right ventricular ejection fraction in some patients with CHD.

Angiography↗

First-pass radionuclide angiography using a multiwire gamma camera and tantalum-178.

A portable multiwire gamma camera (MWGC) with enhanced imaging characteristics relative to conventional sodium iodide camera has been evaluated with 178Ta, a short-lived, generator-produced radioisotope (half-life 9.3 min). First-pass radionuclide angiography (FPRA) was performed and results were compared to those obtained with FPRA using a multicrystal camera (MCC) and 99mTc in 38 patients. The overall left ventricular count sensitivity (counts/mCi/sec/millisteradians [msr]) was significantly higher with MWGC/178Ta (176 +/- 132 versus 108 +/- 49, p less than 0.001) yielding images of higher statistics with higher resolution collimation (31 versus 63 msr). Left ventricular ejection fraction was 0.54 +/- 0.18 by MWGC and 0.54 +/- 0.18 by MCC with an excellent correlation between the two techniques (r = 0.94, s.e.e. = 0.06). The detection of wall motion abnormality was virtually identical with the two techniques. Intra- and interobserver reproducibility by MWGC was excellent (r = 0.99 and 0.99, respectively). Thus, this new technology provides first-pass studies of higher statistical quality and improved resolution, affording more precise assessment of left ventricular performance and likelihood of further substantial improvement by use of even higher doses of 178Ta.

Adult↗

Right ventricular pressure-volume loops using simultaneous radionuclide angiography with a multiwire gamma camera and right heart catheterization.

BACKGROUND: The purpose of this study was to generate right ventricular (RV) pressure-volume loops (PVLs) from time-activity curves obtained by first-pass radionuclide angiography (RNA) and RV pressures obtained by right heart catheterization. METHODS AND RESULTS: Short-lived tantalum 178 was used to obtain first-pass RNA at baseline (n = 31), after nitroglycerin (n = 5), or after the conclusion of cardiac catheterization (n = 13). From the radionuclide-derived RV ejection fraction and thermodilution stroke volume, the RV end-diastolic volume and end-systolic volume were measured. Special proprietary software was developed and used to integrate the pressure and the RNA data. The mean heart rate was 80 +/- 17 beats/min; RV ejection fraction, 39% +/- 12%; RV end-diastolic volume, 217 +/- 79 mL; RV end-systolic volume, 142 +/- 74 mL; and RV end-diastolic pressure, 10 +/- 7 mm Hg. The RV PVLs were of high quality and reproducible. CONCLUSIONS: This study provides proof of concept of the feasibility of generating RV PVL; the short half-life (10 minutes) and low energy (59 keV) of Ta-178 allow the generation of multiple loops at low radiation exposure. Such studies could be performed at the bedside and provide a wealth of information that may have clinical and research merits.

Blood Pressure↗

Method for noninvasive measurement of central aortic systolic pressure.

A method for noninvasive generation of central aortic systolic pressure curves is presented. The method is based on plotting the occlusive pressure values applied at the brachial artery level against the time intervals needed for the aortic pressure wave to equalize and break through the occlusive pressure at the brachial artery level. These time intervals were obtained by measuring the time from the beginning of depolarization (the QRS complex) to the detection of the pressure wave at the temporarily occluded brachial artery. The validity of the method was documented by 3 different approaches. The pressure values measured by a device developed by us were superimposed on the simultaneously measured central intra-aortic pressure waves and all values were within one standard deviation from the central aortic recordings in 8 of the 10 patients studied. At the same time, the noninvasively recorded pressure waves were completely different from the peripheral artery pressure recorded simultaneously at the femoral artery site. The DP/DT values derived from the central aortic recordings and the noninvasive device correlated (r = 0.83). These results indicate that the noninvasive device measures the central aortic pressure or a close approximation of it. By combining noninvasive pressure measurements with volume measurements obtained by radionuclide angiography, noninvasive pressure-volume curves were generated in 10 subjects. Possible clinical application of the systolic noninvasive pressure-volume curves is suggested.

Aorta↗