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Direct radiolabeling of monoclonal antibodies with rhenium-188 for radioimmunotherapy of solid tumors--a review of radiolabeling characteristics, quality control and in vitro stability studies.

188Re is one of the radioisotopes expected to emerge as useful for therapy. Development of new radiopharmaceuticals based on 188Re depends on the radiolabeling methods used, which would give stable complexes having predefined radiochemical properties and in vitro and in vivo stability. This paper has attempted to provide a perspective of 188Re-labeled monoclonal antibodies, their radiolabeling characteristics, methods for quality control of radioimmunoconjugates and in vitro stability for radioimmunotherapy of solid tumors. The direct method of 188Re radiolabeling of antibodies by reductive attachment of 188Re in which free sulfhydryl groups have been generated by reduction of the intramolecular S-S disulfide bonds has been shown to be a promising approach in particular. Moreover, excellent methods have been developed to test the radionuclide, radiochemical purity and stability of 188Re-radioimmunoconjugates using high performance liquid chromatography (HPLC) and paper chromatography.

Animals↗

Characterization of long-lived radioactive dust in uranium mill operations.

The characteristics of long-lived radioactive dust clouds generated in several mechanical and physiochemical operations in a uranium mill have been investigated. The study consisted of the determination of dust size distribution and of the size distribution of radionuclides associated with particulate matter in the size range less than 0.1 to 26 microns. Experiments were conducted by using two different types of cascade impactors operating at different sampling flow rates. Radionuclide identification was done by using alpha-spectrometry. Long- and short-lived radionuclides were identified in dust samples. The characteristics of the dust clouds depended on the mill operation, such as crushing (vibrating grizzly, jaw crusher, cone crusher); screening; ore transportation; grinding; acid leaching; counter-current decantation; yellow cake precipitation and drying; and yellow cake packaging. In addition, other dust and radioactivity measurements have been carried out.

Air Pollutants, Occupational↗

Overview of samarium sm 153 lexidronam in the treatment of painful metastatic bone disease.

Bone pain associated with advanced prostate and other cancers is a frequent and significant complication, and the effective management of metastatic bone disease and accompanying symptoms continues to be one of the major problems facing patients and their physicians. Treatment is in part dependent on prior treatments; usually a combination of systemic and local modalities is used because no single treatment regimen is effective for an extended period of time. The 3 radionuclides currently approved for treatment of bone pain (phosphorus-32, strontium-89, and samarium-153) are discussed in this review as viable treatment options, with emphasis on the third-generation agent in this category, samarium Sm 153 lexidronam. Clinical trial data are described that support the use of this agent in patients with hormone-refractory prostate cancer with painful metastatic bone disease, and the efficacy of and role for combination therapies are also discussed.

Journal Article↗

The influence of cycle length on the radionuclide left ventricular volume curve acquired with a scintillation camera and ECG-triggered data processor.

This study was designed to evaluate the effect of cycle length on the parameters of left ventricular function such as left ventricular ejection fraction (LVEF), ejection rates and ejection times. Radionuclide (in vivo 99mTc-labelled red blood cells) volume curves were obtained from ten chacma baboons. Transoesophageal atrial pacing of the baboon hearts was controlled by a microcomputer. A sequence of four beats was generated during arrhythmic pacing, consisting of two beats of equal cycle lengths, followed by a beat 15% shorter and a subsequent beat after a compensatory pause. Triggering impulses were sent to the data processor coincident with one of these beats until sufficient counts were obtained, before advancing to the next beat. Global LVEFs were found to be influenced by the preceding cycle length, increasing on a previous long cycle and decreasing on a previous short cycle and were even found to be influenced one normal beat on from the unrepresentative cycle. Similar trends were found for ejection times and rates. Discarding specific unrepresentative cycle lengths in order to correct for arrhythmia without attention to the previous cycle and even to the following cycle is therefore inappropriate.

Animals↗

A method for recovering physiological components from dynamic radionuclide images using the maximum entropy principle: a numerical investigation.

A method based on the maximum entropy principle is described for recovering physiological components from a sequence of dynamic radionuclide images. The method does not require any assumption about the shapes of the component curves. It is, however, assumed that the components are nonnegative. The method requires normalization of component curves. The sum of squares of each component curve to be estimated is normalized so as to be unity. A first-pass cardiac study and a hepatic study are selected for investigation of applicability of the method. The method is investigated numerically using computer-generated time-activity curves with six components for the cardiac study and seven components for the hepatic study. Within the regions studied, the results have demonstrated that the method may recover the component time-activity curves and the corresponding images of physiological components from a sequence of dynamic radionuclide images. The ability and limitations of the method to recover physiological components are discussed and potential applications are suggested.

Heart↗

Non-invasive three-dimensional localisation of arrhythmogenic foci in Wolff-Parkinson-White syndrome and in ventricular tachycardia by radionuclide ventriculography: phase analysis of double-angulated integrated single photon emission computed tomography (SPECT).

A new tomographic technique combined with phase analysis was used to detect premature and ectopic ventricular contraction patterns in 15 patients with Wolff-Parkinson-White syndrome and during ventricular tachycardia in seven patients. Data generated by gated single-photon emission computed tomography (SPECT) were analysed by backprojection of the Fourier coefficients, double-angulation, and integration to thick slices containing the ventricles, thus allowing visualisation of the contraction patterns in three perpendicular views. The results were compared with those of catheter mapping. In nine patients with Wolff-Parkinson-White syndrome the site of initial contraction detected was identical with the site of the accessory pathway found by catheter mapping. The sites of origin of the ventricular tachycardias determined by catheter mapping were within 3 cm of the sites detected by the new technique. This new technique seems to be a promising non-invasive method for localising ectopic ventricular activity that will considerably shorten the time required for subsequent invasive procedures.

Adult↗

An assessment of current achievements in the systemic management of breast cancer.

Over the past twenty years, breast cancer has come to be much more commonly regarded and treated as a systemic disease. Conventional chemotherapy and endocrine therapy used according to schedules that are tolerable to patients are generally effective and often induce worthwhile responses; nevertheless, the responses in general have a median duration of less than a year, and these therapies are rarely if ever curative. Continued efforts to use available agents with mere modifications of schedule and intensity seem unlikely to substantially improve upon the modest success already achieved. Rather, we desperately need radically new schedules, new agents (especially non-myelosuppressive agents), and new approaches (e.g. monoclonal antibody targeting of drugs, toxins, or radionuclides, perhaps combined with tumor sensitizing agents such as heat). It is our hope that consideration of some of these issues will encourage others to be bolder in devising the next generation of clinical trials.

Antineoplastic Agents↗

Contrast CT in localization of acute lower gastrointestinal bleeding.

Localization of the source of acute lower gastrointestinal bleeding is of paramount importance in its management as it allows for planned segmental resection rather than a "blind" abdominal total colectomy. Various methods of localization with radionuclide scan, mesenteric angiography and colonoscopy have been utilized, but none has been shown to be superior to others. The recent use of contrast-enhanced multislice computed tomography (MSCT) has generated much interest as it is rapid, noninvasive and readily accessible, and allows for excellent reformation on different planes. These are clear advantages in an emergency setting for accurate localization prior to surgery. We report a case where the use of MSCT resulted in prompt and accurate localization in a patient who presented acutely with massive lower gastrointestinal bleed. We believe that contrast-enhanced MSCT has the potential of accurately localizing the source of bleeding in an emergency setting, and should be part of the algorithm in the management of acute lower gastrointestinal bleeding.

Aged↗

Correlations between cardiac imaging and electrophysiological studies: what is the state of the art?

Changes in ventricular activation produced by bundle branch block, pre-excitation, and ventricular tachycardia and pacing have been studied by various cardiac imaging modalities. We reviewed results of previously published and newly generated imaging data correlated with known or measured electrophysiological studies. Echocardiography has been demonstrated to grossly correlate with abnormal ventricular wall motion when activation sequence was altered. However, phase analysis of radionuclide and cine-computed tomography have provided detailed noninvasive activation data that correlated reasonably well with measured electrical activation sequence in both animals and man. Analysis of wall motion may not predict activation sequence when muscle is damaged or excessive translational movement of the heart occurs. Body surface mapping of electrical potentials has the capability to accurately but noninvasively register an electrical activation image of the heart that circumvents the problems of imaging contraction sequence. In the future, body surface potential mapping should be more widely used clinically and experimentally.

Animals↗

Tumor and organ biochemical profiles determined in vivo following uptake of a combination of radiolabeled substrates: potential applications for PET.

This paper describes a method which generates an in vivo metabolic profile of tumors and organ tissues derived from the tissue uptake of a combination of radiotracers. Metabolic substrates labeled with carbon-11, a positron-emitting radionuclide (T1/2 = 20.4 min) have been used to probe tumor metabolism in vivo using positron emission tomography (PET). Carbon-11 labeled radiotracers which have been used include alpha-aminoisobutyric acid (AIB), 2-deoxy-D-glucose (2-DG), and thymidine (TdR). This paper reports data on the tissue distribution of carbon-14 labeled analogues of AIB, 2-DG, and TdR. Tissue distribution studies were carried out in normal male Copenhagen rats, in rats bearing Dunning R3327G or R3327H prostatic adenocarcinomas, and in tumor rats that have been treated with difluoromethylornithine and methylglyoxal-bisguanylhydrazone, or with diethylstilbestrol. A combination of the tissue distribution data of these radiolabeled agents is used to provide a metabolic description of the state of a tumor or tissue in vivo. This approach to defining a tissue's biochemical profile may be useful for the assessment and prediction of a therapeutic response, even at low tracer concentrations in a tumor, and may be useful in relating the biochemical characteristics of one tissue to that of another.

Adenocarcinoma↗

Differential lung function in an infant with the Swyer-James syndrome.

A previously healthy two year old boy had an adenoviral infection at the age of 13 months and developed hyperlucency of the left lung, chronic respiratory distress, and failure to thrive. Bronchodilators and steroid treatment had no effect. Radionuclide lung scans using an intravenous bolus of xenon-133 both before and after treatment showed substantially reduced function on the hyperlucent side and modestly reduced function on the other side. Fibreoptic bronchoscopy showed no structural abnormalities. Partial forced expiratory flow volume (PEFV) curves, generated from end inspiration by rapid compression of the chest wall with an inflatable jacket, were obtained from the total respiratory system and from each lung separately by inflating a Fogarty catheter in the contralateral mainstem bronchus. Expiratory flow rates and volumes during both tidal breathing and PEFV manoeuvres were considerably decreased in the hyperlucent lung. PEFV curves from the "healthy" right lung and from the total respiratory system were similar in shape and showed a moderately obstructive pattern. The right lung ventilated about four times as much as the left when measured by bronchospirometry and about three times as much when measured by the radionuclide technique. The lung scans appeared to reflect adequately the functional abnormality in this infant with the Swyer-James syndrome.

Child, Preschool↗

Diagnosis of exercise-induced left bundle branch block at rest by scintigraphic phase analysis.

Accurate diagnosis of diseases of the ventricular conducting system is essential for their appropriate therapy. Some conduction abnormalities, such as exercise-induced left bundle branch block (EX-LBBB), are not apparent on resting electrocardiograms. Phase analysis of rest and exercise radionuclide ventriculograms (RVG's) was used to compare four EX-LBBB patients with six normal controls. All patients had normal resting electrocardiograms, ejection fractions, and visually normal wall motion. First harmonic phase images were generated reflecting the timing of ventricular contraction. Dynamic phase displays were reviewed and graded in a blinded fashion by three independent experienced observers. Phase angle histograms of the right and left ventricle were determined for both resting and exercise images. The mean phase angle and standard deviation were also calculated for each ventricle. Visual grading of the resting phase images failed to show a significant difference between normal patients and patients with EX-LBBB. Quantitative analysis, however, revealed a significant difference in mean phase angle differences (LV-RV) in resting studies: 0.8 degrees (+/- 1.9 degrees SEM) in normals versus 9.3 degrees (+/- 2.3 degrees SEM) in EX-LBBB patients (P less than 0.03). Exercise accentuated the phase angle differences: 1.8 degrees in normals vs. 31.2 degrees in EX-LBBB patients (P less than 0.001). Quantitative phase analysis of resting RVG's permits the diagnosis of cardiac conduction disease that is not apparent on the resting EKG and may result in better monitoring and treatment.

Bundle-Branch Block↗

Effect of scatter radiation on the planar source sensitivity of a collimated detector.

A theoretical model is proposed to describe the effect of a scattering medium on the plane-source sensitivity of a collimated detector. According to this model the scatter fraction fs(z) of the system is a linear function of the thickness z of the scattering medium and for any collimator geometry depends on the photopeak energy and the window settings as well as on the geometrical and physical characteristics of the scintillation detector. To calculate the parameters of the linear function fs(z), physical constants from the literature were used. The validity of the model was verified by experimental data. The computed parameters were found to differ slightly from the experimental ones and the differences were attributed to several approximations made during the theoretical analysis. The approach used for the determination of these parameters has contributed to a better understanding of the physical meaning of the factors affecting the generation of the scattered radiation and its detection by scintigraphic imaging systems.

Mathematics↗

A multiwire proportional gamma camera for imaging 99Tcm radionuclide distributions.

A gamma camera made of multiple multiwire proportional chambers with thin converter foils has been evaluated for clinical application. Results are presented from a small prototype (10 cm x 10 cm)showing good imaging of 99Tcm radionuclide distributions and comfirming the predictions of the theory regarding quantum efficiency and spatial resolution. The technique is especially aimed at creating a gamma camera with an active area greater than or approximately equal to 1 m2, a quantum efficiency of 15% and a spatial resolution approximately 3 mm, to be applied in whole body scanning and tomographic applications. The results generated by the current prototype indicate that the above requirements can be met using relatively cheap mass production techniques from the electronic industry. This apparatus is covered by patent applcation number 26595/77.

Gamma Rays↗

In vitro characterization of a bivalent anti-HER-2 affibody with potential for radionuclide-based diagnostics.

The 185 kDa transmembrane glycoprotein human epidermal growth factor receptor 2 (HER-2) (p185/neu, c-ErbB-2) is overexpressed in breast and ovarian cancers. Overexpression in breast cancer correlates with poor patient prognosis, and visualization of HER-2 expression might provide valuable diagnostic information influencing patient management. We have previously described the generation of a new type of affinity ligand, a 58-amino-acid affibody (Z(HER2:4)) with specific binding to HER-2. In order to benefit from avidity effects, we have created a bivalent form of the affibody ligand, (Z(HER2:4))2. The monovalent and bivalent ligands were compared in various assays. The new bivalent affibody has a molecular weight of 15.6 kDa and an apparent affinity (K(D)) against HER-2 of 3 nM. After radioiodination, using the linker molecule N-succinimidyl p-(trimethylstannyl) benzoate (SPMB), in vitro binding assays showed specific binding to HER-2 overexpressing cells. Internalization of 125I was shown after delivery with both the monovalent and the bivalent affibody. The cellular retention of 125I was longer after delivery with the bivalent affibody when compared to delivery with the monovalent affibody. With approximately the same affinity as the monoclonal antibody trastuzumab (Herceptin) but only one tenth of the size, this new bivalent molecule is a promising candidate for radionuclide-based detection of HER-2 expression in tumors. 125I was used in this study as a surrogate marker for the diagnostically relevant radioisotopes 123I for single photon emission computed tomography (SPECT)/gamma-camera imaging and 124I for positron emission tomography (PET).

Amino Acid Sequence↗

Effects of atrial natriuretic peptide on myocardial contractile and diastolic function in patients with heart failure.

Atrial natriuretic peptide alters left ventricular performance in patients with heart failure. To assess the direct effects of this hormone on myocardial function, its actions were compared with those of the pure vasodilator nitroprusside in 10 patients with heart failure. Simultaneous left ventricular micromanometer pressure and radionuclide volume were obtained during a baseline period, during nitroprusside infusion, during a second baseline period and during atrial natriuretic peptide infusion. The baseline end-systolic pressure-volume relation was generated in nine patients from pressure-volume loops obtained during the two baseline periods and during afterload reduction with nitroprusside. Mean arterial pressure decreased with atrial natriuretic peptide (89 +/- 3 to 80 +/- 2 mm Hg, p less than 0.05) and by a greater amount with nitroprusside (90 +/- 4 to 73 +/- 3 mm Hg, p less than 0.05). Left ventricular end-diastolic pressure also decreased with atrial natriuretic peptide (24 +/- 2 to 16 +/- 3 mm Hg, p less than 0.05) and by a greater amount with nitroprusside (24 +/- 2 to 13 +/- 3 mm Hg, p less than 0.05). Cardiac index increased during infusion of each agent from 2.0 +/- 0.2 to 2.4 +/- 0.2 liters/min per m2 (p less than 0.01). Heart rate increased slightly with nitroprusside but did not change with atrial natriuretic peptide. Peak positive first derivative of left ventricular pressure (dP/dt), ejection fraction and stroke work index were unchanged by either agent. The relation between end-systolic pressure and volume during atrial natriuretic peptide infusion was shifted slightly leftward from the baseline value in four patients, slightly rightward in four and not at all in one patient, indicating no consistent inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗