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Postpartum cell-mediated immunity induced in the rat following perinatal exposure to iodine-131.

Studies were undertaken with the intent to establish the degree of risk experienced by a mother and her immediate offspring in developing gastrointestinal cancer following exposure to iodine-131 during pregnancy. An indirect approach in the identification of tumor induction for risk determination was utilized in this study which relied upon the measurement of antitumor cell-mediated immunity (CMI) occurring in the host following exposure to the radionuclide. Fischer F344 inbred pregnant rats were selected as the animal model, and the radionuclide exposure was accomplished by a single intraperitoneal administration of iodine-131 [Na131] at the stage of 16-18 days of pregnancy; then at two months postpartum, the dams and pups were evaluated for the capacity of their peripheral blood lymphoid cells to express specific cytotoxic responses towards target cells consisting of cultured X-ray induced rat small bowel adenocarcinoma cells. The results indicate that an antitumor immunity was induced in the pups upon such a prenatal exposure, while none could be detected existing in their mothers. In addition, there appeared to be a possible sex or hormonal component as a preliminary consideration of the data suggested the male offspring were approximately 1.7 times more immunoresponsive to the perinatal insult. Threshold detection level for detecting such responses to the iodine-131 was found to be in the range of a 9.25 kBq (250 nCi) quantity of exposure. The implication of these preliminary findings based upon such indirect measurements is that the first generation may be at an increased risk to gastrointestinal cancer following peritanal exposure to iodine-131 in the later stage of pregnancy.

Animals↗

Clinical applications of monoclonal antibodies against ovarian cancer-associated antigens.

Monoclonal antibodies (McAbs), reactive with tumour-associated antigens (TAAs) present on tumour cells, appear to offer new possibilities in the diagnosis and treatment of cancer (Table I). In addition to these prospects for clinical application, monoclonal antibodies also serve as useful instruments in basic cancer research. The hybridoma technology initiated by Köhler and Milstein in 1975, underwent a very rapid development and has now shown its potential in the field of oncology. This technique made it possible to produce very large quantities of homogeneous antibodies of a stable quality. These McAbs often recognize only one antigenic determinant, or epitope, of cell surface and other molecules. This high specificity is essential for in vivo applications, especially in therapeutic immunotargeting. A central question is whether the antibodies can reach and identify those antigens on ovarian tumour cells that are not shared with normal tissues. Various antibodies have been described in the field of gynaecological oncology, which are assumed to be capable of recognizing such ovarian tumour-related antigens. These McAbs, single or in combination, are capable of showing, unambiguously, the presence of various tumour-associated antigens on ovarian carcinoma cells either in tissue or, when antigen shedding occurs, in blood. However, these McAbs may also react with tumour-associated antigens present on endometrial, cervical, colorectal, breast or other carcinoma cells. The original immunogens used to generate these McAbs differ as to their origin: ovarian cancer cells, breast cancer cells, human milk-fat preparations, trophoblastic cells, endometrial cancer cells have been used as well as osteogenic sarcoma cells, epidermoid carcinoma cells and small-cell lung cancer, colorectal, pancreatic and laryngeal carcinoma cells. The histological distribution patterns of the antigens recognized by these McAbs vary widely: cross-reactions with normal tissue and with carcinomas different from those used as immunogen are frequently seen.

Antibodies, Monoclonal↗

Measurement of hepatocellular function with deconvolutional analysis: application in the differential diagnosis of acute jaundice.

A direct, noninvasive technique was developed to quantitate hepatocyte function with computer assessment of scintiscans obtained after administration of technetium-99m disofenin in 53 patients with acute jaundice: 32 patients with normal livers, 10 patients with acute biliary obstruction, and 11 patients with acute hepatocellular dysfunction. In all patients a final clinical diagnosis was obtained with follow-up for a minimum of 4 months and, in most patients with obstruction or dysfunction, with surgery, intraoperative cholangiography, ultrasound, and/or computed tomography. Heart (blood pool) and liver time-activity curves were generated for 32 minutes after intravenous injection of 5-15 mCi (185-555 MBq) of Tc-99m disofenin and were subjected to deconvolutional analysis to determine the first-pass hepatocyte extraction fraction (HEF) of the tracer. The difference in HEF between patients with obstruction and those with dysfunction was highly significant (P = 3.3 X 10(-19)). Deconvolutional analysis eliminates the effects of tracer recirculation, thus permitting direct measurement of hepatic disofenin extraction, and appears to provide functional information useful in evaluation of the patient with acute jaundice.

Acute Disease↗

[Necessity of radiopharmaceutical control and vigilance].

A recent problem with radiopharmaceutics in Val-de-Grâce hospital proves the necessity of a control. Using of the 99mTc (Hydroxy-methylene diphosphonate [HMDP] skeletal image we got a kidney scintigraphic images instead of the expected skeleted. The investigation of the occurrences has rapidly shown no possible confusion: At the day of failed examination, only 99mTc microspheres (target: Lung), methoxy-isobutyl-isonitrile, MIBI (target: heart) and 99mTc Phytate (target: Reticulo-Endothelial System) were used. Radioactivity control of 99mTc generator was conformable and labelled efficiency of the whole of HMDP assays were satisfying. This test is only an approach of radiochemical purity and was not adequate here. The renal image had suggested a chelate use. Accordingly, we have realized the Pharmacopoeia identification of DTPA with dimethyl-glyoxime-Ni, HMDP standards, DTPA (diethylene-triamino pentacetate), and HMDP residues from the vials used on the incident's day. It has been shown that residues of HMDP contain, like DTPA, but not like HMDP standards, a nickel chelating system. This proves a substitution of compound unknown to medical users.

Bone and Bones↗

The biodistribution and pharmacokinetics of meta-iodobenzylguanidine in childhood neuroblastoma.

MIBG is generating considerable interest for the treatment of neuroblastoma. This study has investigated the biological variation in handling of the compound in children with neuroblastoma. The biodistribution of the compound has been characterised in children undergoing tracer administrations of 123I and 131I-mIBG. Estimates of hepatic and whole body radiation dose delivery have been made. The results indicate substantial interpatient variation in hepatic dose delivery. This organ may be critical in some patients undergoing targeted radiotherapy with mIBG.

3-Iodobenzylguanidine↗

Positron emission tomography in drug development and drug evaluation.

Positron Emission Tomography (PET) is an imaging modality which can determine biochemical and physiological processes in vivo in a quantitative way by using radiopharmaceuticals labeled with positron emitting radionuclides as (11)C, (13)N, (15)O and (18)F and by measuring the annihilation radiation using a coincidence technique. This includes also measurement of the pharmacokinetics of labeled drugs and the assessment of the effects of drugs on metabolism. Because only very low amounts of the radiolabeled drug have to be administered, far below toxicity levels, human studies can be carried out even before the drug is entered in Phase I. Such studies can provide cost-effective predictive toxicology data and information on the metabolism and mode of action of drugs. PET is also very useful to study the metabolic consequences of gene expression or gene defects. In the last decade many genetically engineered small animal models have been developed. The study of these animals with high resolution small animal PET cameras provides new opportunities in drug development. Especially valuable is the contribution of PET to bridge the gap between molecular biology, understanding of pathology and to the design of a new generation of drugs.

Drug Evaluation↗

Design, synthesis and preclinical evaluation of radiolabeled peptides for diagnosis and therapy.

Recent years have seen an increased effort in the development of peptide based radiopharmaceuticals for nuclear medicine applications in imaging and therapy. This field is of particular interest in the development of new cancer imaging and treatment strategies. Major developments in the molecular biology of cancer have brought forth the discovery of a number of receptor systems and other cell surface molecules that can be utilized as molecular targets for peptide based agents. Although such a strategy is very appealing and shows great potential for application in humans, there are as yet very few radiopharmaceuticals developed based on this scheme that have made it into clinical practice. Many different factors contribute to the generation of a successful radiopharmaceutical. Among these, a thorough and efficient pre-clinical evaluation process is necessary to single out those lead compounds that show more promise and are most likely to be winners in clinical applications. To maximize the efficacy of pre-clinical testing one must utilize currently available technology to the best extent possible. Expertise in different areas of drug development is indispensable for this type of research. This work will analyze currently available methods utilized to evaluate radiopharmaceuticals being developed, from compound design to evaluation in pre-clinical animal models.

Animals↗

RMDP: a dedicated package for 131I SPECT quantification, registration and patient-specific dosimetry.

The limitations of traditional targeted radionuclide therapy (TRT) dosimetry can be overcome by using voxel-based techniques. All dosimetry techniques are reliant on a sequence of quantitative emission and transmission data. The use of (131)I, for example, with NaI or mIBG, presents additional quantification challenges beyond those encountered in low-energy NM diagnostic imaging, including dead-time correction and additional photon scatter and penetration in the camera head. The Royal Marsden Dosimetry Package (RMDP) offers a complete package for the accurate processing and analysis of raw emission and transmission patient data. Quantitative SPECT reconstruction is possible using either FBP or OS-EM algorithms. Manual, marker- or voxel-based registration can be used to register images from different modalities and the sequence of SPECT studies required for 3-D dosimetry calculations. The 3-D patient-specific dosimetry routines, using either a beta-kernel or voxel S-factor, are included. Phase-fitting each voxel's activity series enables more robust maps to be generated in the presence of imaging noise, such as is encountered during late, low-count scans or when there is significant redistribution within the VOI between scans. Error analysis can be applied to each generated dose-map. Patients receiving (131)I-mIBG, (131)I-NaI, and (186)Re-HEDP therapies have been analyzed using RMDP. A Monte-Carlo package, developed specifically to address the problems of (131)I quantification by including full photon interactions in a hexagonal-hole collimator and the gamma camera crystal, has been included in the dosimetry package. It is hoped that the addition of this code will lead to improved (131)I image quantification and will contribute towards more accurate 3-D dosimetry.

Humans↗

A practical approach to the hepatobiliary kinetics of 99mTc-HIDA. Clinical validation of the method and a preliminary report on its use for parametric imaging.

99mTc-diethyl-HIDA cholescintigraphy was performed on 24 patients with histologically proven liver disease and on 10 normal adult subjects. Liver mass transport of HIDA was interpreted with the aid of a probabilistic model, assuming that the tracer particles undergo mixed random walks with drifts. The radiohepatograms were thus fitted with a gamma-variate function and the fitting parameters were evaluated as estimates of the severity of the disease. These parameters, together with the transit times, were also used to generate parametric images of liver function. The advantages of this approach are discussed and the following conclusions are drawn: (1) The gamma-fit is highly satisfactory with any type of experimental curve (0.98 less than r less than 1). (2) The parameters derived from the gamma-fit make it possible to objectively assess the extent of liver functional impairment. (3) Parametric imaging of the liver mass transport of HIDA is easily implemented, but still more experience is needed to assess its impact on patient care.

Bile Ducts↗

A real-time system for multi-image gated cardiac studies.

A minicomputer-based system is described that allows real-time construction and simultaneous display, in flicker-free movie format, of a cardiac-cycle-spanning sequence of ECG-gated scintigraphic images. In as little as 2 min, the endless-loop flicker-free movier clearly displays cardiac anatomy, time-dependent volume variations of cardiac chambers, and abnormalities of cardiac wall motion that would be difficult or impossible to detect from static gated images. Simultaneously, a time-activity curve with high temporal resolution can be generated from a previously defined region of interest, thereby quantifying additional parameters of cardiac function. Because the movie and time-activity curve are displayed in real time and require only a short data-collection interval to achieve statistical reliability, the physician can use the system interactively, modifying the form, intensity, or duration of diagnostic and therapeutic interventions based on the observed response. This system is well suited for intervention studies, for continuous cardiac monitoring, and for the rapid screening of patients with suspected cardiac disease.

Computers↗

Scintigraphic detection of congenital intracranial vascular malformations.

Nine children with arteriovenous malformations (AVMs), and a tenth with a cerebral aneurysm, had computer-processed dynamic scintigraphy with static scintigrams, transmission computed tomography (CT) both with and without contrast injection, and radiopaque cerebral angiography. All ten lesions were detected by dynamic scintigraphy and angiography, whereas two AVMs were missed on CT scans and the aneurysm and two AVMs (one missed by CT) were not identified on static scintigrams. Time-activity curves generated from regions of interest placed over the cerebral hemispheres, AVMs and/or various venous structures permitted, respectively, estimation of interhemispheric partition of perfusion, estimation of the fraction of total cerebral hemispheric perfusion preferentially directed into a malformation, and indication of the route of venous drainage from the lesions. While dynamic scintigraphy and CT scanning both identified the aneurysm, scintigraphy was the most effective screening test for detecting AVMs owing to its accuracy, lower cost, and lack of required anesthesia, heavy sedation or iodinated contrast agents.

Adolescent↗

Computerized quantitation of regional myocardial perfusion in man.

A computerized procedure has been developed for the generation, graphic presentation and quantitative evaluation of circumferential profiles of thallium-201 myocardial perfusion. The computer data are first filtered using a two-dimensional fast Fourier transform. The optimum criteria for evaluating the profiles of the left anterior oblique (LAO) view have been empirically determined for both rest and stress. The sensitivity of 89 percent and specificity of 75 percent compare well with the results of other methods and are free of the variables of visual interpretation.

Coronary Circulation↗

Behavior of Chernobyl fallout radionuclides in peat combustion.

The fallout from the explosion and fire at the Chernobyl nuclear power plant concentrated levels of up to 10 kBq 137Cs kg-1 dry weight in the fuel peat harvested during the summer of 1986 in Finland. We investigated the behavior of fallout radionuclides 137Cs, 134Cs, 106Ru, 144Ce, 125Sb, 95Zr, and 110mAg together with naturally occurring 210Pb and 226Ra in the combustion of this contaminated peat in four different power plants. The elements antimony, ruthenium, lead, and cesium were enriched on the smallest particles, indicating that they were in a volatile chemical form, while cerium, zirconium, and radium were nonvolatile at the combustion temperatures. This result confirms the previous finding that ruthenium is volatile in combustion. Although metallic ruthenium requires 2,310 degrees C to melt, some of its oxides melt and evaporate at much lower temperatures.

Accidents↗

Single isotope evaluation of pulmonary capillary protein leak (ARDS model) using computerized gamma scintigraphy.

Using a canine oleic acid model, a computerized gamma scintigraphic technique was evaluated to determine 1) ability to detect pulmonary capillary protein leak in a model temporally consistent with clinical adult respiratory distress syndrome (ARDS), 2) the possibility of providing a quantitative index of leak, and 3) the feasibility of closely spaced repeat evaluations. Study animals received oleic acid (controls, n = 10; 0.05 ml/kg, n = 10; 0.10 ml/kg, n = 12; 0.15 ml/kg, n = 6) 3 hours prior to a tracer dose of technetium-990m (99mTc) HSA. One animal in each dose group also received two repeat tracer injections spaced a minimum of 45 minutes apart. Digital images were obtained with a conventional gamma camera interfaced to a dedicated medical computer. Lung: heart ratio versus time curves were generated, and a slope index was calculated for each curve. Slope index values for all doses were significantly greater than control values (P(t) less than 0.0001). Each incremental dose increase was also significantly greater than the previous dose level. Oleic acid dose versus slope index fitted a linear regression model with r = 0.94. Repeat dosing produced index values with standard deviations less than the group sample standard deviations. We feel this technique may have application in the clinical study of pulmonary permeability edema.

Animals↗

Condensed images for evaluating gastric motility patterns.

A condensed imaging technique was applied to gastric emptying studies to investigate (a) whether different types of motility disorders may be distinguished by characteristic image patterns and (b) whether the findings obtained provide additional information compared to standard quantitative measurements. Condensed images and quantitative data of gastric emptying were evaluated in 75 consecutive patients with normal function (n = 16) and various disorders (n = 59) such as peptic ulcer, postvagotomy, pyloric obstruction, dumping syndrome, gastroparesis etc. Condensed images were generated from a gastric region of interest. They display the distribution and behaviour of a radioactive test meal in a space-time matrix, whose horizontal and vertical dimensions are temporal and spatial, respectively. As shown in a series of representative examples condensed images disclose a variety of well-defined image patterns reflecting different pathophysiological mechanisms. This qualitative characterization of gastric emptying patterns provided in 34 of the 75 patients (45%) important new information compared to quantitative data. The application of condensed imaging techniques to gastric emptying studies (complementary to quantitative measurements) may, therefore, enhance the diagnostic value of scintigraphic techniques.

Gastric Emptying↗

Investigation into the effect of Fenoterol on mucociliary clearance in patients with chronic bronchitis.

We investigated the effect of Fenoterol, a selective beta 2 adrenoceptor stimulant, on mucociliary clearance in 12 patients with chronic bronchitis. Mucociliary clearance was measured with a scintillation camera after inhalation of a 99mTc labelled aerosol. Fenoterol was administered one h after acquisition commenced and imaging was maintained for a further two h. Three regions of interest (ROI) were selected over each lung to generate time activity curves. Corrections for decay, alveolar deposition (using 24 h image), cough and movement of activity through each ROI were carried out. An exponential function was fitted to the clearance curves to determine clearance rates. The increase in percentage clearance after Fenoterol administration for the left and right whole lung ROI was 35% and 36% per h respectively (P = 0.006 and 0.020). Fenoterol enhances cilial clearance in chronic bronchitis patients.

Adult↗

Does autoantibody-negative Graves' disease exist? A second evaluation of the clinical diagnosis.

Advanced technical methods are essential for accurate diagnosis of Graves' or Basedow's disease (GD). Inadequate methods may lead to a false diagnostic conclusion. We have analyzed the clinical features and methodology aspects of cases diagnosed as GD with negative findings for TSH receptor autoantibodies. The initial diagnosis was based on clinical findings (patient record, hypermetabolic state, goiter palpation) and laboratory testing (fT4 and TSH). From a total of 255 newly registered patients with GD, fifty-one (20%) were negative in a conventional porcine TBII assay. All fifty-one patients were retested with 131I or 99mTc uptake tests, thyroid scintigraphy, and a second-generation TBII assay. Results disclosed twenty-one cases (8.3%) with diagnosis other than GD: ten cases of autonomous hyperthyroidism (Plummer's disease), seven cases of painless thyroiditis and four cases of euthyroid endocrine ophthalmopathy. All twenty-one patients remained negative in the second-generation TBII assay. Measurement by second-generation TBII assay was performed on the remaining thirty patients initially found negative for TBII. As a result of this reevaluation, only 234 of the original 255 patients had GD. Of those, 231 (204 according to porcine plus 27 according to human TRAb assay) had detectable TBII (98.7%). This investigation stresses the problem of correct diagnosis and the methodological limitations in the assessment of laboratory parameter validity in GD. Based on this work, TSH receptor autoantibody-negative GD is extremely rare.

Adolescent↗

[Efficacy of three-dimensional image fusion of lymphoscintigraphy and MDCT data sets in breast cancer].

The aim of this study was to evaluate the clinical usefulness of image fusion of lymphoscintigraphy with (99m)Tc phytate and volume-rendering images generated by multidetector-row CT (MDCT) in patients with breast cancer. The subjects were 25 patients with clinically negative nodes. Data from the two imaging modalities were fused on a personal computer. Thirty-five axillary sentinel nodes were identified by lymphoscintigraphy. The anatomical locations of sentinel nodes in 27 patients were clearly demonstrated by 3D-fusion imaging (84%). Image fusion of lymphoscintigraphy with (99m)Tc phytate and volume-rendering images is helpful for sentinel node biopsy in breast cancer.

Breast Neoplasms↗