Immunolymphoscintigraphy and immunoscintigraphy of ovarian and fallopian tube cancer using F(ab')2 fragments of monoclonal antibody OC 125.

We have used immunolymphoscintigraphy (ILS) alone or in combination with immunoscintigraphy with 131I-labeled F(ab')2 fragments of monoclonal OC 125 antibodies to improve detection of retroperitoneal lymph node metastases of ovarian and fallopian tube cancer. ILS was carried out with bilateral dorsopedal s.c. injections on nine patients and with bilateral iliopelvic injections into the ischiorectal fossa on two other patients. Radioimaging was performed 2-4 times between 0 and 5 days. An additional dose of labeled antibody fragments was given i.v., and imaging was done 2-3 days later. Conventional immunoscintigraphy without preceding ILS was carried out on another nine patients. Dorsopedal ILS improved detection of pelvic and paraaortic lymph node metastases. Malignant lymph nodes were detectable as early as 3 h after s.c. injection of the tracer. Combined results of ILS and immunoscintigraphy in 16 surgically verified cases indicated a true positive finding in 9 patients, true negative finding in 5, false positive in one, and false negative in 1. Calculated from these figures the sensitivity, specificity, and accuracy of the method were 90, 83, and 88%, respectively. Involved lymph nodes were found more frequently in those patients whose serum CA 125 concentration was elevated demonstrating that an elevated serum CA 125 level does not preclude successful radioimmunodetection.

Fatty acid-induced increase in serum dialyzable free thyroxine after physical exercise: implication for nonthyroidal illness.

In 14 healthy males, prolonged running exercise resulted in a mean 25% increase in serum free T4 (FT4) concentration (P less than 0.001) which was significantly correlated (P less than 0.01-0.02) with an over 5-fold increase in the concentration of serum FFA and the FFA/albumin molar ratio. Hemoconcentration, as reflected in a mean 19% increase in serum albumin, caused an increase in serum T4-binding globulin and therefore also in serum total T4. As there was no change in the serum T4/T4-binding globulin molar ratio, the rise in serum FT4 was probably not caused, or only partly caused, by an exercise-induced shift of T4 from the extravascular to the intravascular compartment. Neither is it likely that the mean 41% increase in serum TSH observed after exercise, partly owing to hemoconcentration, was the reason for the increase in serum FT4 and T4 as there was no correlation between the increases in the TSH and thyroid hormone levels. Further support for the assumption that the elevation in serum FT4 after exercise was FFA-induced was provided by the observation that addition of 2.5 mmol/L oleic acid to normal serum in vitro resulted in a 33% increase in serum FT4 (P less than 0.001). There is an association between increased concentrations of serum FT4 and unsaturated FFA in patients with various nonthyroidal illnesses according to earlier observations, but it is unlikely, in the light of the present data from healthy subjects, that FFA are directly involved in raising the serum FT4 concentration in nonthyroidal illnesses patients unless the serum FFA concentration exceeds 2 mmol/L or the FFA/albumin molar ratio rises above 2.5.

Acute effects of alcohol on anterior pituitary secretion of the tropic hormones.

The plasma or serum concentrations of GH, TSH, LH, PRL, testosterone, cortisol, T4, and T3, and the values of the T3 uptake test were monitored in 12 healthy male volunteers for a period of 20 h after administration of one large dose of ethanol (1.5 g/kg BW). The effects of TRH and LRH on the secretion of TSH, PRL, and LH were studied in these subjects once during the period of acute alcohol intoxication (4 h after the start of drinking) and once during the hangover period (14 h after the start of drinking). Each subject served as his own control by drinking water only during another experimental session. Alcohol had no significant effect on basal concentrations of GH, TSH, LH, T4, T3, or testosterone. The concentration of cortisol in plasma was elevated during the whole 20-h period after ingestion of alcohol, as compared with the control values. Alcohol also did not significantly alter the effects of TRH and LRH on plasma TSH and LH levels at 4 and 14 h. During the hangover period, the PRL response to TRH was totally blocked, but during alcohol intoxication, there was a slight increase in the PRL response to TRH. The lack of response of PRL to TRH during the hangover suggests that withdrawal symptoms are associated with increased dopaminergic activity in the hypothalamus.

Antimyosin scintigraphy compared with magnetic resonance imaging in inflammatory myopathies.

OBJECTIVE: To compare indium In 111 altumomab pentetate-labeled antimyosin scintigraphy with magnetic resonance imaging (MRI) in the diagnosis and follow-up of patients with myositis. DESIGN AND METHODS: Sixteen patients with polymyositis and 1 patient with dermatomyositis, all verified with biopsy samples, were examined during diagnostic evaluation with antimyosin antibody scintigraphy and low-field MRI of the thighs and calves using T1- and T2-weighted sequences. Both examinations were repeated 6 to 22 months after therapeutic intervention with antiinflammatory drugs. The performance of the 2 methods for the assessment of the severity of muscle inflammation was evaluated using comparison with clinical examination and the serum creatine kinase level. RESULTS: At diagnosis all patients had increased uptake of antimyosin antibody in the thighs and/or calves. In T2-weighted MRI images, increased signal intensity changes reflecting intramuscular edema and inflammation were seen in all patients in at least 1 muscle group in the thighs or calves. After anti-inflammatory drug therapy, the mean uptake of antibody and the mean signal intensity changes in T2-weighted MRI had decreased. However, in T1-weighted MRI the signal intensity changes reflecting intramuscular fatty degeneration were more pronounced in the follow-up study. The level of serum creatine kinase had decreased markedly by the second examination except in 1 patient who also had more accumulation of antibody in the calves after than before treatment. The clinical condition improved in 8 patients and remained unchanged in 9 patients. CONCLUSIONS: Antimyosin scintigraphy and T2-weighted MRI are feasible tools for the detection and follow-up of lesions in patients with myositis. Scintigraphy findings correlate with serum creatine kinase activity and seem to reflect disease activity better than T2-weighted MRI changes, whereas secondary degenerative intramuscular lesions are only detectable using T1-weighted MRI.

Unilateral hyperfusion in brain-perfusion SPECT predicts poor prognosis in acute encephalitis.

We studied 88 patients with acute encephalitis using hexamethylpropyleneamine oxime and single photon emission computed tomography (SPECT). All patients had been initially treated with intravenous acyclovir. The etiology could be disclosed in 37 patients (42%), which included 15 patients with herpes simplex encephalitis, 7 with varicella-zoster encephalitis, and 29 with other encephalitides (Mycoplasma, adenovirus, influenza, rotavirus, rubella, Epstein-Barr, arbovirus, syphilis, and tuberculosis). Unilateral hyperperfusion in SPECT was an independent predictor of poor prognosis, whereas neither clinical outcome variables, such as seizures, state of consciousness, and focal neurologic findings, nor CSF or EEG findings were not. Focal unilateral hyperperfusion is an indicator of severe inflammation of the brain tissue and predicts a poor outcome as assessed in terms of activities of daily living after recovery.

Decreased striatal dopamine transporter density in JNCL patients with parkinsonian symptoms.

OBJECTIVE: To explore whether striatal dopamine transporters are involved in juvenile neuronal ceroid lipofuscinosis (JNCL) with extrapyramidal signs. METHODS: Seventeen patients with JNCL entered the study (mean age, 15 years; age range, 10 to 31 years). For clinical evaluation, the authors used the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). For studying the density of dopamine transporters in the striatum, they employed iodine-123-labeled 2beta-carbomethoxy-3beta-(4-iodophenyl) tropane as a SPECT tracer. The SPECT images were evaluated visually, and tracer accumulation was semiquantified from transverse slices as striatum-to-cerebellum activity ratios. MRI (1.5-T) signal intensities of the striatum were measured and compared with those of the thalamus. RESULTS: The mean UPDRS score was 20 (range, 2 to 41). On SPECT, the mean striatum-to-cerebellum uptake ratio was lower in patients than in control subjects (3.1 +/- 0.6 versus 6.8 +/- 1.0; p < 0.001), with the decrease being more pronounced in the putamen than in the caudate nucleus. On MRI, the mean striatum-to-thalamus signal intensity ratio was higher in patients than in control subjects (1.14 +/- 0.02 versus 1.08 +/- 0.02; p < 0.001). There was a negative correlation between uptake ratios in SPECT and UPDRS scores, and a positive correlation between the MRI ratios and UPDRS. The SPECT and MRI ratios also correlated significantly, providing additional evidence for the contributions of nigrostriatal, striatal, and thalamic dysfunction to the parkinsonian symptoms. CONCLUSIONS: The observed decrease in the striatal dopamine transporter density in JNCL offers a rational basis for a trial of dopaminergic drugs in this disease.

Diagnostic significance of indium-111 granulocyte scintigraphy in febrile patients.

Sixty-eight patients with fever of unknown origin, 32 patients with postoperative fever, and 26 patients with therapy-resistant fever after bacteremia were investigated with [111In] granulocyte scintigraphy for the detection of abscesses. The results showed that the value of [111In]granulocyte scintigraphy in the detection of infectious foci vary in these three types of febrile conditions. The overall sensitivity and specificity were 86.5% and 87.8%, respectively. We observed, however, a relatively low predictive value of a positive result in the fever of unknown origin group (73.1%), and also a low predictive value of a negative result in the bacteremia group (66.7%). The C-reactive protein (CRP) levels in patients with a true-positive scintigram were significantly (p less than 0.001) higher than in patients with a true-negative scintigram. There was also a significant positive correlation (p less than 0.01) between the serum CRP concentration and the intensity of the granulocyte accumulations. There was no correlation between the peripheral leukocyte count or the erythrocyte sedimentation rate (ESR) and the intensity of the granulocyte uptake. Therefore CRP, but not the leukocyte count or ESR, appears useful for selecting the patients who benefit most from granulocyte scintigraphy.

Localization of human malignant tumors with radioiodinated recombinant tissue plasminogen activator.

Human recombinant tissue plasminogen activator (tPA), labeled with 131I(1.1 to 6.2 mCi) by the iodogen method, was administered intravenously to 15 patients with various soft-tissue malignant tumors after blocking of thyroidal radioiodine uptake. Gamma camera imaging was performed 4 and 24 hr after injection; three patients were also imaged 5 days following injection. We observed accumulation of radioactivity in primary and secondary lesions in 11 patients. In this preliminary study we did not detect any definite association between the magnitude of uptake and type of tumor. Tumors were usually visualized already after 4 hr but the uptake was more intense at 24 hr. The target-to-nontarget ratios at 24 hr, determined by computer analysis of stored images, varied from less than 1.2 to 2.1. This is the first demonstration of accumulation of radiolabeled tPA in malignant tissue. We do not know the mechanism of the uptake but because tPA is known to be avidly bound to fibrin, a component of the stroma of many malignant tumors, it is possible that [131I]tPA is bound to fibrin rather than taken up by the malignant cell; various possible cell uptake mechanisms are discussed. Due to the relatively early maximal uptake of this radiopharmaceutical it will be possible to substitute 123I for 131I, a possibility suggesting a potential clinical use of radioiodinated tPA for the detection of malignant tumors of various origin.

Splenic dynamics of indium-111 labeled platelets in idiopathic thrombocytopenic purpura.

Splenic dynamics of 111In-labeled platelets and platelet-associated IgG in 33 patients with idiopathic thrombocytopenic purpura (ITP) were studied. Two half-lives were calculated for the biexponential splenic time-activity curve after i.v. injection of 111In-labeled platelets. There was no difference in the mean half-life of the rapid component of the splenic curve (ST1) when patients with negative or slightly positive platelet suspension immunofluorescence test (PSIFT) were compared to those with strongly positive PSIFT (3.0 +/- 0.7 min vs. 3.6 +/- 0.4, p greater than 0.05). Mean half-life of the slow component of the splenic curve (ST2) was found to be longer in patients with a strongly positive than a negative or weakly positive PSIFT (26 +/- 5 min vs. 13.2 +/- 1.0 min, p less than 0.01). It seems that determination of the two components of the splenic time-activity curve provides a useful method for studying platelet kinetics in ITP.

Imaging of soft-tissue sarcomas with indium-111-labeled monoclonal antimyosin Fab fragments.

Some soft-tissue sarcomas contain intracellular myosin. We therefore studied the possibility of localizing various soft-tissue sarcomas with 111In-labeled monoclonal antibody Fab fragments binding specifically to myosin, assuming that damage to the cell membrane could expose intracellular myosin. Nineteen patients with different types of soft-tissue sarcomas were studied. Eighteen patients were found to have abnormal antibody uptakes. Antibody uptake was not observed in an additional patient operated for a benign tumor (gastric leiomyoma). The immunoscintigraphy results were generally in good agreement with those of other radiologic findings (computed tomography, ultrasound, magnetic resonance imaging). Surprisingly, the immunohistochemistry results showed that tumors not stainable for myosin can also be imaged with antimyosin. Thus, the mechanism of antibody uptake does not seem to be related entirely to specific antigen recognition. Irrespective of the exact mechanism for the uptake of labeled antibody this method appears to be useful for localizing soft-tissue sarcomas.

Hyperfixation of 99mTc-HMPAO and hypofixation of 123I-iomazenil in acute herpes encephalitis.

We studied two patients with herpes encephalitis (HSE) by [99mTc]HMPAO and [123I]iomazenil single photon emission computed tomography. Increased uptake of HMPAO was seen for up to 63 days in the HSE affected brain area. Iomazenil binds to benzodiazepine receptors and can measure neurone loss. Decreased iomazenil uptake was observed a few days after onset, at a time when hyperfixation of HMPAO occurred. Because in HSE neurone loss occurs simultaneously with hyperfixation of HMPAO, it is unlikely that this hyperfixation is caused by increased neuronal activity, as in epilepsy. This suggests that the hyperfixation of HMPAO in HSE occurs in glia and is sustained by inflammation-related hypermetabolism and acidity. The early neurone loss in HSE stresses the importance of immediate antiviral treatment.

Platelet splenic transit times in idiopathic thrombocytopenic purpura. Compartmental vs. non-compartmental model.

Platelet splenic transit times following injection of autologous or homologous 111In-labeled platelets were studied in 42 patients with idiopathic thrombocytopenic purpura. The transit times were determined by two methods from the splenic time-activity curves recorded with a gamma camera: closed two-compartmental model and non-compartmental model (deconvolution analysis). By compartmental analysis the mean splenic transit time for platelets was 6.3 +/- 0.3 min (mean +/- S.E.) and by non-compartmental analysis 7.6 +/- 0.4 min for all cases studied. The mean splenic transit time for autologous platelets was significantly (p less than 0.001) shorter (5.1 +/- 0.3 min) in patients with platelet-associated IgG (measured by platelet suspension immunofluorescence test) than in those with no autoantibodies (7.1 +/- 0.4 min), when the compartmental model was employed. There was no significant difference between mean transit times for autologous platelets in antibody positive and negative patients when deconvolution analysis was applied, but the residue of the splenic transfer function was lower for antibody positive than negative patients (7.2 +/- 1.0% vs. 11.7 +/- 1.6%, p less than 0.05). It is concluded that in idiopathic thrombocytopenic purpura the presence of platelet-associated autoantibodies expands the splenic platelet pool and reduces recirculation of platelets.

Comparison of serum free thyroxine indices and "corrected" thyroxine tests.

A dual competitive protein-binding assay for serum thyroxine (T4) is described. The assay is called the "corrected" T4 index and can be performed simultaneously with the determination of total T4. This method correlated significantly with the free T4 index and the effective T4 ratio. The "corrected" T4 index was compared for precision and diagnostic accuracy with the effective T4 ratio and two different free T4 indices. Improved modifications of the thyroxine and triiodothyronine Sephadex uptake tests, used for calculation of the free T4 indices, are also reported. In spite of better precision, the "corrected" T4 index and effective T4 ratio gave twice as many incorect classifications of both hyper- and hypothyroidism as the free T4 indices. Previous reports on the effective T4 ratio and other basically similar tests might give an overly optimistic view of what can be expected in routine clinical practice. The free T4 index, which is a good estimate of the free T4 concentration, may still be the thyroid function test of choice when serum T4 and clinical impression are not in conformity.

Effect of fatty acids on thyroid function tests in vitro and in vivo.

Addition of long-chain fatty acids to serum increased thyroxine (T4), measured by a competitive protein binding assay, and triiodothyronine (T3) uptake by Sephadex or resin (T3U tests). This is compatible with the assumption that fatty acids compete with thyroxine for binding sites on T4-binding proteins. When equimolar concentrations of various saturated and unsaturated fatty acids were added to serum it was observed that the effectiveness in raising tests based on protein binding of thyroid hormones incrreased serum T3 determined by radioimmunoassay (RIA). T4(RIA) was not significantly influenced by either saturated or unsaturated fatty acids. Serum T4(CPB) rose during storage at 22degreesC and 37degreesC but was stable at 4degreesC and --20degreesC for periods up to two weeks. The proportional increase in T4(CPB) and free fatty acids (FFA) indicated that this phenomenon was due, at least partly, to the interference from FFA formed during storage of the serum. There was also a small, significant increase in T3U, T3(RIA) and CT4I (a free thyroxine estimate) after storage of serum at room temperature or higher for one to two weeks. Serum T4(RIA) did not alter during two weeks of storage. In five subjects with raised serum FFA after eating a fat meal followed by a heparin injection an increase in T4(CPB), T3U, T3(RIA) and CT4I that was proportional to the increase in FFA was observed. This effect on the thyroid tests was small until the increase in FFA concentration exceeded 2 mmol/l. T4(RIA) did not respond to the increase in FFA. In ten patients with raised levels of FFA due to uncontrolled diabetes T4(CPB), T4(RIA) and T3(RIA) decreased while T3U increased. These unexpected alterations were probably related to the severe, chronic illness in these patients. Increased FFA in vivo seem to be of little importance for the interpretation of thyroid tests in clinical practice.

Nuclear binding of triiodothyronine and thyroxine in lymphocytes from subjects with hyperthyroidism, hypothyroidism and resistance to thyroid hormones.

Binding of triiodothyronine (T3) and thyroxine (T4) to nuclei of intact human lymphocytes was studied. The binding characteristics were analysed by Scatchard's method. In lymphocytes from euthyroid healthy subjects there was a single set of saturable nuclear T3 and T4 binding sites with an apparent mean equilibrium association constant of 3.3 X 10(10) l/mol and 1.7 X 10(10) l/mol, respectively. The estimated mean maximal specific binding capacity for T3 was 50 fmol/mg DNA and for T4 was 55 fmol/mg DNA, indicating that these two hormones may have a common receptor. In hyperthyroid and hypothyroid patients nuclear affinity for T3 and T4 was very similar to that for euthyroid reference subjects. In hyperthyroidism, T3 and T4 binding capacity was unaltered, whereas in hypothyroidism it was nearly twice as high as in euthyroidism. Lymphocytes from three members of a family with hereditary peripheral resistance to thyroid hormone action were studied. One set of saturable T3 and T4 nuclear binding sites with affinity constants similar to those in the euthyroid group was found. However, in these subjects the estimated binding capacity for T3 and T4 was rather low, indicating that the biochemical defect in this family might be a mild deficiency of nuclear receptor protein. Incubation with diphenylhydantoin and salicylate added in vitro did not alter the binding of T3 and T4 to lymphocyte nuclei. Nuclear binding was also not affected in patients receiving therapeutic amounts of diphenylhydantoin.

The evaluation of a chemiluminescent assay for free thyroxine by comparison with equilibrium dialysis in clinical samples.

We have investigated the diagnostic performance of a chemiluminescence immunoassay for free thyroxine (Ciba Corning Magic Lite) in comparison with equilibrium dialysis. Agreement between the methods was satisfactory across a wide range of samples including those from patients with non-thyroidal illness. The results suggest that the chemiluminescence immunoassay is not subject to the artefacts of widely used analogue tracer methods for free thyroxine estimation.

Segmentation methods for volume determination with 111In/99Tcm SPET.

Objective determination of regions of interest (ROIs) is a prerequisite for the accurate quantification of radionuclide volume distributions in single photon emission tomographic (SPET) images. In this study, we compared four segmentation methods: fixed thresholding (FT), grey level histogram (GL), region growing (RG) and combined region growing and edge detection (RGE). For this purpose, an elliptical phantom containing two cylinders with varying volumes (8-360 ml) and activities of 111In and 99Tcm (2.9-37 kBq ml-1) was employed. Using these methods, the following correlation was observed between true and measured phantom volumes: 111In, r = 0.95 (FT), 0.73 (GL), 0.93 (RG) and 0.92 (RGE); 99Tcm, r = 0.85 (FT), 0.72 (GL), 0.85 (RG) and 0.89 (RGE). Volume determination with FT and RG was not sensitive to the cut-off frequency used in image filtering. A significant correlation was observed between spleen volumes measured with the different segmentation methods, except GL, when applied to the SPET images of 25 patients administered 111In-labelled platelets. On the basis of these results, FT and RG are recommended for the clinical determination of ROIs, although they can be difficult to apply if the signal-to-noise ratio is very low or highly variable, when a combination of different imaging modalities may be the only accurate solution to the segmentation problem. The RGE method can also produce accurate results, but estimation of parameters is laborious with this method. Before being applied clinically, all segmentation methods tested in this study require phantom measurements for the determination of optimal parameters.

99Tcm-HMPAO SPECT in suspected dementia.

To evaluate the usefulness of 99Tcm-hexamethylpropyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) in suspected dementia we studied 160 consecutively imaged elderly patients from our hospital's memory disorder clinic. The diagnosis was based on clinical data, laboratory tests, neuropsychological examination, computed tomography (CT) and EEG. The patients were divided into six diagnostic categories: Alzheimer's disease (AD), multi-infarct dementia (MID), frontal lobe-type dementia (FTD), vascular encephalopathy not fulfilling the criteria of dementia, specific organic conditions, and psychiatric disorders. SPECT images were assessed without knowing the clinical diagnosis, and divided into AD pattern, FTD pattern, MID pattern, abnormal but unclassifiable, and normal. Twenty-three of 36 patients with clinical AD, 25/33 patients with clinical MID, and 2/5 patients with clinical TFD had compatible SPECT patterns. SPECT distinguished AD from MID in the majority (80%) of cases. In patients with depression or anxiety SPECT was abnormal in 16/21 cases, suggesting that SPECT may give early clues to the presence of an underlying organic disease in such elderly patients. Thus, SPECT with 99Tcm-HMPAO seems to be useful in the diagnosis of suspected dementia.

Brain perfusion defect size in SPECT predicts outcome in cerebral infarction.

The results of previous reports on the usefulness of brain perfusion single photon emission computed tomography (SPECT) in predicting the outcome of patients with acute cerebral infarction are conflicting. We therefore studied brain perfusion in 64 patients with a single supratentorial infarction. Contradictory to previous results the perfusion defect volume estimated from transversal and coronal slices correlated significantly with both presenting clinical findings and outcome. Although the clinical status at admission also correlated well with outcome, there was a subgroup of patients in which the favourable outcome was predicted only by SPECT and not by physical or any other examination at admission.

111In-labelled bleomycin complex for the differentiation of high- and low-grade gliomas.

The aim of this study was to evaluate 111In-labelled bleomycin complex (111In-BLMC) SPET in the differentiation of high- and low-grade gliomas. Nineteen glioma patients, 14 with high-grade and five with low-grade tumours, were studied 1, 4 and 24 h after the injection of 111In-BLMC. In the high-grade glioma group, there was significant uptake of 111In-BLMC in 12 patients and no uptake in two patients based on the visual classification of SPET images at 4 and 24 h. In the low-grade glioma group, one patient had low uptake at 4 and 24 h, but the other four patients showed no visible uptake. The mean tumour to extracerebral circulation activity ratio (T/Cr) at 4 h was 0.13 +/- 0.10 (n = 5) in low-grade gliomas and 1.7 +/- 1.0 (n = 14) in high-grade gliomas. At 24 h the T/Cr ratios were 0.56 +/- 0.21 and 3.4 +/- 1.7, respectively. The mean tumour to contralateral normal brain activity ratios (T/Br) were 5.0 +/- 3.9 (4 h) and 3.0 +/- 2.8 (24 h) in low-grade gliomas, and 37.2 +/- 37.3 (4 h) and 8.3 +/- 8.2 (24 h) in high-grade gliomas. These higher T/Br ratios did not, however, result in improved differentiation between the two groups of gliomas; at 4 h the T/Cr and T/Br ratios were of equal value, as two high-grade gliomas would have been misclassified as low-grade, but at 24 h the T/Br ratio resulted in more misclassifications. Our results show that 111In-BLMC can be used in the differentiation of high- and low-grade gliomas and that the selection of the reference area for calculating tumour to non-tumour ratios is important.