Curative radioimmunotherapy of human mammary carcinoma xenografts with iodine-131-labeled monoclonal antibodies.

The radioiodinated monoclonal antibody BW 495/36 showed an exceptionally high uptake and long residence time in human ductal mammary carcinoma xenografts in nude mice. There was a mean tumor uptake of 82%/g 24 hr p.i., decreasing with a biologic half-life of approximately 6 days, to 15%/g by Day 16. The tumor-to-blood ratio increased from 2.8 to 21.4 and the percentage of the whole-body retention recovered in the tumor from 47% to 80% during the same time interval. The therapeutic efficiency of two injections of 7.4 MBq 131I-BW 495/36 was evaluated by comparing the tumor size with that in mice injected with either the same amount of the unlabeled MoAb, the same radioactivity of an 131I-labeled nonspecific MoAb, or with saline only. The high tumor accumulation of 131I-BW 495/36 led to a total tumor dose of 77 Gy resulting in a mean reduction in tumor diameter of 50%, corresponding to a reduction in tumor volume of 88% within 42 days p.i. Unlabeled MoAb had no effect on tumor growth compared with controls, whereas 131I nonspecific antibody caused a slight inhibition of tumor growth. Histologic tumor sections showed large areas of necrosis and a pronounced vacuolation of the tumor cell cytoplasm between Days 7 and 30 p.i. By Day 42 all remaining tissue in the tumor was identified as mouse connective tissue.

Measurement of myocardial fatty acid metabolism: kinetics of iodine-123 heptadecanoic acid in normal dog hearts.

To define the potential of iodine-123 heptadecanoic acid (IHA) for the noninvasive assessment of myocardial fatty acid metabolism with gamma camera imaging, the influence of myocardial oxygen consumption (MVO2) and blood flow (MBF) on extraction and half-times of IHA were investigated in dogs. Following IHA injection into the left circumflex coronary artery, extraction fraction and half-times were derived from the peak and slope of the IHA time activity curve, which consisted of a vascular, early, and late phase. Single-pass extraction fraction of IHA averaged 0.53 +/- 0.11 s.d. at control and was not influenced by MVO2 and MBF. The half-time of the early phase (T = 9.3 min +/- 2.8 s.d. in controls) as well as the ratio between the size of the early and late phase increased with MVO2 (r = 0.82, r = 0.87, respectively). Thus, early phase intracellular turnover of IHA increased, yet clearance of 123I activity was slowed by augmented cardiac work. Preliminary data of HPLC and electrophoretic analysis of myocardial arterial and venous blood samples over time indicate that the early phase is characterized by a decreasing washout of IHA and a relative increase of radioiodine washout. The half-time of the late phase (T = 245 min +/- 156 s.d. at control) was not related to MVO2 and MBF. In conclusion, myocardial fatty acid metabolism cannot be measured from the half-time of the early phase but might be analyzed from the ratio between the size of the early and late phase when using IHA.

Lacrimal dacryoscintigraphy.

Lacrimal dacryoscintigraphy facilitates definite diagnosis of obstructions and stenosis of the lacrimal drainage system with little stress to the patient. Together with x-ray dacryocystography it is an important diagnostic tool especially for pre- and postoperative evaluation of the drainage apparatus. Dacryoscintigraphy is the best method for measuring the dynamics of tear drainage especially in the canaliculi. Although it is not a substitute for other methods in general use, it complements them and expands their diagnostic accuracy.

[Skeletal scintigraphy for the observation of course and treatment of carcinoma of the prostate ]. / Skelettszintigraphische Verlaufs- und Therapiekontrolle beim Prostatakarzinompatienten.

Serial skeletal scintigraphy was carried out on 259 patients with carcinoma of the prostate; 5-10% developed bone metastases each year. Isotope uptake was measured in 79 patients receiving treatment; in 60.6% (48 patients) there was a reduction or disappearance of the areas of uptake, in 16.6% (13 patients) they were stationary and 22.8% (18 patients) the metastases progressed. Skeletal scintigraphy is therefore useful during the course of the disease in showing its extent and the effect of treatment.

[After care of differentiated thyroid gland carcinoma with special reference to serum thyroglobulin level]. / Nachsorge des differenzierten Schilddrüsenkarzinoms unter spezieller Berücksichtigung des Serum-Thyreoglobulin-(hTg-)Spiegels.

The histories of 358 patients with carcinomas of the thyroid have been evaluated. Differentiated carcinomas of the thyroid (84.6%) were treated by means of thyroidectomy, ablative radio-iodine therapy (tissue dose 1000 Gray), TSH-suppressive thyroid hormone medication and, in special cases, external radiation. Even differentiated carcinomas showed a high recurrence rate. Metastases occurred particularly in the lungs, the skeleton and locally; low iodine uptake, particularly in distant metastases from papillary carcinomas, often made it impossible to reach a diagnosis by using radio-iodine. Some pulmonary metastases could only be demonstrated radiologically and some skeletal metastases could be shown radiologically or scintigraphically. A modified follow-up program for differentiated carcinomas is suggested, based on the highly sensitive and specific thyroglobulin determination under TSH suppression (sensitivity 97.9%, specificity 93.6%).

[Measurement of renal blood flow with the Anger scintillation camera after selective intra-arterial injections of 133xenon and 99mtechnetium]. / Die Messung der Nierendurchblutung mit der Anger-Szintillationskamera nach selektiver intraarterieller Injektion von 133-Xenon und 99m-Technetium

A "region of interest" technique for measuring renal blood flow is described, using as Anger camera and selective intra-arterial injection of 133Xe and 99mTc. The sequence of measurements has the advantage of providing information on regional blood flow. The values for RBF and RBFD obtained with 133Xe agree with those in the literature. Selective determination of the RCBF with the "region of interest" technique using 133Xe was not possible. Mean transit time for 99mTc was calculated after correction of the 99mTc indicator dilution curve with respect to recirculation and background activity. All typer of pathological changes in the kidney showed a statistically significant increase in mean transit time when compared with a control group. In patients with uncomplicated essential hypertension, the mean transit time was signigicantly reduced. A comparison of the mean transit time of 99mTc with the haemodynamic parameters derived from the 133Xe studies, and experiments with pharmocologically induced vasoconstriction indicates that the mean transit time represents a measure of the RCBF.

[Clinical and experimental investigations with 201tl for noninvasive myocardial scintigraphy (author's transl)]. / Klinishce und experimentelle Untersuchungen mit 201Tl zur nichtinvasiven Myokardszintigraphie

The biological distribution of 201Tl after intravenous injection was studied experimentally in 42 rats. It was found (see figure 1) that the kidneys showed the greatest affinity for 201Th, reaching an activity concentration of 6.6% per gramme of tissue, almost independently of time. Within the first 30 minutes of injection, myocardial activity exceeds that of the surrounding structures (10 min. p.i.: 4.24%/g; 30 min. p.i.: 2.58%/g). During this time the myocardium can be well demonstrated by "image processing". The relatively fast myocardial kinetics of 201Tl (half value time 33 minutes) make it necessary, strictly speaking, to use a scintillation camera. The clinical value of this method is illustrated by a number of case histories.

[The weighting of SE, IE and GE sequences in tumors of the head and neck]. / Wertigkeit von SE-, IE- und GE-Sequenzen bei Tumoren im Kopf-Hals-Bereich.

In a review of 82 patients having different benign and malignant head and neck tumours we studied the value of spin echo (SE), inversion echo (IE) and gradient echo (GE) sequences. The strong T1 weighted IE mode is highly sensitive to demonstrate pathological tissue. Tumour diagnosis was in 20% and lymph node diagnosis in 29% better than T2 weighted SE sequences. According to this experience we choose the IE mode as the first one for all patients examined for tumour staging. All other sequences and orientations are planned on this tomograms knowing the location of the tumour and lymph nodes. T1 weighted SE mode is indispensable and should be recorded in transversal orientation, covering the whole head and neck region. This mode has the best imaging of anatomical structures as the known fatty limitations. The best differentiation of the tumour is usually obtained after contrast enhancement by i.v. Gd-DTPA. The highest contrast enhancement is seen on T1 weighted GE tomograms, which we prefer. T2 weighted SE sequences are less sensitive than IE sequences and T1 weighted tomograms after Gd-DTPA to show the tumour. The T2 weighted SE mode cannot be replaced by the T2 weighted GE mode having a better signal to noise ratio. To minimise the scan-time of T2 weighted SE mode, only one measurement is performed; the quality of the tomograms is satisfactory.

[Assessment of haemodynamic parameters using a scintillation camera and ECG-triggered data acquisition (author's transl)]. / Erfassung hämodynamischer Grössen durch EKG-getriggerte Verfahren mit Hilfe einer Szintillations-Kamera.

Useful ECG-gated scintigrams of the heart can only be obtained when using a suitable tracer (99mTc-HSA or labeled red cells), a good camera and a computer system with special hard and software. The haemodynamic parameters of left (and right) heart function as derived from scintigrams are only precise when the representative cycle was reconstructed correctly. In patients with arrhythmia, counts should be only summed up when the cardiac cycle follows a preceding heart beat of well defined length. The frames composing the representative cycle must be normalized to the same recording time. When these prerequisites are fulfilled, correct values for ejection fraction and maximal rates of systolic emptying and diastolic filling as global parameters of heart function can be derived. Evaluation of these parameters by means of a completely automated computer program is difficult in pathologically altered heart function. In our nuclear medicine department an interactive computer program has been developed which supplies the investigator with certain information facilitating the definition of the end-diastolic and end-systolic ROI. The program allows for an exact and reproducible evaluation within a short time. Functional images of both amplitudes and phases are very helpful. Functional scintigraphy of the heart is only possible when using certain instrumentation, which is much more expensive than when using a 'cardiac probe', but the additional visual information obtained does significantly improve diagnostic sensitivity.

[Dual-photon absorptiometry: a new method of determining bone mineral content. I. Basic principles]. / Doppelphotonen-Absorptiometrie: Eine neue Methode zur Bestimmung des Knochen-mineralgehaltes. I. Grundlagen.

Today dual-photon absorptiometry (DPA) is recommended as the best procedure for diagnosing osteoporosis at an early stage considering its low cost, low radiation exposure and reasonable reliability. Cortical (neck of femur) and trabecular (L 2-4) bone mass has been determined repeatedly with DPA using 153Gd (NOVO Lab 22 a) in 545 females and 112 males with no evidence of bone diseases. Measured "normal" (age- and sex-related average) values for bone mineral content (BMC) differed significantly (p less than 0.01) from those of US inhabitants determined by the same equipment, i.e., they were on average about 30% lower, but matched well with corresponding results from Belgium. BMC-area was found the most suitable parameter both for cross-sectional and longitudinal studies, since it is independent of height and weight. But there is still need to reduce the overlap and improve accuracy and reproducibility for making decisions after shorter intervals. Assessment of the individual mineral loss and fracture risk by comparison with average values remains problematical due to the wide range of "normal" BMC values, and in women additionally due to the variable onset of menopause. For estimations of the individual fracture risk of elderly patients BMC should not be normalized on age, because at the age of 65 half of the women had "pathologic" values, i.e. were below the so-called "osteoporosis threshold". Comparison of the individually measured postmenopausal BMC with average values of premenopausal women and with BMC values normalized to their menopausal age may be helpful approaches to overcoming these difficulties.(ABSTRACT TRUNCATED AT 250 WORDS)

Serial bone scintigraphy for assessing the effectiveness of treatment of osseous metastases from prostatic cancer.

130 serial bone scintigrams were performed to evaluate the course of skeletal metastases under treatment in 36 patients with prostatic cancer. During a successful treatment scintigraphic controls revealed a significant decrease of the metastatic 99mTc-diphosphonate uptake in 14 patients and sometimes even a complete normalization of the skeletal radioactivity distribution, whereas a progression characterized by an increased multifocal radioactivity concentration was registered in 16 patients indicating the failure of the initiated therapy. Based on these results of follow-up studies scintigraphic bone imaging can be recommended for the assessment of the effectiveness of on-going therapy of skeletal metastases.

[Scintigraphic and experimental studies with 67Ga in 142 patients with bronchial cancer (author's transl)]. / Szintigraphische und klinisch-experimentelle Untersuchungen mit 67Ga an 142 Bronchialkarzinomen.

In 142 patients with untreated bronchial carcinoma positive 67Ga scintigrams were obtained in 132 cases (93%). 6 of 10 scintigraphically not detected tumors had diameters less than 2 cm, 4 carcinomas presumably consisted of necrotic tumor masses. There was no dependence of 67Ga accumulation on the histomorphological type of tumor. Differentiated and undifferentiated carcinomas showed a comparably high 67Ga uptake. These scintigraphic findings were confirmed by measuring the quantitative 67Ga concentration in 132 tissue samples of various tumors. In addition these studies revealed an absent or decreased 67Ga accumulation in more or less necrotic tumor masses. The positive tumor scintigraphy with 67Ga-citrate as a non-invasive method is suitable for detecting untreated bronchial carcinomas, especially those localized in the hilar or mediastinal region, which cannot be visualized roentgenologically as well as for indicating the effectiveness of radio- or chemotherapy. 67Ga scanning is also useful in establishing the reappearance of viable tumor tissue in follow-up studies of tumor diseases. The use of 67Ga as a tumor-seeking scanning agent is limited because of its lack of tumor specifity and of its inability to detect tumors smaller than 2 cm in diameter.

[Simultaneous determination of kidney glomerular and tubular partial functions with 99mTc-DTPA and 131I-hippuran using a partially shielded whole body counter]. / Die simultane Bestimmung der glomerulären und tubulären Nierenpartialfunktion mit 99mTc-DTPA und 131J-Hippuran am teilabgeschirmten Ganzkörperzähler.

The methodical prerequisitis and the clinical results-of simultaneous double-radionuclide determinations of renal clearances of 99mTc-DTPA (Sn) and 131I-Hippuran, using a partially shielded whole-body counter, are reported. Examination of the in vitro stability of the 99mTc-DTPA (Sn) complex by radiochromatographic separation revealed an unbound 99mTc fraction of 4.7%. The whole body measurement geometry was found over the non-shielded regions of the body to be independent of the various physiological distribution volumes of the clearance substances. The simultaneously determined clearances of 51Cr-EDTA and 99mTc-DTPA resulted in a strong linear correlation (r = 0.96; n = 20). The relation between serum creatinine concentration and 99mTc-DTPA clearance was approximately hyperbolic (r = 0.89; n = 154). In a group of normals (n = 102) the renal filtration fraction (FF - ClTc-DTPA/ClOIH) was 0.18 +/- 0.04. In a group of urological patients (n = 72) this fraction did not change appreciably before and after operations, whereas it was found increased to 0.25 and 0.24, respectively, in patients with diabetes and albuminuria or urinary tract infection (n = 37). The relative error of the clearance determination with a partially shielded whole-body counter was about 15% down to clearances of some 50 ml/min, and higher than 50% with clearances below 20 ml/min.

Improved radioimmunoscintigraphy of human mammary carcinoma xenografts after injection of an anti-antibody.

The low tumor-to-background ratio obtained after administration of radiolabeled whole monoclonal antibodies (MAbs) is one of the major problems in immunoscintigraphy and -therapy. To reduce the blood pool label caused by the circulation of radiolabeled MAb we have investigated the advantage of injecting an anti-antibody after administration of a tumor-specific MAb in nude mice bearing human mammary carcinoma xenografts. The MAb MA 10-11 of rat origin, used in these studies, had shown a high affinity to human mammary carcinoma tissue on frozen sections and low cross-reactivity with various normal human tissues. 24 h after injection of 1.5 MBq 131I-labeled MAb containing 10 micrograms IgG2a one group of mice received an additional injection of 100 micrograms anti-rat antibody. Blood taken 2 min after the second antibody injection showed nearly the whole activity bound to antibody aggregates, that cleared very rapidly from the circulation and accumulated in liver and spleen. The transitory high liver activity decreased within several hours because of rapid deiodination of the antibody-complex in this organ. The release of radioactivity from the spleen, however, was found to be much slower. The rapid excretion of the radioactivity from the blood pool combined with a nearly constant tumor activity allowed early tumor detection with tumor-to-blood ratios of 250:1 at 48 h after anti-antibody injection compared to 1.1:1 obtained for the control animals. In addition the results may explain the reported reduction of imaging quality and high uptake of radioactivity in the spleen of patients having repeated injections of mouse MAbs due to complex formation after development of human anti-mouse antibodies.

[Early detection of morphologic-functional changes in the airways using a simple method of inhalation scintigraphy]. / Früherkennung von morphologisch-funktionellen Veränderungen der Atemwege durch eine einfache Methode der Inhalationsszintigraphie.

In order to validate a method of inhalation scintigraphy with 99mTc-labeled human serum albumin in the early diagnosis of morphologic-functional changes of the airways 35 volunteers and patients (12 healthy non-smokers and smokers each, 11 patients with bronchitis) were studied. Deposition of the aerosol immediately after inhalation was calculated quantitatively by a ROI technique and qualitatively (scoring of central deposition, homogeneity, and recognizability of lung outline). Additionally, the regional clearance of the inhaled aerosol was determined by continuous lung imaging up to 60 min (mainly regional mucociliary removal rates). Discrimination between healthy volunteers and patients with bronchitis was possible by means of deposition patterns immediately after inhalation. On the other hand, no differences could be recognized in this way between healthy non-smokers and smokers. Regional mucociliary removal was higher in non-smokers than in smokers, but there was no difference between smokers and patients with bronchitis.

[Unilateral pulmonary artery aplasia with special reference to lung scintigraphy (author's transl)]. / Die einseitige Lungenarterienaplasie unter besonderer Berücksichtigung der nuklearmedizinischen Lungendiagnostik.

In a case of unilateral aplasia of one Arteria pulmonalis, i.e. proximal interruption, the diagnostic value of perfusion and ventilation scintigraphy is shown to be simple and non-invasive, exposing the patient to a lower radiation dose than other diagnostic screening methods. When an interruption of a main pulmonary artery is radiologically suspected the scintigraphic examination allows to distinguish between vascular and/or parenchymatous pulmonary diseases, thus clarifying the diagnosis of primary pulmonary malperfusion. The results of other examinations, the relevant literature, the pathogenesis and pathophysiology of unilateral pulmonary artery aplasia as well as therapeutical and prognostic aspects are reviewed.

[Evaluation by means of ECG-gated cardiac blood pool scintigraphy of global and regional left ventricular function at rest and during exercise in patients with coronary artery disease (author's transl)]. / Die Beurteilung der globalen und regionalen linksventrikulären Funktion in Ruhe und während Ergometerbelastung bei Patienten mit koronarer Herzkrankheit mit der EKG-getriggerten Herzbinnenraumszintigraphie.

ECG-gated cardiac blood pool scintigraphy permits a non-invasive determination of the end-diastolic and end-systolic ventricular volumes and of the ejection fraction as well as a qualitative description of regional ventricular wall motion at rest and during excercise. In 6 healthy persons a significant increase of the ejection fraction from 66 +/- 7% at rest to 78 +/- 3% during exercise (p less than 0.01) was observed. In contrast, the ejection fraction decreased in 15 out of 18 patients with coronary artery disease, with a significant (p less than 0.01) difference between patients with and without angina pectoris. Thus, the ejection fraction fell in 12 patients without angina during excercise from 60 +/- 11% to 52 +/- 11% (p less than 0.05) whereas in 6 patients with angina a decrease from 61 +/- 7% to 30 +/- 8% (p less than 0.01) was observed. This non-invasive technique makes it possible to demonstrate in a simple and safe manner changes of cardiac function during excercise in patients with coronary artery disease.

[Clinical relevance of I-123/I-131-MIBG scintigraphy in intestinal carcinoid tumors]. / Klinische Relevanz der I-123/I-131-MIBG-Szintigraphie bei intestinalen Karzinoiden.

AIM: Of this retrospective study was to determine the value of MIBG-scintigraphy in patients with intestinal carcinoids dependent on histological, clinical, and biochemical parameters. METHODS: In 15 patients uptake in carcinoid tumors and metastasis was correlated with location of the primary tumor, intra- and extrahepatic tumor masses, histology, immunhistochemistry, neuroendocrinological markers, and clinical symptoms. RESULTS: High uptake was to be seen almost only in tumor masses of primary tumors located in the terminal ileum. There also was a positive correlation with clinical symptoms for carcinoids and urinary 5-HIAA level. No correlation between MIBG uptake and tumor masses, histology, and most of the immunhistochemical and neuroendocrinological markers could be found. CONCLUSION: There is a limited indication for MIBG-scintigraphy in follow up of intestinal carcinoids. In patient with proven uptake MIBG scintigraphy is suitable for long-term follow up and therapy monitoring.

Non-linear correlation of basal serum TSH and TRH-stimulated TSH response: new aspects in pituitary-thyroid regulation.

The relationship between basal and TRH-induced TSH in the 200 micrograms i.v. TRH test has been reinvestigated using one of the new 'supersensitive' TSH-IRMA assays. A total of 761 consecutive TRH tests (1522 sera) in unselected patients attending the Thyroid Out-patient Department was studied. The closest correlation (r = 0.962, In S.D. = 0.46787) of both TRH test parameters was found using logarithmic transformation of TSH-levels and a least squares fit based on a sixth degree polynomial approach. The resulting correlation curve revealed three points of inflection, one located in the subnormal, one in the normal and one in the high-normal range of the basal as well as the TRH-induced TSH concentrations. This indicated that 'fine-tuning' of pituitary-thyroid axis occurs according to a non-linear dose-response relationship. Consequently, the interpretation of the TRH test on the basis of delta-TSH used hitherto has to be reconsidered.

Performance of two new solid-phase ligand assays for TSH using monoclonal antibodies.

Three ligand assays for TSH using monoclonal antibodies, an IRMA, an ELISA and a DELFIA were compared with a standard DAB RIA technique. The IRMA proved to be superior in respect to sensitivity, precision, reproducibility and practicality. The highest sensitivity yet, was achieved by DELFIA. IRMA, ELISA and DELFIA are performable on a daily routine basis. ELISA and DELFIA have the additional advantage of being non-isotopic immunoassays (NIIA). Under routine conditions IRMA reveals the best discrimination of hyperthyroid from euthyroid patients by basal TSH. This fact improves the TSH determination's clinical value considerably and may in the future--if confirmed--change the diagnostic schemes in use at present, e.g. rendering most of the TRH-tests unnecessary.