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S M Larson

Publications and source records attributed to S M Larson.

At least 253 records · Page 14Linked to original sources
PubMed1984

Short-term thymidine uptake in normal and neoplastic tissues: studies for PET.

Uptake of H-3 thymidine was studied in mice, both normal and with spontaneous lymphoma, and in the organs and tumors of dogs with spontaneous tumors. Uptake was compared with relative blood flow as measured by the distribution of C-14 iodoantipyrine. Initial distribution of thymidine in normal mice measured 20 sec after injection, correlated with the relative perfusion measurements; however, all measurements of thymidine uptake made between 1 and 60 min after injection showed no correlation with perfusion. This indicates that the distribution more than 1 min after injection is primarily dependent on subsequent redistribution and/or metabolism of thymidine. A time-course study demonstrated that normal mouse organs with high rates of proliferation retained all the labeled thymidine initially taken up. Organs with low rates of proliferation lost their label in a nearly exponential washout. These studies provide further evidence of the feasibility of using C-11 thymidine for positron emission tomography (PET).

Animals↗
PubMed1984

High-level iodination of monoclonal antibody fragments for radiotherapy.

Two different murine monoclonal antibody Fab fragments specific for p97, a melanoma-associated antigen, were labeled with I-131 at high activity levels without excessive chemical damage. Up to 20 mg of Fab were labeled with up to 300 mCi of I-131 using the chloramine-T method and large working volumes at room temperature. As much as 90% of the initial activity was recovered as labeled product. The labeled Fabs varied in their sensitivity to radioiodination damage, as measured by an in vitro cell-binding assay. Radioiodination was performed safely using a remote iodination apparatus. The final product was of radiopharmaceutical quality suitable for clinical diagnosis and experimental radiotherapy in humans.

Animals↗
PubMed1983

Localization of 131I-labeled p97-specific Fab fragments in human melanoma as a basis for radiotherapy.

33 patients with advanced malignant melanoma were studied after intravenous administration of 131I-labeled Fab fragments specific for p97, an oncofetal glycoprotein of human melanoma. In all, 47 gamma camera imaging studies were performed for the purpose of localization of metastatic deposits. In addition to tumor, 131I-Fab uptake was also seen in liver and kidney. 20 of these studies included simultaneous administration of both an 131I-labeled Fab specific for p97, and an 125I-labeled Fab not specific for p97. Blood clearance of p97-specific Fab was significantly more rapid than for nonspecific Fab. Eight of these patients had biopsies of subcutaneous nodules at 48 and 72 h postinjection in order to assess whether localization of radioactivity was antigen specific. Antigen-specific localization was observed with average ratios of specific/nonspecific uptake of 3.7 (48 h) and 3.4 (72 h); uptake was strongly correlated with tumor p97 concentration (r = 0.81, P less than 0.01). Also, imaging studies of the bio-distribution of 131I-labeled anti-p97 Fab in patients selected for high p97 tumor concentration showed avid tumor uptake and more prolonged retention of labeled Fab in tumor than in normal tissues. Based on these studies, we estimated that total 131I doses of 500 mCi could be safely given to patients before dose-limiting toxicity would be observed. Accordingly, in seven selected patients, phase I radiotherapeutic trials were begun. For improved radiation safety, we developed automated methods to label Fab fragments with up to 200 mCi of 131I. So far, a total of 12 individual therapeutic doses, ranging from 34 to 197 mCi of 131I-labeled to 5 to 10 mg of Fab, have been administered with excellent tumor localization and without major target organ toxicity. Cumulative doses ranged from 132 to 529 mCi 131I. Side effects attributable to the radiation were mild, with a transient drop slightly greater than 50% in platelet and absolute neutrophil counts being observed in the two patients who received cumulative doses greater than 500 mCi. In the combined series of 47 diagnostic and 12 therapeutic studies, four acute reactions were observed: one episode each of transient chills and fever; flushing and hypotension; and two skin rashes. All of these reactions responded promptly to symptomatic therapy. After multiple administrations of 131I-(anti-p97) Fab (IgG1), isotype-specific immunity was observed in three patients. In two of these patients it was possible to successfully reinfuse after immunity had developed with 131I-(anti-p97) Fab of a different isotype (IgG2a). Dosimetry estimates were performed based on the biodistribution of (131)I-Fab in these patients,and for every 100 mCi of (131)I-Fab given, tumor receives 1,040 rads; liver. 325 rads; and bone marrow, 30 rads. Marrow would be expected to be the critical organ, if doses >500 mCi (131)I-Fab are given. These studies demonstrated that, with proper precautions, large doses (of an (131)I-labeled murine Fab fragments immunologically specific for a human melanoma-associated antigen) could be safely given to humans by using repetitive intravenous injections.

Animals↗
PubMed1983

Single-photon emission computed tomography of the normal liver.

Single-photon emission computed tomography (SPECT) is a new imaging method that offers the advantage of cross-sectional imaging and improved contrast resolution as compared with conventional planar imaging. Preliminary SPECT studies of the liver for detection of metastatic disease are very promising. However, these studies indicate some potential pitfalls in the interpretation of the normal liver SPECT images. Experience with 58 tomographic studies obtained with a General Electric 400T rotating gamma camera is presented, with special emphasis on the areas of potential misinterpretation and on recognition of the normal anatomy as seen by this technique.

Elementary Particles↗
PubMed1983

Optimum fourier filtering of cardiac data: a minimum-error method: concise communication.

Random fluctuations limit the accuracy of quantities derived from cardiac time-activity curves (TACs). To overcome this problem, TACs are often fitted with a truncated Fourier series giving rise to two sources of error: (a) the truncated series may not adequately describe the TAC shape, causing errors in parameters calculated from the fit: and (b) successive TACs acquired from the same subject under identical circumstances will fluctuate due to limited counts, causing the Fourier fits (and parameters derived from them) to fluctuate. These two errors, respectively, decrease and increase as the number of harmonics increases, suggesting the existence of a minimum in total error. This number of harmonics for minimum error (NHME) was calculated for each of six common parameters used to describe LV TACs. The "true" value of each parameter was determined from TACs of very high statistical precision. Poisson noise was added to simulate lower count rates. For low-count TACs, use of either a smaller or a larger number of harmonics resulted in significantly greater error. NHME was found to occur at two harmonics for the systolic parameters studied, regardless of the noise level present in the TAC. For diastolic parameters, however, NHME was a strong function of the noise present in the TAC, varying from three harmonics for noise levels typical of regional TACs, to five or six harmonics for high-count global TACs.

Diastole↗
PubMed1983

Imaging of melanoma with L-131-labeled monoclonal antibodies.

Mouse monoclonal antibodies and Fab fragments specific for p97, a melanoma-associated antigen, were used to image metastatic human melanoma. Preclinical studies in athymic mice showed antigen-specific uptake in melanoma xenografts, and toxicity tests in rabbits gave no evidence for tissue damage after injection of up to 100 times the amount of antibody used in humans. Six patients received 1 mg labeled antibody, and one patient received 1 mg of labeled Fab. No. toxic side effects were observed. All of the six patients had positive scans, visualizing 22 of 25 (88%) of lesions larger than 1.5 cm. In tumors from two patients, greater uptake of p97-specific, versus control IgG and Fab, respectively, was documented by biopsy. Antibodies to mouse immunoglobulin appeared in three patients receiving 1 mg or more of radiolabeled mouse antibody.

Adult↗
PubMed1982

Tumor cell toxicity of stable gallium nitrate: enhancement by transferrin and protection by iron.

The cytotoxicity of citrated gallium nitrate (NSC 15200) to EMT-6/UW mouse sarcoma cells growing in vitro was assayed as growth inhibition in treated cultures as well as cell survival (colony-forming ability) after acute or chronic exposure to graded doses. Gallium nitrate is both cytostatic and lethal to cells, with some growth inhibition occurring after chronic exposure to low doses (10 micrograms/ml) which kill essentially no cells. Cell kill and growth inhibition were both observed if cells were exposed for 24 hr or more to doses greater than 50 micrograms/ml. The growth inhibitory and lethal effects of gallium nitrate were enhanced by the addition of human transferrin to the medium. This enhanced toxicity was consistent with, and proportional to, the increased gallium uptake in the presence of transferrin rather than a direct effect of this iron transport protein. The addition of ferric citrate greatly reduced the toxic effect of the gallium salt. Cells in stationary plateau phase cultures appear to be as sensitive to gallium nitrate as exponentially growing cells. Ga3+ may mimic Fe3+ in some aspects of cellular metabolism, and competition between the two metals occurs at the initial uptake step, binding to transferrin, and possibly at other points in cell metabolism.

Animals↗
PubMed1982

Radiometric measurement of differential metabolism of fatty acid by mycobacteria.

An assay system has been developed based on automated radiometric quantification of 14CO2 produced through oxidation of [1-14C] fatty acids by mycobacteria. Two stains of M. tuberculosis (H37Rv and Erdman) and one of M. bovis (BCG) in 7H9 medium (ADC) with 1.0 microCi of one of the fatty acids (butyric, hexanoic, octanoic, decanoic, lauric, myristic, palmitic, stearic, oleic, linoleic and linolenic) were studied. Results previously published on M. lepraemurium (Hawaiian) were also included for comparison. Both strains of M. tuberculosis had maximum 14CO2 production from hexanoic acid. Oxidation of butyric and avid oxidation of lauric acids were also found with the H37Rv strain but not with Erdman. In contrast, 14CO2 production by M. bovis was greatest from lauric and somewhat less from decanoic acid. M. lepraemurium showed increasing oxidation rates from myristic, decanoic and lauric acids. Assimilation studies of M. tuberculosis H37Rv confirmed that most of the oxidized substrates were converted into by-products with no change in those from which no oxidation was found. These data suggest that the radiometric measurement of differential fatty acid metabolism may provide a basis of strain identification of the genus Mycobacterium.

Carbon Dioxide↗
PubMed1981

Assessment of cobalt 57 tagged bleomycin as a clinical aid in staging of head and neck carcinoma.

Critical assessment of head and neck cancer with respect to staging has, on occasion, been disappointingly ineffective. We have attempted to correlate the incidence of measureable uptake of cobalt 57 tagged bleomycin by primary squamous cell carcinoma and metastatic cervical lymph nodes. Forty-six cases have been evaluated with respect to histopathological confirmation of the suspected metastatic disease. We have found that this diagnostic measure increases our acumen in staging of head and neck cancer. The relevance of the Co-Bleo scans as a diagnostic aid is reported in 46 cases. Malignant tumors greater than 2 cm in size appear to demonstrate active uptake of the imaging agent. Small tumor size and excess background radioactivity contribute to the false-negatives (17%). Inflammatory conditions or benign tumors of the salivary apparatus may result in minimal uptake, thus, a false-positive result (10%). An increase in the radioactivity of the Co-Bleo may enhance the benefits of this procedure in the search for an undiagnosed primary, as well as undiagnosed local or distant metastases.

Adult↗
PubMed1981

Positron imaging feasibility studies. I: Characteristics of [3H]thymidine uptake in rodent and canine neoplasms: concise communication.

Uptake [3H] thymidine was studied in BALB/c mice with EMT-6 sarcoma, in Buffalo rats with Morris 7777 hepatoma, and in nine dogs with spontaneous neoplasms: four lymphomas, two osteosarcomas, two soft-tissue sarcomas, and a thyroid carcinoma. High tumor-to-tissue ratios were observed for all tumor types assayed, and absolute uptakes, when computed as percent dose per gram tumor normalized for body weight, were similar for transplanted and spontaneous tumors. In the rodent tumors, radiothymidine was retained for at least 3 hr in the tumor without appreciable loss. In canine neoplasms, although the highest uptakes were observed in cellular tumors with many mitotic figures, tumor uptake showed significant variability that did not correlate with any obvious histologic change, and thus may reflect true biologic differences in metabolism among tumors at different sites in the same animal. These studies provide additional experimental evidence that the ratios of neoplastic to normal tissue and the kinetics of thymidine uptake by tumors are suitable for positron emission tomography of neoplasms in small and large animals, including both transplanted and spontaneous tumors.

Animals↗
PubMed1981

Positron imaging feasibility studies. II: Characteristics of 2-deoxyglucose uptake in rodent and canine neoplasms: concise communication.

Uptake of [3H]2-deoxyglucose was studied in BALB/c mice with EMT-6 sarcoma, in Buffalo rats with Morris 7777 hepatoma, and in eight dogs with spontaneous neoplasms: five osteosarcomas and three diffuse lymphomas. High tumor-to-tissue ratios were observed for all tumor types studied. In rodents, peak levels of uptake occurred between 30 min and 1 hr, with a slow loss from the tumor of about 10% per hour thereafter. In dogs there was considerable variability in uptake, both between individuals and at different tumor sites within an individual. Necrotic tumor did not take up the radiotracer. Absolute uptakes, when normalized for body weight, were similar for spontaneous and transplanted neoplasms. These studies provide additional support for the concept that positron emission tomography can be used to obtain functional images of important metabolic processes of tumors, including glycolysis.

Animals↗
PubMed1980

Positron imaging feasibility studies: selective tumor concentration of 3H-thymidine, 3H-uridine, and 14C-2-deoxyglucose.

The potential usefulness of substrates for glycolysis and nucleic acid synthesis as tumor imaging agents was compared to that of 67Ga-citrate. In separate experiments, 3H-thymidine, 3H-uridine, 14C-2-deoxyglucose, and 67Ga-citrate were injected intraveneously into BALB/c mice with solid subcutaneous EMT-6 sarcomas. For the 3H- and 14C-labeled substrates, absolute uptakes in tumor and tumor-to-blood ratios were as high 1 hour after injection as the comparable maximum values achieved for 67Ga-citrate after 48 hours. These studies suggest that positron-labeled analogues of thymidine, uridine, and 2-deoxyglucose should be useful radiopharmaceuticals for tumor imaging by positron-emission tomography.

Animals↗
PubMed1980

Comparison of the regulation of calcitonin in serum of old and young Buffalo rats.

Studies were carried out to characterize the secretion and the effects of calcitonin in the Buffalo rat. Mean basal concentrations of calcitonin and parathyroid hormone were significantly increased in serum of rats older than 6 months of age as compared with rats between 2 and 3 months of age. The mean concentration of calcium in serum was independent of age. In both age groups, serum calcitonin was increased by administration of calcium (1 mmol/kg body wt) or isoproterenol (100 microgram/kg body wt), was diminished by beta-adrenergic blockade with DL-propranolol (1 mg/kg body wt) and was not altered by either pentagastrin or glucagon (200 and 100 microgram/kg body wt respectively). The average weight of the thyroid glands was significantly greater in the old than in the young animals but the mean concentration of calcitonin in the thyroids was the same. Thyroparathyroidectomy produced a transient increase followed by a fall in mean serum calcium in the old rats. In contrast, a progressive decline in the mean concentration of calcium in serum was observed after thyroparathyroidectomy in the young rats. Treatment of old animals with reserpine (2.5 mg/kg body wt) markedly depleted noradrenaline in the thyroid, lowered calcitonin in serum and converted the pattern of response of serum calcium to thyroparathyroidectomy to that observed in young animals. The results provide evidence that hypercalcitonaemia occurs in aged Buffalo rats, as does hyperparathyroidism, and that the concentrations of calcitonin in blood are modulated by beta-adrenergic affectors. Glucagon and pentagastrin exhibit little if any effects on calcitonin secretion in this strain of rat regardless of age.

Aging↗
PubMed1980

Common pathway for tumor cell uptake of gallium-67 and iron-59 via a transferrin receptor.

We studied the tumor uptake of [67Ga]citrate, [59Fe]citrate, and 125I-labeled transferrin (TF) by the in vitro growth form of EMT-6, a sarcoma-like mammary tumor of BALB/c mice. In analyzing the binding experiments, we developed a new mathematical model based on a formulation originally used to express the interaction of hormones with specific tissue receptors. The uptake of both carrier-free 67Ga and 59Fe by tumor cells was mediated by kinetically identical TF receptors. We also studied teric acid extracts of the stroma of EMT-6 tumors grown both in vivo and in vitro. Chromatography of these extracts on Sephacryl S-200 SF demonstrated that the cellular stroma contained specific TF-binding macromolecules. On the basis of these findings, we proposed the "transferrin receptor hypothesis" for the mechanism of 67Ga uptake by tumors. According to this view, a tumor-associated TF receptor is the functional unit responsible for the affinity of gallium for certain neoplasms. This receptor was also active in the uptake of iron by tumors.

Animals↗
PubMed1979

Pharmacologic enhancement of gallium-67 tumor-to-blood ratios for EMT-6 sarcoma (BALB/c mice).

At various intervals after intravenous injection of carrier-free 67Ga-citrate, iron dextrane or deferoxamine mesylate was injected into EMT-6 tumor-bearing BALB/c mice. After treatment, rapid clearance of 67Ga from soft tissues was observed. Tumor uptake was not greatly affected, and so increased tumor-to-blood ratios were observed. The authors conclude that these drugs can enhance target-to-nontarget uptake ratios for tumors.

Animals↗