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R J Ott

Publications and source records attributed to R J Ott.

At least 37 records · Page 2Linked to original sources

Fast accurate iterative reconstruction for low-statistics positron volume imaging.

A fast accurate iterative reconstruction (FAIR) method suitable for low-statistics positron volume imaging has been developed. The method, based on the expectation maximization-maximum likelihood (EM-ML) technique, operates on list-mode data rather than histogrammed projection data and can, in just one pass through the data, generate images with the same characteristics as several ML iterations. Use of list-mode data preserves maximum sampling accuracy and implicitly ignores lines of response (LORs) in which no counts were recorded. The method is particularly suited to systems where sampling accuracy can be lost by histogramming events into coarse LOR bins, and also to sparse data situations such as fast whole-body and dynamic imaging where sampling accuracy may be compromised by storage requirements and where reconstruction time can be wasted by including LORs with no counts. The technique can be accelerated by operating on subsets of list-mode data which also allows scope for simultaneous data acquisition and iterative reconstruction. The method is compared with a standard implementation of the EM-ML technique and is shown to offer improved resolution, contrast and noise properties as a direct result of using improved spatial sampling, limited only by hardware specifications.

Image Processing, Computer-Assisted↗

Three-dimensional dosimetry for intralesional radionuclide therapy using mathematical modeling and multimodality imaging.

UNLABELLED: A method of dosimetry is described that quantifies the three-dimensional absorbed-dose distribution resulting from an intralesional administration of a radiolabeled monoclonal antibody, allowing for both spatial and temporal heterogeneity of distribution of the radionuclide and without the need for a calibration scan. METHODS: A mathematical model was developed to describe the distribution of activity as a function of time resulting from infusion at a single point within the solid component of a tumor. The parameters required for this model are either known directly or may be obtained from SPECT image data registered to computed tomography. Convolution of this distribution with a point-source dose kernel enabled the three-dimensional absorbed-dose distribution to be obtained. RESULTS: This method was applied to a set of patient data acquired in the course of a clinical study performed at our center, and dose profiles and dose-volume histograms were produced. It was shown that the three-dimensional distribution of dose was significantly nonuniform. CONCLUSION: Initial results suggest that this method offers a means of determining the absorbed dose distribution within a tumor resulting from intralesional infusion. This method extends the Medical Internal Radiation Dose computation, which, in these circumstances, would make erroneous assumptions. Furthermore, it will enable individual patient treatment planning and optimization of the parameters that are within the clinician's control.

Humans↗

Imaging technologies for radionuclide dosimetry.

Targeted radionuclide therapy is becoming an increasingly popular treatment modality as an alternative or as an adjunct to external beam radiotherapy and chemotherapy. The present method of dosimetry based on the MIRD system requires measurements of the concentration of the radionuclide in the target and risk tissues and the effective half-life of the radionuclide in these tissues. Radionuclide imaging techniques including planar scintigraphy, rectilinear scanning, single-photon emission computed tomography and positron emission tomography have all been used to provide data from which this information can be obtained. Additionally anatomical imaging has been used to aid these estimates. This paper reviews the application of imaging technology and methodology to radionuclide dosimetry.

Gamma Cameras↗

Imaging metastatic testicular germ cell tumours with 18FDG positron emission tomography: prospects for detection and management.

The aim of this study was to investigate the role of positron emission tomography (PET) with [18F]fluoro-2-deoxyglucose (18FDG) in metastatic testicular germ cell tumours. Twenty-one patients with stage II-IV testicular germ cell tumours were imaged by PET with a multiwire proportional chamber PET system and 18FDG. Avid 18FDG uptake was seen in metastatic disease from primary seminoma and malignant teratoma. Normal tissue uptake was seen in differentiated teratoma or necrotic, fibrotic tissue. 18FDG standard uptake values and tumour to normal tissue ratios were 6.0 +/- 1.4 and 1.7 +/- 0.4 (mean +/- 1SD), respectively, for malignant tissue. Reduction of 18FDG tumour to normal tissue ratios from pre-treatment to on-treatment scans was predictive of response (n = 3). No significant reduction in 18FDG uptake was seen in patients not responding to therapy (n = 2). These results suggest a role for 18FDG PET in the detection and management of metastatic testicular germ cell tumours.

Abdominal Neoplasms↗

Pharmacokinetics and biodistribution of radiolabelled idoxifene: prospects for the use of PET in the evaluation of a novel antioestrogen for cancer therapy.

With a view to evaluating the role of PET imaging in the development of new anticancer drugs, we are investigating the novel antioestrogen pyrrolidino-4-iodotamoxifen (idoxifene). [125I]idoxifene and [131I]idoxifene have been produced in no-carrier-added form using a tributyl stannylated precursor, and the bio-distribution and dynamic behaviour of the compound investigated using syngeneic transplantable mammary tumours in the rat. Our findings support the use of PET imaging with 124I to study the clinical pharmacology of idoxifene. Factors other than hormone receptor levels appear to influence tumour uptake and therefore, possibly the biological effects of this compound.

Animals↗

Dose-response study on thyrotoxic patients undergoing positron emission tomography and radioiodine therapy.

With the acknowledged problems associated with assessment of functioning thyroid mass and hence radiation dose, our policy had been to give 75 MBq iodine-131 at 6-monthly intervals to patients with Graves' disease until they became euthyroid. Since positron emission tomography (PET) has been available at this hospital, the radiation dose to the thyroid has been calculated with an accuracy of approximately 20%, the thyroid mass being determined from an iodine-124 PET scan. A dose-response study has been carried out on 65 patients who have received single or cumulative radiation doses of < 80 Gy. The results show that patients who receive a low radiation dose (< 20 Gy) at their first treatment have a high probability of remaining toxic at 12 months. In contrast, patients who receive higher radiation doses (> 40 Gy) at their first treatment have a high probability of control. The probability of becoming euthyroid increases more rapidly with increasing radiation dose than the probability of becoming hypothyroid. Following this dose-response study, a new treatment protocol has been introduced. A 124I PET tracer study prior to 131I therapy will be performed to enable a prescribed thyroid dose of 50 Gy to be delivered to patients with Graves' disease. Further 131I therapy will only be considered if patients are still toxic at 12 months.

Dose-Response Relationship, Radiation↗

Effect of phenylisothiocyanate on organic cation transport in opossum kidney cells.

In this study tetraethylammonium (TEA) was used as a model compound to determine the effect of the lysine selective modifying reagent, phenylisothiocyanate (PITC), on organic cation transport across the brush-border membrane of opossum kidney (OK) cells. TEA uptake in OK cell monolayers treated with PITC was reduced in a time- and concentration- dependent manner (IC50, 200 microM). Two lines of evidence suggested that amine rather than sulfhydryl residues were being modified by PITC. First, treatment of the cells with PITC at pH 8.5 was significantly more effective in reducing TEA uptake than PITC treatment at pH 7.4. Secondly, dithiothreitol (10 mM) could not reverse the effect of PITC on TEA uptake. Preincubation of OK cell monolayers with PITC (50 microM) resulted in a significant increase in the Km of TEA (control cells: 81 +/- 10 microM; treated cells: 165 +/- 54 microM), whereas the Vmax was unaffected. Incubation of the cells with quinine or unlabeled TEA significantly altered the inhibitory effects of PITC on TEA uptake. At low concentrations, quinine protected the transporter from the inhibitory effects of PITC, whereas at higher concentrations (> 2.5 microM) quinine enhanced PITC inhibition of TEA uptake. Other organic cations that are substrates for the transporter including cimetidine and N1-methylnicotinamide did not alter the effects of PITC on TEA transport. Collectively, these data suggest that covalent modification of amine groups reduces the transport of TEA in OK cells by decreasing the affinity of TEA to the transporter.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Wire chambers revisited.

Detectors used for radioisotope imaging have, historically, been based on scintillating crystal/photomultiplier combinations in various forms. From the rectilinear scanner through to modern gamma cameras and positron cameras, the basic technology has remained much the same. Efforts to overcome the limitations of this form of technology have foundered on the inability to reproduce the required sensitivity, spatial resolution and sensitive area at acceptable cost. Multiwire proportional chambers (MWPCs) have long been used as position-sensitive charged particle detectors in nuclear and high-energy physics. MWPCs are large-area gas-filled ionisation chambers in which large arrays of fine wires are used to measure the position of ionisation produced in the gas by the passage of charged particles. The important properties of MWPCs are high-spatial-resolution, large-area, high-count-rate performance at low cost. For research applications, detectors several metres square have been built and small-area detectors have a charged particle resolution of 0.4 mm at a count rate of several million per second. Modification is required to MWPCs for nuclear medicine imaging. As gamma rays or X-rays cannot be detected directly, they must be converted into photo- or Compton scatter electrons. Photon-electron conversion requires the use of high atomic number materials in the body of the chamber. Pressurised xenon is the most useful form of "gas only" photon-electron convertor and has been used successfully in a gamma camera for the detection of gamma rays at energies below 100 keV. This camera has been developed specifically for high-count-rate first-pass cardiac imaging. This high-pressure xenon gas MWPC is the key to a highly competitive system which can outperform scintillator-based systems. The count rate performance is close to a million counts per second and the intrinsic spatial resolution is better than the best scintillator-based camera. The MWPC camera produces quantitative ejection fraction information of the highest quality. The detection of higher energy gamma rays has proved more problematical, needing a solid photon-electron convertor to be incorporated into the chamber. Several groups have been working on this problem with modest success so far. The only clinical detectors have been developed for positron emission tomography, where thin lead or lead-glass can provide an acceptable convertor for 511 keV photons. Two MWPC positron cameras have been evaluated clinically and one is now in routine use in clinical oncology. The problems of detection efficiency have not been solved by these detectors although reliability and large-area PET imaging have been proven.(ABSTRACT TRUNCATED AT 400 WORDS)

Gamma Cameras↗

Interaction of nucleoside analogues with the sodium-nucleoside transport system in brush border membrane vesicles from human kidney.

The therapeutic efficacy of nucleosides and nucleoside analogues as antitumor, antiviral, antiparasitic, and antiarrhythmic agents has been well documented. Pharmacokinetic studies suggest that many of these compounds are actively transported in the kidney. The goal of this study was to determine if therapeutically relevant nucleosides or analogues interact with the recently characterized Na(+)-driven nucleoside transport system of the brush border membrane of the human kidney. Brush border membrane vesicles (BBMV) were prepared from human kidney by divalent cation precipitation and differential centrifugation. The initial Na(+)-driven 3H-uridine uptake into vesicles was determined by rapid filtration. The effect of several naturally occurring nucleosides (cytidine, thymidine, adenosine), a pyrimidine base (uracil), a nucleotide (UMP), and several synthetic nucleoside analogues [zidovudine (AZT), cytarabine (Ara-C), and dideoxycytidine (ddC)] on Na(+)-uridine transport was determined. At a concentration of 100 microM the naturally occurring nucleosides, uracil, and UMP significantly inhibited Na(+)-uridine transport, whereas the three synthetic nucleoside analogues did not. Adenosine competitively inhibited Na(+)-uridine uptake with a Ki of 26.4 microM (determined by constructing a Dixon plot). These data suggest that naturally occurring nucleosides are substrates of the Na(+)-nucleoside transport system in the renal brush border membrane, whereas synthetic nucleoside analogues with modifications on the ribose ring are not. The Ki of adenosine is higher than clinically observed concentrations and suggests that the system may play a physiologic role in the disposition of this nucleoside.

Adenosine↗

Stereoselective interactions of organic cations with the organic cation transporter in OK cells.

Recent studies have suggested that certain organic cations, such as pindolol and the diastereomers, quinine and quinidine, may be stereoselectively secreted by the kidney in humans. The goal of this study was to determine if the enantiomers of pindolol, verapamil, and disopyramide and the diastereomers, quinine and quinidine, interact stereoselectively with the organic cation transporter in the brush border membrane of the opossum kidney cell line. All organic cations tested inhibited the uptake of tetraethylammonium (TEA). The IC50 values (mean +/- SD) were as follows: quinine (17 +/- 2 microM). quinidine (51 +/- 13 microM), S-(-)-pindolol (23 +/- 4 microM), R-(+)-pindolol (30 +/- 4 microM), S-(-)-verapamil (0.4 +/- 0.04 microM), R-(+)-verapamil (7 +/- 2 microM), R-(-)-disopyramide (27 +/- 4 microM), and S-(+)-disopyramide (66 +/- 12 microM). Each individual organic cation pair showed significant stereoselective differences in their IC50 values, with quinine, S-(-)-pindolol, S-(-)-verapamil, and R-(-)-disopyramide being the more potent species. Both enantiomers of pindolol, quinine, and quinidine appear to exhibit simple competitive inhibition of TEA uptake based upon a derived slope similar to 1.0, using a sigmoidal inhibition model. The enantiomers of verapamil and disopyramide exhibited a slope of much less than 1.0, suggesting a more complex interaction of these organic cations with the TEA transporter. Our results suggest that organic cations stereoselectively interact with the organic cation transporter in the brush border membrane of OK cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Nucleoside transport in brush border membrane vesicles from human kidney.

The goal of this study was to elucidate the mechanisms of nucleoside transport in the brush border membrane of the human kidney. [3H]Uridine was transported into brush border membrane vesicles (BBMV) from human kidney via Na(+)-independent and Na(+)-dependent processes. The Na(+)-dependent transport was saturable (Km = 4.76 +/- 0.39 microM; Vmax = 6.42 +/- 0.17 pmol/mg proteins per s) and was trans-stimulated by unlabeled uridine. Structural analogs of uridine (100 microM), 2'-deoxyuridine (2-dU) and dideoxyuridine (ddU), significantly inhibited Na(+)-uridine uptake into BBMV. Previous studies have suggested that Na(+)-nucleoside co-transport occurs via two major systems (Vijayalakshmi et al. (1988) J. Biol. Chem. 263, 19419-19423). One system (cit) is generally pyrimidine-selective; thymidine serves as a model substrate. The other system (cif) is generally purine-selective; formycin B serves as a model substrate. Uridine and adenosine are substrates of both systems. Thymidine and cytidine (100 microM), but not formycin B (100 microM) inhibited Na(+)-uridine uptake. In addition, [3H]thymidine exhibited an Na(+)-driven overshoot phenomenon whereas [3H]formycin B did not. Na(+)-thymidine uptake was inhibited by (100 microM) adenosine, uridine, guanosine, but not by formycin B and inosine. Further studies demonstrated that guanosine trans-stimulated thymidine uptake suggesting that guanosine and thymidine share a common transporter in the human renal BBMV. A different pattern was identified in BBMV from the rabbit kidney where both [3H]thymidine and [3H]formycin B as well as [3H]uridine exhibited a transient Na(+)-driven overshoot phenomenon. Collectively, these data suggest that in rabbit renal BBMV both cif and cit systems are present whereas in human renal BBMV, there appears to be a single concentrative Na(+)-nucleoside cotransport system that interacts with uridine, cytidine, thymidine, adenosine and guanosine but not with formycin B and inosine. The system is similar to the previously described cit system except that guanosine is also a substrate.

Animals↗

Inhibition of N-linked glycosylation affects organic cation transport across the brush border membrane of opossum kidney (OK) cells.

Many organic cations are transported across the apical membrane of the proximal tubule by specific saturable mechanisms. The goal of this study was to determine if the transporter for tetraethylammonium (TEA) in the brush border membrane of an established opossum kidney (OK) cell line is glycosylated and to elucidate the function of this glycosylation. The uptake of TEA was determined in OK cell monolayers treated with tunicamycin (TM), a compound that prevents synthesis of the core oligosaccharide precursor molecules. TM exposure significantly decreased the incorporation of [3H]mannose in OK cell proteins and significantly reduced TEA uptake in a time and a concentration dependent manner. No effect of TM exposure on cellular protein synthesis, DNA content, cell viability, or on [3H]proline uptake was observed. The transport of TEA in control cells was characterized by a Km of 26.9 +/- 16.4 microM and a Vmax of 378 +/- 39 pmol/mg of protein/min. TM treatment (1 microgram/ml for 21 h) significantly increased the Km by over 4-fold to 111.5 +/- 18.4 microM while not affecting the Vmax. The apparent KI values of other organic cations known to interact with this transport system were also significantly increased by TM exposure. Estimated KI values of N1-methylnicotinamide, cimetidine, and mepiperphenidol increased by 6-fold, 4-fold, and 2-fold, respectively, after exposure of OK cells to TM. An increased KI for protons was also observed. Additional inhibitors of the N-linked glycosylation pathway, castanospermine, deoxynojirimycin, and deoxymannojirimycin significantly decreased TEA transport, whereas swainsonine had no effect. Our results suggest that the organic cation transporter is glycosylated. The N-linked oligosaccharide side chain appears to be of the hybrid type, and it either directly or indirectly affects the binding site of the transporter for both organic cations and protons. This is the first report describing the importance of glycosylation in the function of the organic cation transporter in the apical membrane of OK cells.

Animals↗

Development of a high performance zinc-62/copper-62 radionuclide generator for positron emission tomography.

Clinical utilisation of positron emission tomography could be enhanced by the availability of short-lived radionuclides derived from generator systems. The zinc-62/copper-62 combination is one such system which could be used as a source for a number of copper-62 radiopharmaceuticals. We have developed and optimised a high activity (5.6 GBq, 150 mCi) zinc-62/copper-62 generator to provide 62Cu in a form that is suitable for direct labelling of pyruvaldehyde-bis-(N4-methylthiosemicarbazone)-copper(II), Cu(PTSM). The distribution coefficients of Zn(II) and Cu(II) between anion-exchange resin and various hydrochloric acid/organic solvent mixtures were measured. Based on these measurements a generator eluent of 0.3 M HCl/40% ethanol provided 62Cu in greater than 90% yield in a 3-ml volume. A very low 62Zn breakthrough of less than 3 x 10(-7)% was achieved. Copper-PTSM was successfully labelled with the no-carrier-added 62Cu eluent directly from the generator with 94% radiochemical yield.

Copper↗

Quantitative analysis of a reconstruction method for fully three-dimensional PET.

The major advantage of positron emission tomography (PET) using large area planar detectors over scintillator-based commercial ring systems is the potentially larger (by a factor of two or three) axial field-of-view (FOV). However, to achieve the space invariance of the point spread function necessary for Fourier filtering a polar angle rejection criterion is applied to the data during backprojection resulting in a trade-off between FOV size and sensitivity. A new algorithm due to Defrise and co-workers developed for list-mode data overcomes this problem with a solution involving the division of the image into several subregions. A comparison between the existing backprojection-then-filter algorithm and the new method (with three subregions) has been made using both simulated and real data collected from the MUP-PET positron camera. Signal-to-noise analysis reveals that improvements of up to a factor of 1.4 are possible resulting from an increased data usage of up to a factor of 2.5 depending on the axial extent of the imaged object. Quantitation is also improved.

Algorithms↗

Monte Carlo modelling of the performance of a rotating slit-collimator for improved planar gamma-camera imaging.

Planar imaging with a gamma camera is currently limited by the performance of the collimator. Spatial resolution and sensitivity trade off against each other; it is not possible with conventional parallel-hole collimation to have high geometric sensitivity and at the same time excellent spatial resolution unless field-of-view is sacrificed by using fan- or cone-beam collimators. We propose a rotating slit-collimator which collects one-dimensional projections from which the planar image may be reconstructed by the theory of computed tomography. The performance of such a collimator is modelled by Monte Carlo methods and images are reconstructed by a convolution and backprojection technique. The performance is compared with that of a conventional parallel-hole collimator and it is shown that higher spatial resolution with increased sensitivity is possible with the slit-collimator. For a point source a spatial resolution of some 6 mm at a distance of 100 mm from the collimator with a x7 sensitivity compared with a parallel-hole collimator was achieved. Applications to bone scintigraphy are modelled and an improved performance in hot-spot imaging is demonstrated. The expected performance in cold-spot imaging is analytically investigated. The slit-collimator is not expected to improve cold-spot imaging. Practical design considerations are discussed.

Equipment Design↗

Treatment planning for 131I-mIBG radiotherapy of neural crest tumours using 124I-mIBG positron emission tomography.

Patients designated to receive 131I-meta-iodobenzylguanadine (mIBG) for the treatment of neural crest tumours have been scanned with 124I-mIBG using the MUP-PET positron camera. Uptake was detected in tumour sites in lung, liver and abdomen. The tomographic images produced have allowed estimates to be made of the concentration of mIBG in both tumour and normal tissue. From these data it is possible to predict the radiation doses that would be achieved using therapy levels (up to 11 GBq) of 131I-mIBG. The levels of tumour uptake are between 0.5 and 2.0 kBq/g indicating that the radiation doses to tumour would be in the range 3 Gy to 7.5 Gy.

3-Iodobenzylguanidine↗

c-erbB2 protein overexpression in breast cancer as a target for PET using iodine-124-labeled monoclonal antibodies.

ICR 12, one of a panel of rat monoclonal antibodies recognizing the external domain of the human c-erb B2 proto-oncogene product, (Styles, 1990) was chosen as a candidate for radiolabeling with 124I for positron emission tomography of selected patients with breast cancer. By using N-bromosuccinimide (NBS), optimal labeling conditions were established using 125I. The labeling efficiency was determined using instant thin-layer chromatography (ITLC) and gel filtration (HPLC). The antibody was then labeled with the positron emitter 124I, and a labeling efficiency of 96% and immunoreactivity of 80%-90% was obtained. The product was stable, with less than 5% of the radiolabel being eluted after six days storage in plasma at 37 degrees C. Immunolocalization studies were performed in athymic mice bearing human breast carcinoma xenografts overexpressing the c-erb B2 gene product using as controls 125I labeled isotype-matched rat antibody, and antigen-negative tumors. Good uptake of 124I-labeled ICR12 was obtained in c-erb B2 expressing tumors (up to 12% injected dose per gram at intervals up to 120 hr), with localization indices of 3.4-6.2. Tumor xenografts of 6 mm diameter were successfully imaged with high resolution at 24, 48 and 120 hr using the RMH/ICR MUP-PET camera. We suggest that 124I-labeled ICR12 is a suitable agent to image and quantify immunolocalization in patients whose tumors overexpress the c-erb B2 proto-oncogene product.

Animals↗

Transport of organic cations by a renal epithelial cell line (OK).

The goal of this study was to determine the mechanisms involved in the transport of the organic cation, tetraethylammonium (TEA), across the apical membrane of OK cells. [14C]TEA accumulated in OK cell monolayers reaching equilibrium in 2 h. The uptake of [14C]TEA at equilibrium was dependent upon temperature and was inhibited by sodium azide and by various organic cations, including N1-methylnicotinamide (NMN), mepiperphenidol, and cimetidine but not by the organic anion, p-aminohippuric acid. The initial uptake of [14C]TEA was characterized by a saturable process. The mean +/- S.D. Km was 27.8 +/- 2.6 microM and the Vmax was 414 +/- 26.5 pmol/mg protein/min. Both an accelerated efflux and influx of [14C]TEA in the presence of a trans-gradient of unlabeled TEA and NMN was observed, whereas a deaccelerated influx and efflux was observed in the presence of a trans-gradient of mepiperphenidol. The mechanism of interaction between NMN and TEA was examined. NMN significantly increased the apparent Km (mean +/- S.D.) of TEA to 82.8 +/- 16.4 microM (p less than 0.001), whereas the Vmax (mean +/- S.D.) was only slightly affected (478 +/- 72 pmol/mg protein/min) suggesting a competitive inhibition. The stimulatory effect of trans-gradients of NMN on TEA transport was due to an increase in the Vmax of TEA suggesting that NMN trans-stimulates TEA transport by increasing the turnover rate of the exchanger. In the presence of an inwardly directed proton gradient, the efflux at 30 s of [14C]TEA from the OK cell monolayers was significantly accelerated (p less than 0.05). Studies with the pH-sensitive fluorescent probe, 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein, suggested that TEA could drive the countertransport of protons. In apical membrane vesicles prepared from OK cells, the uptake of [3H]NMN exhibited an apparent "overshoot phenomenon" in the presence of an initial outwardly directed proton gradient. Protons competitively inhibited TEA uptake suggesting that the proton/organic cation and the organic cation/organic cation self exchange mechanism are the same mechanism. This is the first report describing both TEA self-exchange and proton/TEA exchange in the apical membrane of a continuous cell line. OK cells are an excellent model for the study of organic cation transport across the apical membrane.

Animals↗