Preparation of a radionuclide/gel formulation for localised radiotherapy to a wide range of organs and tissues.

Localised radiotherapy by instillation of radiolabeled particles is being used to treat rheumatoid arthritis and certain tumors. Such therapy is limited to organs and tissues capable of retaining the radioactive compound until the radioactivity is sufficiently low, and the leakage to other parts of the body is no longer unacceptable. In this study, radiolabeled particles, i.e. 90Y-silica colloid particles, were encapsulated in calcium alginate gels, and the leakage of radioactivity from the gels was monitored. The purpose of the study was to develop a formulation suitable for the localised delivery of radiation therapy to a wide range of organs and tissues. An injectable gel formulation was developed, liberating only small amounts of radioactivity into the surrounding medium. The formulation is a viscous liquid at room temperature and forms a gel on heating to normal body temperature. Thus, it should be suitable for the localised delivery of radiolabeled particles to a wide range of organs and tissues. The study also includes a formulation exhibiting time-dependent gelation. However, this formulation was not found to be suitable for the purpose.

Blood flow in six human melanoma xenograft lines with different growth characteristics.

Blood flow in six human melanoma xenograft lines grown s.c. in BALB/c-nu/nu mice was studied and analyzed in relation to tumor growth characteristics. Two different methods were used to measure blood flow, i.e., uptake of 86Rb and clearance of 133Xe. The percentage of the injected 86Rb taken up per g of tumor tissue and the 133Xe clearance rate were used as parameters for blood flow. The results achieved with these two methods were consistent. Blood flow differed significantly among individual tumors of the same line, even for tumors of similar size. All lines showed a decrease in blood flow with increasing tumor volume. This was due to an increase in necrotic fraction as well as a decrease in blood supply per viable tumor cell. Blood flow also differed significantly among the xenograft lines. All lines showed a lower blood flow than the kidney, spleen, liver, and foot. The blood flow was generally lower in the xenograft lines than in the EMT6 and Lewis lung murine tumor lines. There was no correlation between tumor blood flow and volumetric growth rate. The xenograft lines could be divided into two distinct groups of three lines each with respect to blood supply per viable tumor cell. The three lines showing a high blood supply also showed a high fraction of cells in S phase (23-31%), whereas the three lines showing a low blood supply had a low fraction of S-phase cells (11-13%). Thus, blood supply per viable tumor cell was probably decisive for the cell proliferation activity in the tumors. Moreover, necrotic fraction increased with increasing tumor volume, and the magnitude of this increase was largest for the three lines showing the lowest blood supply per viable tumor cell. These observations were possibly consequences of basic differences in vascular architecture between the two groups of xenograft lines.

Internal radionuclide therapy of primary osteosarcoma in dogs, using 153Sm-ethylene-diamino-tetramethylene-phosphonate (EDTMP).

Fifteen dogs were referred because of a spontaneous bone tumor, lameness, and local pain. The osteosarcoma diagnosis was established by clinical examination, X-ray, bone scintigraphy, and histological examination of biopsy material. The tumors were located in the extremities (n = 12), scapula (n = 1), maxilla (n = 1), and the frontal bone (n = 1). The dogs were given one to four i.v. injections of 153Sm-labeled ethylene-diamino-tetramethylene-phosphonate (153Sm-EDTMP; 36-57 MBq/kg body weight). Three dogs had surgery in addition to the radionuclide treatment. Platelet and WBC counts showed a moderate and transient decrease. No other toxicity was observed. Average tumor doses after a single injection were approximately 20 Gy, considerably higher in some areas because of inhomogeneous uptake. Macroscopically distant metastases were detected in seven dogs at autopsy. One dog died from an intercurrent disease, free of cancer, 5 months after the radionuclide treatment. None of the dogs was cured. The median and mean survival times from the first treatment to death or euthanasia were 150 and 252 days, respectively. Nine of the dogs had obvious pain relief, and five of them seemed pain-free: one for 20 months and one for 48 months. It is concluded that high tumor doses may be deposited in dog osteosarcomas by 153Sm-EDTMP, and the ratio between tumor dose and the dose to surrounding tissues is favorable. The treatment gives pain relief and in some cases tumor growth delay. In combination with surgery, 153Sm-EDTMP may prolong life significantly and possibly cure the disease because the development of metastases are seemingly postponed. No serious side effects were observed.

Immunoscintigraphy of bone sarcomas--results in 5 patients.

The feasibility of using the murine monoclonal antibody, TP-1, for clinical immunoscintigraphy was examined in a pilot study involving 5 patients with bone sarcomas. 131I-labelled F(ab')2 antibody fragments were injected in doses of 0.8-1.0 mg (90-130 MBq), and the accumulation of radioactivity was examined by scintigraphy, and assessed by direct measurements on biopsied tumour and normal tissue. One osteosarcoma patient had a primary tumour in the femur, whereas the other 4 had single lung metastases detected by other diagnostic methods. Immunoscintigraphy of the femoral primary was optimally visualised after 22 h. In 2 patients, the method failed to detect lung metastasis, in 1 of the cases possibly related to less than optimal methodological conditions. In 2 other patients, increased accumulation of radioactivity indicated one and three lung tumours, in addition to the single metastasis observed by X-ray and CT scanning, tumours that were later confirmed and removed surgically. The concentration of radioactivity in tumour and normal tissues 44-72 h after antibody injection could be measured in 4 patients. The tumour to blood ratios were in the range of 1.2-4.2, compared to 0.1-0.8 for various normal tissues. The results indicate that immunoscintigraphy with TP-1 antibody fragments have a potential for early detection of lung metastases in patients with bone sarcoma.

Evaluation of labelled monoclonal antibodies by simultaneous estimation of the association constant, the immunoreactive fraction, and the number of effective binding sites on the specific target.

The reaction between a labelled monoclonal antibody (MoAb) and its specific target is characterised by three parameters: the association constant (Ka) of the labelled MoAb, the number (N) of effective binding sites on the specific target, and the immunoreactive fraction (F) of the labelled MoAb preparation. Immunological binding parameters are usually estimated graphically, by fitting the experimental data to linear equations derived from the first order law of mass action (FLMA) at equilibrium. However, only two parameters can be estimated simultaneously in a two-dimensional plot. Consequently, graphical estimation of Ka, F and N must be performed stepwise, using at least two different plots. The three parameters are interdependent, and therefore a stepwise estimation procedure might give suboptimal results. In order to investigate whether this is a problem of practical significance in the evaluation of labelled MoAbs, a computerised iterative nonlinear least squares (INLSQ) method was applied to estimate the three parameters simultaneously. The binding parameters in reactions between different 125I-labelled MoAbs and different types of targets were significantly changed when a graphical procedure was replaced by the computerised INLSQ method, and the goodness of fit to FLMA was improved. Hence, the nonlinear least squares method is the preferred procedure. Values were affected when only a subset of the data was included in the estimation procedure, indicating some heterogeneity even in these presumably homogeneous MoAb reactions. The radiolabelling procedure was presumed to be the main reason for this heterogeneity.

Migration of 99mTc-labelled syngeneic lymphocytes in the rat. Biological and theoretical models predict radiation damage and poor scintigraphic detectability.

The possibility of obtaining useful scintigrams of secondary lymphoid organs after infusion of syngeneic lymphocytes labelled with technetium-99m (99mTc) was explored in a rat model. Thoracic duct lymphocyte (TDL) accumulation in various organs was measured with both 99mTc and 51Cr labelled cells, the latter processed with a method that has been shown not to damage lymphocytes. 99mTc labelled TDL did not localize properly in the lymph nodes and spleen. We could not visualize lymph nodes in scintigrams, neither could we demonstrate any difference between normal and hyperplastic spleens. Our conclusion is that radiation from the 99mTc label readily influences lymphocyte migration so that useful scintigraphy in rats and other small experimental animals becomes impossible. This was supported by results from culture experiments with 99mTc labelled, radiosensitive mouse haemopoietic progenitor cells. Theoretical considerations, including the calculations of lymphocyte self-irradiation and signal/noise ratios during scintigraphy of rat tissues, supported our conclusion that scintigraphy in small animals, to disclose the physiological migration of lymphocytes, may be impossible with the present sensitivity of gamma cameras.

Determination of 3D dose distribution from intracavitary brachytherapy of cervical cancer by MRI of irradiated ferrous sulphate gel.

BACKGROUND AND PURPOSE: MRI ferrous sulphate gel dosimetry has proven to be a valuable method for assessment of dose delivered in teletherapy. The intention of this study was to investigate ferrous sulphate gel as a possible dosimeter for intracavitary brachytherapy applications. MATERIALS AND METHODS: A plastic duplicate of a cervix ring applicator set was submerged in Fe2(+)-infused gelatin gel. The gel was subsequently irradiated by a stepwise moving 192Ir source, using automatic afterloading equipment (Microselectron, Nucletron-Oldelft International BV, Veenendaal, The Netherlands). A 3D dose distribution was reconstructed from MR images of the gel. RESULTS: The gel dose measurements were found to be of the same accuracy as TLD measurements. Isodose curves based on gel dosimetry and isodose curves computed by a dose planning system were generally less than 2 mm apart. MR images showing the position of the applicator set in a patient during treatment were used to obtain images describing patient anatomy in the sagittal and ring planes of the applicator set. Isodose curves computed from the gel measurements were then superimposed on these images, illustrating one possible way of linking dosimetrical and anatomical data. CONCLUSIONS: Our study shows that MRI ferrous sulphate gel dosimetry is a useful tool for studies of dose distributions in brachytherapy and their relation to critical organs. Possible improvements of the gel dosimeter lie in reducing the diffusion of ferric ions and increasing the radiation sensitivity of the gel.

Attitude of the Norwegian population to drug policy and drug-offences.

A national survey on people's conceptions of various intoxicants and their attitudes towards such substances shows a high degree of support in Norway for the current very restrictive drug policy. Only 6% were in favour of a more liberal practice with regard to use of cannabis. The attitudes had changed little from 1968, when a similar study was carried out. Even a majority of those who reported having used cannabis themselves said that all use should be prohibited. A comparison of the crime of possessing quite a small quantity of cannabis with other commonplace violations of the law showed that the drug offence was considered a serious crime. Although the penalties for drug offences have been raised dramatically several times since the end of the 1960s, a majority still said that the punishment prescribed by the Norwegian law for being involved with drugs is too mild.

An iterative computer algorithm for optimization of radionuclide subtraction studies.

A new algorithm for off-line computer optimization of radionuclide subtraction studies is presented. Within the digitized image, any region of interest may be chosen for study. No prior knowledge is required concerning the position and extent of the principal and interfering objects, nor concerning their image intensities. Tests show that even when statistical fluctuations are relatively large, the intensity quotient calculated by this algorithm may be used to estimate a uniform background and correct for its contribution. The effect of smoothing the images prior to the use of the algorithm has been investigated. The method has also been used for pancreas imaging and one example of this application is presented.

Methods for separation of contributions from two radionuclides in autoradiography with a silicon strip detector.

Two methods have been developed for the separation of contributions from two different nuclides in an autoradiography picture. Both approaches, a modified least squares (LS) and a maximum likelihood (ML) algorithm, are based on the position and energy information available from a digital detector. Tests and comparisons, using artificially as well as measured data, demonstrate that the ML approach performs slightly better, but is much more computationally demanding than the LS method.

Measurement of the ferric diffusion coefficient in agarose and gelatine gels by utilization of the evolution of a radiation induced edge as reflected in relaxation rate images.

A method has been developed to determine the diffusion coefficients of ferric ions in ferrous sulphate doped gels. A radiation induced edge was created in the gel, and two spin-echo sequences were used to acquire a pair of images of the gel at different points of time. For each of these image pairs, a longitudinal relaxation rate image was derived. From profiles through these images, the standard deviations of the Gaussian functions that characterize diffusion were determined. These data provided the basis for the determination of the ferric diffusion coefficients by two different methods. Simulations indicate that the use of single spin-echo images in this procedure may in some cases lead to a significant underestimation of the diffusion coefficient. The technique was applied to different agarose and gelatine gels that were prepared, irradiated and imaged simultaneously. The results indicate that the diffusion coefficient is lower in a gelatine gel than in an agarose gel. Addition of xylenol orange to a gelatine gel lowers the diffusion coefficient from 1.45 to 0.81 mm2 h-1, at the cost of significantly lower Rl sensitivity. The addition of benzoic acid to the latter gel did not increase the Rl sensitivity.

Methods for fully automated verification of patient set-up in external beam radiotherapy with polygon shaped fields.

Methods have been developed to perform fully automated comparisons of the radiotherapy simulator and portal images in the most common cases where the field edges consist of straight lines. The field defining wires or rods in the simulator image, and the edges of the portal image, are localized by means of a truncated Radon transform. Edges are enhanced with the use of a generalized Laplacian operator. From the detected field outlines, a geometrical mapping function is determined that rotates, scales, and translates one image with respect to the other. A subsequent match of field shapes is executed. If satisfactory agreement is established, the anatomical structures of the simulator and portal images are compared by correlating a new pair of images that only contain the intensity ridges representing bone outlines. The correlation determines the rotation and translation that must be applied to align the anatomical structures. With the simulator image already processed, the remaining automatic processing takes approximately 2 min on a SUN Sparcstation 2. By use of a priori knowledge of the fields, the computation time needed after acquisition of the portal image may be reduced to about 40 s for 512 x 512 images and about 12 s for 256 x 256 images.

Radionuclide therapy with bone-seeking compounds: Monte Carlo calculations of dose-volume histograms for bone marrow in trabecular bone.

The purpose of the present work was to investigate how haematopoietic stem cell survival is affected by the differences in the dose distribution that arise from different radionuclides contained in bone-seeking radiopharmaceuticals. This was carried out in three steps: (a) calculations of representative dose distributions in individual bone marrow cavities that are irradiated by sources of 89Sr, 186Re, 117mSn or 153Sm, uniformly distributed on the bone surfaces; (b) assessment of the corresponding haematopoietic stem cell survival and (c) a comparison of these results with results obtained using the assumption of a uniform dose distribution. Two different idealized models of the geometry of trabecular bone were formulated, each consisting of an infinite array of identical elements. Monte Carlo simulations were used to generate dose-volume histograms that were used to assess haematopoietic stem cell survival with two different assumptions about spatial cell distributions. Compared with a homogeneous dose distribution, the estimated cell survival was markedly higher for 117mSn and 153Sm, and only slightly different for 89Sr and 186Re. The quantitative results differed between the two geometric models and the assumptions about spatial cell distribution, but the trends were the same. The results imply that it is necessary to include dose distributions for individual bone marrow cavities in considerations concerning bone marrow toxicity.

Measurement of dynamic wedge angles and beam profiles by means of MRI ferrous sulphate gel dosimetry.

The purpose of this study is to examine the possible value of measuring the dose distribution in dynamic wedge photon beams using ferrous sulphate gel phantoms analysed by MRI. The wedge angles and dose profiles were measured for a field size of 70 x 70 mm2 and for dynamic wedge angles of 15 degrees, 30 degrees, 45 degrees and 60 degrees using a 15 MV photon beam generated from a Clinac 2100 CD (Varian). The dose profiles obtained from MRI ferrous sulphate gel were in good agreement with the dose measurements performed with a diode detector array. Also, the wedge angles determined from the MRI ferrous sulphate gel agreed well with the values obtained by using film dosimetry and with calculations by use of TMS (treatment planning system) (Helax, Uppsala, Sweden). The study demonstrated that MRI ferrous sulphate gel dosimetry is an adequate tool for measurements of some beam characteristics of dynamic radiation fields.

Dose distribution measurements by MRI of a phantom containing lung tissue equivalent compartments made of ferrous sulphate gel.

Gel dosimetry based on magnetic resonance imaging (MRI) has previously been shown to provide verification of calculated dose distributions in soft tissue equivalent homogeneous phantoms. This study demonstrates how measurements of dose distribution can also be achieved in a phantom containing porous, lung-equivalent, Fricke gel. A phantom was made of Fe2+ infused low-density gel and conventional ferrous sulphate gel, filled in separate compartments in a Perspex container. Absorbed dose measurements were accomplished by MR imaging and by calibrating the proton spin-lattice relaxation rate (R1) versus absorbed dose by means of TLD measurements. This study shows that the production of lung-equivalent low-density (LD) dosimeter gel (mean CT number of -610 HU) is feasible. The MR signal detected in the LD gel dosimeter was substantially more noisy (i.e. displayed larger random fluctuations) than the signal from conventional gel, as expected. A deviation between calculated (TPS) and measured dose of about 3% (6 MV) and 4-7% (15 MV) was found in the LD region of the phantom. These results correspond well with data from other studies of dose distribution in lung-equivalent phantoms. The Fe2+ infused LD gel therefore seems suitable for measurement of absorbed dose distribution in phantoms that contain lung tissue compartments.

Measurement of the extracellular volume of human melanoma xenografts by contrast enhanced magnetic resonance imaging.

The magnitude of the extracellular volume fraction (ECV) of tumors is of importance for the transport of macromolecular therapeutic agents from the vessel wall to the tumor cells. The aim of this study was to develop a method for measurement of tumor ECV by contrast enhanced MRI. Tumors of two human amelanotic melanoma xenograft lines (A-07 and R-18) grown intradermally in Balb/c nu/nu mice were used as model system, and muscle tissue was used as control. The renal arteries of the mice were ligated prior to i.v. administration of Gd-DTPA, and an MRI protocol for calculating Gd-DTPA concentration in tissue was followed. ECV was calculated from the Gd-DTPA concentrations in the tissue and in a plasma sample. In muscle tissue, the concentration reached a constant level after 1 min and the ECV was calculated to be 0.12 (+/- 0.01), consistent with values reported in the literature. Individual tumors showed large differences in the uptake of Gd-DTPA. The Gd-DTPA concentration in the tissue at 40 min after the Gd-DTPA administration was used to calculate tumor ECV. The ECV was found to differ significantly among regions of individual tumors and among individual tumors. The ECV ranged from 0.075 to 0.33 for A-07 tumors and from 0.016 to 0.097 for R-18 tumors. The intra- and intertumor heterogeneity in ECV was confirmed by histologic findings, showing that contrast enhanced MRI is suitable for non-invasive studies of the ECV in experimental tumors without necrosis.

An anthropomorphic phantom for receiver operating characteristic studies in CT imaging of liver lesions.

The purpose of the study was to develop a methodology that allowed quantitative assessment of image quality in CT and its relationship to dose. An anthropomorphic phantom was designed for use in receiver operating characteristic (ROC) studies of the detectability of liver lesions with CT. The lesions were simulated by different mixtures of glycerol and water that were filled into holes of different diameters in a liver tissue substitute. A pilot study was carried out on five different scanners that were operated at various exposure settings. A positive correlation was demonstrated for each of the scanners between the weighted CT dose index (CTDIW) and the area under the ROC curve. For the exposure settings used in the clinical routine in the five laboratories, the CTDIW ranged from 15 to 31 mGy. Three observers who read the corresponding set of five phantom images agreed, as judged from the areas under the ROC curves, that there was a marked difference in quality between the three best images and the other two. The two newest scanners in the study had the lowest CTDIW, and at the same time the best ROC results. The phantom and the ROC methodology may, with a set of suggested improvements, be used for comparison of the performance in different CT laboratories, and to establish the dose needed to ensure adequate image quality for a particular scanner.

Whole-body distribution of radioactivity after intraperitoneal administration of 32P colloids.

The whole-body distribution of radioactivity after intraperitoneal instillation of 32P-labelled chromic hydroxide particles has been studied in patients operated for early-stage ovarian cancer. Gamma-camera imaging of the abdominal 32P-distribution revealed that the administration procedure was critical for obtaining a homogeneous plating of the radiocolloids on the serosal surface. Dose calculations based on a uniform distribution of 32P in a capillary layer covering the intraperitoneal surface gave an estimated tissue surface dose of about 30 Gy per 370 MBq of 32P administered. The amount of 32P in peripheral blood increased for seven days after instillation followed by a continuous decrease. Bone marrow concentration was from two to five times as high as that in blood, but the total amounts were too small to give significant radiation doses. Gel chromatography showed that 33% of the activity in blood consisted of high molecular weight material, probably colloids. The remainder of the activity (67%) was attached to material of very low molecular weight, appearing as a consequence of physiological degradation of the colloids.

Predicting detectability in radioguided surgery: a study based on physical characterization of the probe and on tissue uptake ratios of 125I-, 153Sm- and 165Er-labelled radiopharmaceuticals.

We performed measurements of the sensitivity in water of the radioguided surgery system, Neoprobe 1000. Point sources of 125I, 153Sm and 165Er were measured to a geometric accuracy of 0.1 mm. These measurements were performed with the detector uncollimated and with two different collimators; the results were used to construct three-dimensional sensitivity matrices from which isosensitivity curves could be derived. The matrices were used to simulate the reliability of detecting tumours of various sizes, at various depths, and with variable uptake ratios and activity levels of the three radionuclides investigated. Simulations showed improved tumour detection with a conical collimator, demonstrating that collimator design is important. To minimize the radiation dose during diagnostic work-up, a novel bone-seeking radiopharmaceutical, 165Er-EDTMP, was developed and tested. It showed rapid bone localization, especially in growth zones, and rapid clearance from blood and non-osseous tissues. Its biodistribution was similar to that of 153Sm-EDTMP. Based on these results and previous clinical data, the simulations predicted that lung metastases with a radius of 1 mm might be reliably detected with the Neoprobe 1000 system, if equipped with a suitable collimator.

Relationship between sharpness and noise in CT images reconstructed with different kernels.

The sharpness expressed as the full-width at half-maximum of the line spread function (LSF) was derived for different CT scanners and reconstruction kernels. The LSFs were calculated from images of a 0.28 mm tungsten bead and successfully fitted to cumulative Gaussians by means of probit plots. The corresponding image noise was measured in a homogeneous material. The investigation showed that the noise increases strongly for small improvements in sharpness. The method was reproducible and insensitive to small positional shifts of the phantom.