A retrospective analysis of catheter-based sources in intravascular brachytherapy.

PURPOSE: Coronary artery disease involves the deposition of plaque along the walls of a coronary artery leading to narrowed or blocked vessels (stenosis) and is one of the main causes of death in developed countries. Percutaneous transluminal coronary angioplasty (PTCA) is used to reverse stenosis. Restenosis (renarrowing) of the treated vessel is a major complication of PTCA. A metal mesh tube (stent) can be placed inside the vessel to prevent restenosis. Tissue stress incurred during PTCA and stenting can provoke neointimal cell proliferation leading to in-stent restenosis (ISR). Intravascular brachytherapy (IVBT), a form of internal radiotherapy, is used to treat ISR. Renewed interest in IVBT is being expressed as a treatment for patients with ISR in drug-eluting stents. Current treatment planning (TP) of IVBT is extremely limited and assumes human tissue can be approximated by water. The interactions of arterial plaque, guidewires, and the stent have been shown to attenuate radiation significantly but are ignored in TP. Other models have determined the degree of attenuation by each factor in isolation. For the first time, we create a model with several inhomogenities present to determine whether attenuation by multiple inhomogenities combines linearly or if a larger dose reduction than anticipated is realized. We are also able to evaluate a spatial distribution of dose around the source and in arterial walls. METHODS AND MATERIALS: A dosimetric analysis of two commercially available IVBT systems was performed in a Monte Carlo-based particle simulation (Geant4). Absorbed dose was calculated using a model of a human coronary artery with a calcified plaque and stent. Dose delivered in water was also calculated to evaluate the accuracy of a water approximation. RESULTS: Dose as a function of θ shows significant variation around IVBT sources. For the Guidant Galileo, dose is reduced by 20% behind stent struts and as much as 66% in a region occluded by the guidewire, plaque, and stent. For the Novoste Beta Cath device, delivered dose is reduced by 19% and 58%, respectively, in the same regions. CONCLUSIONS: Our findings show that the water approximation used in clinical practice to calculate dose is inaccurate when inhomogeneities are present. Methods proposed for calculating dose perturbations in IVBT may underestimate the magnitude of dose reduction. Increasing source dwell time seems unlikely to resolve dosimetric issues in IVBT. The effectiveness of currently existing ß-emitting devices may be reduced in patients with complex lesions at the treatment site. Investigation of new radioisotopes and off-centering devices should be considered to improve dose outcomes.

Dosimetry study of [I-131] and [I-125]- meta-iodobenz guanidine in a simulating model for neuroblastoma metastasis.

The physical properties of I-131 may be suboptimal for the delivery of therapeutic radiation to bone marrow metastases, which are common in the natural history of neuroblastoma. In vitro and preliminary clinical studies have implied improved efficacy of I-125 relative to I-131 in certain clinical situations, although areas of uncertainty remain regarding intratumoral dosimetry. This prompted our study using human neuroblastoma multicellular spheroids as a model of metastasis. 3D dose calculations were made using voxel-based Medical Internal Radiation Dosimetry (MIRD) and dose-point-kernel (DPK) techniques. Dose distributions for I-131 and I-125 labeled mIBG were calculated for spheroids (metastases) of various sizes from 0.01 cm to 3 cm diameter, and the relative dose delivered to the tumors was compared for the same limiting dose to the bone marrow. Based on the same data, arguments were advanced based upon the principles of tumor control probability (TCP) to emphasize the potential theoretical utility of I-125 over I-131 in specific clinical situations. I-125-mIBG can deliver a higher and more uniform dose to tumors compared to I-131 mIBG without increasing the dose to the bone marrow. Depending on the tumor size and biological half-life, the relative dose to tumors of less than 1 mm diameter can increase several-fold. TCP calculations indicate that tumor control increases with increasing administered activity, and that I-125 is more effective than I-131 for tumor diameters of 0.01 cm or less. This study suggests that I-125-mIBG is dosimetrically superior to I-131-mIBG therapy for small bone marrow metastases from neuroblastoma. It is logical to consider adding I-125-mIBG to I-131-mIBG in multi-modality therapy as these two isotopes could be complementary in terms of their cumulative dosimetry.

Immunology of Diabetes Society T-Cell Workshop: HLA class I tetramer-directed epitope validation initiative T-Cell Workshop Report-HLA Class I Tetramer Validation Initiative.

BACKGROUND: Identification of T-cell reactivity to ß-cell antigen epitopes is an important goal for studying pathogenesis and for designing and monitoring of immunotherapeutic interventions in type 1 diabetes (T1D). METHODS: We performed a multicentre validation of known human leukocyte antigen (HLA) class I CD8+ T-cell epitopes. To this end, peripheral blood T-cell responses were measured in 35 recently (<2 years) diagnosed HLA-A*02:01+ T1D patients using blind-coded HLA-A2 tetramers (TMrs) and pentamers (PMrs), encompassing two epitopes of preproinsulin (PPI; PPIA12-20 and PPIB10-18) and two epitopes of glutamic acid decarboxylase (GAD; GAD114-122 and GAD536-545). We also compared the readout of TMrs and PMrs with a CD8+ T-cell interferon-γ enzyme-linked immunospot assay. RESULTS: Despite the minute frequencies of autoreactive cells detected by TMrs/PMrs, most (73-77%) T1D patients had responses to one or more of the epitopes used. All four epitopes were recognized by T1D patients, with a prevalence ranging from 5 to 25%. TMrs and PMrs detected more positive responses to the ß-cell epitopes than CD8+ T-cell interferon-γ enzyme-linked immunospot. However, concordance between positive responses to TMrs and PMrs was limited. CONCLUSIONS: Using a multicentre blind-coded setup and three different T-cell assays, we have validated PPI and GAD epitopes as commonly recognized CD8+ T-cell targets in recently diagnosed T1D patients. Both TMrs and PMrs showed higher detection sensitivity than the CD8+ T-cell interferon-γ enzyme-linked immunospot assay. However, there are some important methodological issues that need to be addressed in using these sensitive techniques for detecting low frequency responses.

A dose-point-kernel model for a low energy gamma-emitting stent in a heterogeneous medium.

A computer dose model for a low energy gamma-emitting stent in a heterogeneous medium is described. The method is based on the Sievert model which is adapted to the dose-point-kernel (DPK) model to compute the dose distribution about filtered gamma sources (Sievert-DPK model). The new gamma stent model can take into account effects such as the metallic wire attenuation and the presence of dense calcified plaque in a stented artery. The Sievert-DPK model is tested against numerical simulations around cylindrical shell sources with dimensions comparable to those of a stent using a Monte Carlo transport code. For low energy gamma sources (Cs-131 and Pd-103), it is shown that the Sievert-DPK model is consistent with the Monte Carlo results to about 5%-10% for distances up to 5 mm from the cylindrical surface and 2.5 mm beyond the cylinder edges. These results indicate that the Sievert-DPK model may be useful to predict the dose in intravascular therapy applications for heterogeneous systems consisting of soft tissue, metal and dense plaque.

Dose model for a beta-emitting stent in a realistic artery consisting of soft tissue and plaque.

A model for the description of the near-field dose deposition from a 32p impregnated stent in an arterial system consisting of soft tissue and dense plaque is presented. The model is based on the scaling property of the dose-point-kernel (DPK) function which is extended to a heterogeneous medium consisting of a series of layers of different materials. It is shown that, for each point source originating from the stent surface, the DPK function for water can be scaled consistently along the path through the different layers of material to predict the dose at a given point in the heterogeneous medium. Radiochromic film dosimetry on actual 32p stents is used to test the new model. The experimental setup consists of a water-equivalent phantom in which a stent is deployed and on which a thin layer of polytetrafluoroethylene (PTFE) is deposited to simulate the presence of plaque. Layers of radiochromic films stacked over the phantom are used to measure the dose at distances varying from approximately 0.1 mm to approximately 3 mm from the stent surface with and without PTFE. It is shown that the proposed new DPK model for a heterogeneous medium agrees very well with the experimental data and that it compares favorably to the usual homogeneous DPK model. These results indicate that the new model can be used with confidence to predict the dose in a realistic artery in the presence of plaque.

Measurement of density and calcium in human atherosclerotic plaque and implications for arterial brachytherapy.

PURPOSE: To measure density of arterial plaque specimens for purposes of improving calculation of intravascular radiation dose. METHODS AND MATERIALS: In the described technique, the mass of the specimen submerged in water is compared with its mass in air. Thirty-three plaque specimens harvested from cadavers and subsequently histologically classified (18 coronary, 15 noncoronary) were subjected to density measurement, and were also assayed for calcium using inductively coupled plasma optical emission spectroscopy (ICPOES). A dose point kernel (DPK) computer model extended to heterogeneous media is used to determine delivered dose to tissues for stents labeled with 32P, 103Pd, and 131Cs, based on measured density values. RESULTS: Plaque specimens identified histologically as noncalcified (non-class VII) had an average density of 1.22 +/- 0.03 g/cm3 (n = 19). Plaque specimens identified as calcified (Class VII) had an average density of 1.45 +/- 0.06 g/cm3 (n = 13). Density of calcified portions of plaque may be even higher because plaque specimens are heterogeneous. Plaque density was found to be correlated with calcium weight percentage (R2 = 0.67) and histologic percent area calcification (R2 = 0.58). Significant variations in calculated dose were found according to isotope, plaque density, and plaque thickness. The assumption of an "all water density" dose model overestimates dose to tissues. For 1-mm thick calcified (class VII) plaque, computed dose to tissues (via DPK model) are decreased by 29%, 34%, and 15%, for 32P, 103Pd, and 131Cs stents, respectively, compared with an "all water density" assumption model, when density is taken into account. Similar decreases are expected for catheter-based brachytherapy systems using beta or low energy (< 100 keV) gamma sources. CONCLUSIONS: This work has importance for radioactive stents and catheter-based brachytherapy due to dependence of dose on density at distances between 0.1 mm and 3 mm away from the radiation source. This dependence is important for both beta- and gamma-based systems.

Radiation dose from a phosphorous-32 impregnated wire mesh vascular stent.

The near field dose distribution of a realistic vascular stent impregnated with radioactive 32P is calculated employing the dose-point-kernel (DPK) method in a homogeneous and uniform medium. The cylindrical wire mesh geometry for the Palmaz-Schatz [Palmaz-Schatz is a tradename of Cordis (a Johnson & Johnson company)] stent is incorporated in the model calculation, and the dose distribution generated by the beta particles emitted from the decayed radioactive 32P is computed at distances ranging from 0.1 to 2 mm exterior to the stent surface. Dose measurements were obtained using radiochromic film dosimetry media on an actual Palmaz-Schatz half-stent impregnated with 32P using ion implantation, and compared to the DPK model predictions. The close agreement between the model calculation and the film dosimetry data confirms the validity of the model which can be adapted to a variety of different stent designs.

Xilobam: analysis, determination of decomposition products, and assessment of stability.

A stability-indicating UV assay was developed for xilobam, a member of a new class of CNS agents. The method was specific, precise, and accurate. TLC and high-pressure liquid chromatography were used to support method specificity. Xilobam is sensitive to heat, moisture, and basic conditions. The degradation products were identified as N-methylpyrrolidone, 2,6-dimethylaniline, and N,N'-bis(2,6-dimethyl-phenyl)urea. At high temperatures, the incorporation of molecular sieves into glass bottles of xilobam tablets was effective in preventing decomposition caused by moisture or volatile decomposition products.

High-performance liquid chromatographic assay of codeine in acetaminophen with codeine dosage forms.

An accurate, rapid, and specific high-performance liquid chromatographic (HPLC) assay was developed for codeine in acetaminophen with codeine combination products. The internal standard (chlorpheniramine maleate), codeine, acetaminophen, and several other test compounds or impurities were well separated. A complete analysis took < 10 min. The relative standard deviations of the retention time, precision, and accuracy were 0.5, 0.4, and 0.5%, respectively. An excellent linear correlation was obtained between the HPLC and GLC methods.

Stability-indicating assay for tolmetin sodium in solid dosage forms.

A spectrophotometric assay for determining tolmetin sodium in pharmaceutical solid dosage forms is described. Tolmetin sodium is separated from common pharmaceutical excipients and probable degradation products. Recovery, precision, and accuracy data are provided. Two TLC methods are included which can be used to monitor qualitatively the stability of aged dosage forms.

High-pressure liquid chromatographic determination of propoxyphene hydrochloride in tablets and capsules.

The determination of propoxyphene hydrochloride by gas chromatography (GC) has been examined. Under a number of operating conditions significant on-column decomposition has occurred. The amounts of decomposition have been found to be dependent on sample size, flow-rate, column temperature, liquid phase loading, and solid support material. In view of this work a high-pressure liquid chromatographic procedure for quantitating propoxyphene hydrochloride has been developed. This method has been found to be specific for propoxyphene hydrochloride in the presence of its heat decomposition products formed with and without acetaminophen. This method does not suffer from problems associated with GC procedures.