Sci-Sat AM(2): Brachy-06: A Comparison of MR/CT fusion versus CT alone for assessment of implant quality in permanent prostate brachytherapy.

Low dose-rate permanent implant brachytherapy is widely used in the management of patients with early stage prostate cancer. An assessment of the implant quality is usually carried out 30 days after the implant is delivered, using computed tomography (CT) to identify the prostate and seeds. This is difficult due to poor contrast of the prostate and the superposition of seeds in the CT images. Magnetic resonance (MR) imaging offers superior contrast but inferior visualization of seeds. At our centre, patients are imaged using both CT and T2 weighted MR 30 days after an implant, and the image sets are fused using a commercial software package. The seeds are identified on CT and the prostate volumes are contoured on MR, with fusion performed by matching seeds on CT with seed signal voids on MR. The purpose of this study was to compare standard prostate post-implant dosimetric parameters (D90, V100, etc.) for prostates contoured on CT alone (MR blinded) versus MR/CT fusion. 25 patients were evaluated with all contouring performed by the same physician. We found that the prostate volume was overestimated using CT alone as compared to MR/CT fusion (mean: 37.2cc vs. 35.0cc respectively, p = 0.033). We also found that dosimetric parameters were underestimated for CT alone compared to MR/CT fusion, including D90 (mean: 144.3Gy vs. 150.8Gy respectively, p = 0.005) and V100 (mean: 89.2% vs. 91.0% respectively, p = 0.01). Centres using CT alone for post-implant dosimetry may therefore be underestimating their implant quality.

Size and positioning reproducibility of an 192Ir brachytherapy stepping source.

In this paper we describe techniques for measuring the dimensions and position reproducibility of an 192Ir brachytherapy stepping source. Measurements were carried out using a 0.25x10x152 mm3 collimator placed in front of a detector of our own design. The brachytherapy source was translated past the collimator in 0.025 mm increments using a stepper motor. The source was found to be 3.58 mm long and 0.69 mm wide, which is in good agreement with the manufacturer's values of 3.5x0.6 mm2. The source position was reproducible to within 0.12 mm.

High-energy electron and photon therapy to the parotid bed: radiation dose perturbations with a titanium mandibular implant.

Adjuvant radiation therapy to the parotid bed is commonly administered following surgical resection using either a pair of angled wedged photon beams or an ipsilateral mixed-beam portal of electrons and photons. The present study seeks to determine the optimal parotid bed treatment technique in the presence of a titanium mandibular implant by investigating perturbations in the dose distribution deep to this implant for a 15-MeV electron beam and a 6-MV photon beam. A titanium mandibular plate was embedded in a tissue-equivalent phantom, and irradiated with 15-MeV electrons, and 6 MV photons. Radiation doses behind the plate were measured with both thermoluminescent dosimeters and radiographic film. With 15-MeV electrons, there is a clinically significant decrease in the dose beyond the titanium plate, which is most important at 5-mm and 10-mm depths (18-27%). With 6-MV photons the dose at the deep interface of titanium and tissue is reduced by between 15 and 18%, but rapidly drops to < 5% at a depth of 5 mm. In adjuvant treatment to the parotid bed, when the clinical target volume includes tissue positioned deep to a titanium implant, significant underdosage occurs with ipsilateral beam arrangements, especially when electrons are used.

Detection of and discrimination between total and free human interleukin-4 and free soluble interleukin-4 receptor by ELISA.

Interleukin-4 (IL-4) signaling is initiated by binding of IL-4 to the high-affinity IL-4 receptor alpha-chain and subsequent interaction with the common gamma-chain. Soluble forms of the extracellular domain of the alpha-chain (sIL-4R) were shown to be present in biological fluids and, dependent on the concentration, enhance or inhibit IL-4 activity by forming IL-4/sIL-4R complexes. To discriminate between free and potentially active IL-4 from the inactive and complexed form, we have established a set of new ELISA systems for the measurement of human IL-4 in its distinct forms. To select suitable pairs of anti-IL-4 antibodies, a chequerboard interference analysis with six highly-selective human IL-4 specific monoclonal antibodies was performed. For the determination of total IL-4, a monoclonal capture antibody was used that binds IL-4 outside the binding site of the IL-4R alpha-chain. Another antibody recognizing an epitope of the alpha-chain binding site was chosen for the detection of free IL-4. The binding of this antibody was inhibited in a dose-dependent fashion by recombinant sIL-4R. Assays for both total and free IL-4 exhibited a sensitivity of 8 pg/ml and a dynamic range up to 1000 pg/ml. Human sIL-4R was detected by two monoclonal antibodies directed against different epitopes. This ELISA was inhibited by recombinant IL-4 suggesting the measurement of predominantly free sIL-4R. Complexes between soluble IL-4R and IL-4 were detected by a monoclonal anti-sIL-4R antibody in combination with an anti-IL-4 antibody. When supernatants of activated T cells were analyzed, the majority of the IL-4 was in free form. The amount of complexed IL-4 was low as indicated by the fact that most of total IL-4 could be detected as free IL-4. Although values obtained for complexed IL-4 correlated with the difference between total and free IL-4, precise values could not be determined, presumably due to the dynamic nature of the complex between the two proteins. We suggest that the ability to quantitate total and free IL-4 in combination with sIL-4R may provide a new insight of the role that IL-4 plays in different pathophysiological conditions.

Demonstration of the therapeutic potential of non-anaphylactogenic anti-IgE antibodies in murine models of skin reaction, lung function and inflammation.

BACKGROUND: Allergies and allergic asthma are believed to be mediated by allergen-specific IgE antibodies. We have investigated the therapeutic potential of inhibiting endogenous IgE by a non-anaphylactogenic anti-mouse IgE antibody 1-5 with respect to its effects on antigen-induced skin reaction, lung function changes and lung inflammation in mice. METHODS: Mice were immunized with benzylpenicillinoyl-KLH or ovalbumin, and antigen-mediated skin reaction, bronchoconstriction, bronchopulmonary hyperresponsiveness (BHR) and lung eosinophilic inflammation determined in anti-IgE 1-5-treated versus untreated animals. RESULTS: Application of anti-IgE 1-5 inhibited (by 90%) the serum IgE and, 3-4 days after onset of treatment, blocked the antigen-induced skin reaction. Furthermore, the antibody also inhibited (by 90%) the antigen-induced infiltration of eosinophils into the lung. This latter effect seems to be mediated by blocking the IgE-CD23 interaction and indicates that lung eosinophilic inflammation also depends on IgE. Moreover, when applied to rats passively sensitized with mouse IgE, antibody 1-5 inhibited the antigen-induced bronchoconstriction. A similar effect could be seen in actively immunized mice, where antibody 1-5 was able to inhibit (by 70%) the ovalbumin-induced bronchoconstriction as well as BHR. CONCLUSIONS: In summary, non-anaphylactogenic anti-IgE antibodies can markedly inhibit IgE levels and IgE-mediated allergic reactions. Since bronchoconstriction, BHR and lung eosinophilic inflammation can be suppressed, such antibodies may be attractive principles for the treatment of allergic asthma.

Central role of immunoglobulin (Ig) E in the induction of lung eosinophil infiltration and T helper 2 cell cytokine production: inhibition by a non-anaphylactogenic anti-IgE antibody.

Elevated levels of immunoglobulin (Ig) E are associated with bronchial asthma, a disease characterized by eosinophilic inflammation of the airways. Activation of antigen-specific T helper (Th) 2 cells in the lung with the subsequent release of interleukin (IL) 4 and IL-5 is believed to play an important role in the pathogenesis of this disease. In this study, we have used a non-anaphylactogenic anti-mouse-IgE antibody to investigate the relationship between IgE, airway eosinophil infiltration, and the production of Th2 cytokines. Immunization of mice with house dust mite antigen increased serum levels of IgE and IgG. Antigen challenge of immunized but not control mice induced an infiltration of eosinophils in the bronchoalveolar lavage associated with the production of IL-4 and IL-5 from lung purified Thy1.2+ cells activated through the CD3-T cell receptor complex. Administration of the anti-IgE monoclonal antibody (mAb) 6h before antigen challenge neutralized serum IgE but not IgG and inhibited the recruitment of eosinophils into the lungs and the production of IL-4 and IL-5 but not interferon gamma. Studies performed using an anti-CD23 mAb, CD23 deficient and mast cell deficient mice suggest that anti-IgE mAb suppresses eosinophil infiltration and Th2 cytokine production by inhibiting IgE-CD23-facilitated antigen presentation to T cells. Our results demonstrate that IgE-dependent mechanisms are important in the induction of a Th2 immune response and the subsequent infiltration of eosinophils into the airways. Neutralization of IgE, for example, non-anaphylactogenic anti-IgE mAbs may provide a novel therapeutic approach to the treatment of allergic airway disease.

Can anti-IgE be used to treat allergy?

A summary of the properties of CGP 51901 is shown in Table 3. On the basis of its binding to IgE and IgE-secreting cells and its activity in vitro and in vivo, CGP 51901 is expected to be able to decrease serum IgE by direct clearance of IgE and by reduction of the numbers and productivity of IgE-secreting cells. The end result of reduction of IgE in the circulation and on mast cells is expected to be the attenuation of IgE-mediated reactions and the improvement in allergy symptoms. The effective serum concentration of CGP 51901 is expected to be in the range 1-10 micrograms/ml. Because CGP 51901 is an antibody specific for IgE, it is expected to be highly selective in its activity. Because IgE does not appear to be essential and because CGP 51901 has been rigorously tested to confirm its non-anaphylactic nature, this treatment is not expected to have any adverse effects. Therefore, CGP 51901 is expected to be safe and to have a good probability of being effective when it is tested in human clinical trials.

Interleukin 4 is localized to and released by human mast cells.

Recent attention has focused on the T helper type 2 (Th2) lymphocyte as a source of interleukin 4 (IL-4) in allergic disease. However, Th2 cells themselves require a pulse of IL-4 to initiate this synthesis. Here we provide immunohistochemical evidence of IL-4 localization to human mast cells of the skin and respiratory tract, and demonstrate that immunoglobulin E-dependent stimulation of purified human lung mast cells leads to the rapid release of IL-4 into the extracellular environment. We propose that mast cell activation in an allergic response provides a rapid and local pulse of IL-4 into the local environment essential for the triggering of T lymphocytes into sustained IL-4 production and to initiate inflammatory cell accumulation and activation.

Characterization of a monoclonal antibody specific for human active renin.

We have identified and characterized an anti-human renin monoclonal antibody R1-20-5 that is selective for human active renin. R1-20-5 binds active renin with a dissociation constant (Kd) of 2.5 x 10(-7) M/l and inhibits renin enzymatic activity with an inhibitory constant (IC50) of 1.4 x 10(-8) M/l. R1-20-5 competes with a synthetic renin inhibitor for binding with renin, demonstrating further that it is binding to or close to the active site. This antibody does not bind prorenin in human plasma or recombinant prorenin expressed by L-929 fibroblasts transfected with human renin gene. Furthermore, trypsin activation of prorenin resulted in immunoreactivity of the activated prorenin toward the antibody. In addition, an immunoaffinity column of R1-20-5 coupled to Sepharose retained active renin but had a low affinity for prorenin. A sensitive and rapid solid phase radioimmunoassay for active renin was developed using a "sandwich" technique employing R1-20-5 and a second non-active site-directed monoclonal antibody to human renin. Renin levels in human plasma samples were determined by the standard enzymatic assay, and by the direct radioimmunoassay for active renin, before and after trypsin activation. Trypsin treatment of plasma resulted in parallel increases in both the plasma renin enzymatic activity and in the plasma active renin concentration as measured by the direct radioimmunoassay. Overall, plasma immunoreactive active renin concentration correlated significantly with plasma renin enzymatic activity (r = 0.96, p less than 0.001). In summary, the monoclonal antibody R1-20-5 is selective for human active renin and should be a very useful tool for studies of the active enzyme in humans.

Doses and population irradiation factors for Canadian radiation technologists (1978 to 1988).

Individual and collective radiation doses received by Canadian radiation technologists (RTs) working in diagnostic radiology, nuclear medicine and radiotherapy are summarized for the period 1978 to 1988. The data were obtained directly from the National Dose Registry, Department of National Health and Welfare. Over the 11-year study period the mean annual dose equivalent fluctuated around 0.2, 1.8 and 1.1 mSv for RTs working in diagnostic radiology, nuclear medicine and radiotherapy respectively. Over the same period the occupational collective dose equivalent decreased in diagnostic radiology (by 44%) and radiotherapy (by 35%) and increased in nuclear medicine (by 45%). Approximately 10,000 RTs are monitored each year, with an estimated total occupational collective dose equivalent of about 3.6 person-sieverts. Analysis of dose distribution data showed that only 1.3% of all monitored RTs received an annual whole-body dose equivalent greater than the current legal limit for members of the public (5 mSv). Approximately half of the RTs working in nuclear medicine and radiotherapy received an annual dose equivalent in excess of 0.5 mSv; only 7.3% of their diagnostic radiology counterparts exceeded this level. Demographic data showed a high preponderance of young women in all three RT classifications, and an analysis of the radiation risks to this occupational group revealed increases of up to 12% above the risk associated with a "standard" adult working population exposed to the same collective dose equivalent.

A simplified method for measuring cerebral blood flow with xenon-enhanced computed tomography.

The measurement of cerebral blood flow using the xenon-enhanced computed tomography (XECT) technique requires that the build-up of xenon in both brain tissue and end-tidal expired air be determined as a function of time. Monitoring of the former is carried out using CT scanning and the latter, most often, using a thermoconductivity analyser or mass spectrometer. This paper examines the possibility of greatly simplifying the XECT technique by eliminating the need for either thermoconductivity analyser or mass spectrometer. In the proposed approach, the patient's expired air is channelled through the scan field using a flexible plastic tube and sampled by the CT scanner in conjunction with the build-up of xenon in brain tissue. Phantom measurements have demonstrated the ability of the CT scanner to detect variations in the xenon concentration in expired air while computer simulations have shown that errors arising as a result of the proposed methodology are small compared to other inherent sources in the XECT technique.

Occupational doses to medical radiation technologists in Manitoba (1978-1988).

In Canada, occupational exposure to medical technologists accounts for about 8 per cent of all occupational exposure. In this paper, occupational doses to Manitoban radiation technologists (RTs) in diagnostic radiology, nuclear medicine and radiotherapy are presented for the period 1978-1988. Particular attention is paid to the distribution of dose among this population. The importance of age and sex demographics on radiation detriment is also estimated.

New concepts of IgE regulation.

B cell switch to IgE expression is mediated by IL-4 and is regarded as a T helper cell-related phenomenon. In this overview we describe that IgE switch can also be induced by mast cell/basophil like cells (from splenic non-B, non-T cells), activated by IgE receptor cross-linking and/or IL-3 which results in IL-4 production by these cells. Furthermore, activated mast cells produce their own growth factors, IL-3 and GM-CSF. Thus, activation of mast cells can provoke an ongoing local allergic reaction as long as antigen confrontation is maintained, a process which is sustained by further IgE production as well as renewal of mast cells. It is furthermore demonstrated that in certain established immune situations the IgE response may become independent of IL-4, namely in the spontaneous in vitro IgE expression of cells from atopic individuals as well as in an in vitro antigen-induced secondary IgE response of spleen cells derived from previously immunized mice. Thus, IgE-switched B cells may persist in vivo and may represent a pool of potentially IgE-producing cells. Finally, a selective inhibition of the IgE response is described in vitro and in vivo by the use of so-called non-anaphylactic monoclonal anti-IgE antibodies. Such antibodies bind to surface IgE+ B cells, but not to IgE-sensitized mast cells, and thereby inhibit IgE responses. Non-anaphylactic antibodies blocked the binding of allergen-specific IgE to mast cells by competing with the Fc epsilon on these cells. As a consequence they do not induce but rather prevent allergen-induced mediator release by mast cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiation doses due to breast imaging in Manitoba: 1978-1988.

The number of mammographic examinations performed annually in the province of Manitoba, Canada, and their associated radiation doses (total collective breast dose and average glandular dose [AGD] per view) are reported for the period 1978-1988. These data indicate that the total number of examinations performed annually increased by a factor of five during the 11-year study. The total annual collective breast dose, meanwhile, increased at a much slower rate, from 40 person-Gy in 1978 to 97 person-Gy in 1988; this difference is attributable to the gradual replacement of xeroradiography by screen-film mammography and to changes in technique. In the late 1980s, the AGD due to xeroradiography for a craniocaudal view was 3.3 mGy, a factor of 2.4 greater than the corresponding dose associated with dedicated screen-film units.

Quantitative computed tomography of the brain with xenon enhancement: a phantom study with the GE9800 scanner.

A recently proposed application of quantitative computed tomography is in the study of cerebral blood flow and partition coefficient using stable xenon as a freely diffusible, radio-opaque tracer. Central to the method is the calibration factor describing the relationship between CT number and xenon concentration in the brain. In this paper we examine the influence of temporal fluctuations, kVp, radial position and beam hardening on this calibration factor through the analysis of a series of phantom measurements. We conclude that under clinically realistic conditions and with correlations for temporal fluctuations, the error associated with the calibration factor is less than 2%. Furthermore, errors of this magnitude translate into errors of less than 3% in derived blood flow and partition coefficient values obtained using xenon-enhanced computed tomography.

The role of noise in the measurement of cerebral blood flow and partition coefficient using xenon-enhanced computed tomography.

Monte Carlo simulations have been used to study the accuracy which can be expected in the quantification of blood flow and the partition coefficient using xenon-enhanced computed tomography in the presence of noise. We have demonstrated that the markedly asymmetric frequency distribution of estimates increases in size rapidly with an increase in the standard error of the input CT data. On the basis of our results, we recommend that controllable sources of noise (eg. CT number drift) be corrected and that estimates be obtained by averaging CT data and then fitting, rather than averaging blood flow and partition coefficients derived from individual pixels, as the latter procedure results in the introduction of considerable bias.

Occupational doses in radiation oncology in Manitoba--1980 to 1986.

The province of Manitoba (population of 1.0 million) has two radiotherapy centers employing a number of people, of whom about 60 are exposed to radiation during the course of their work. The individual and collective radiation doses to these workers, as recorded by thermoluminescent dosimeter plaques, were reviewed for the period 1980 to 1986. Whole-body doses to radiotherapy technologists responsible for operating the treatment machines and brachytherapy afterloading procedures ranged from 0.5 to 2.5 mSv y-1, whereas the corresponding doses to nursing staff working on a hospital brachytherapy ward were about 1.0 mSv y-1. The collective occupational dose from radiotherapy in Manitoba was approximately 70 person-mSv. Trends show individual operator and collective doses to be increasing at a higher rate than the number of patients undergoing radiotherapy. Occupational exposure in radiotherapy in this province was found to be comparable to that encountered in nuclear medicine in Manitoba and greater than that in diagnostic radiology.

Radiation doses in extracorporeal shock wave lithotripsy.

Patients undergoing lithotripsy on the Siemens Lithostar system are exposed to radiation in three modes: film radiography, electronic radiography and fluoroscopy. Radiation exposure techniques (kVp, field size, number of exposures and projection) were recorded for the first 125 patients undergoing treatment on a recently installed Lithostar unit at a Winnipeg hospital. These data were then used in conjunction with phantom-based radiation dose measurements to calculate entrance skin dose and total energy imparted for each patient. Values of 142 mGy and 53 mJ, respectively, were found. In the case of energy imparted, 20% of the total arose from film radiography, 30% from electronic radiography and the remaining 50% from fluoroscopy. The estimated effective dose-equivalent, HE, to the average patient undergoing lithotripsy was 0.75 mSv. This corresponds to an estimated radiation risk for the induction of fatal cancers and genetic defects (in the first two generations of offspring) of between 5 and 11 per million.

Effects of chronic administration of a monoclonal antibody against human renin in the marmoset.

In this study, the hypotensive efficacy of R-3-36-16, a monoclonal antibody against human kidney renin, was investigated during chronic administration to a primate. R-3-36-16 was given by continuous intraperitoneal infusion with osmotic minipumps to normotensive marmosets fed a low-sodium diet in doses of 30 or 300 micrograms/kg/day for 14 days. The lower dose had no effect on blood pressure (BP) or plasma renin activity (PRA). After two days of treatment, the higher dose reduced PRA by 57% and lowered BP by 13 +/- 7 mm Hg. Although the hypotensive response persisted after 14 days of treatment (-17 +/- 2 mm Hg), PRA had recovered to pretreatment levels. BP gradually returned to pretreatment values in the week after stopping the treatment. There was no evidence of an immune reaction when an acute challenge dose of R-3-36-16 was given 7 weeks after stopping the chronic treatment. Thus, R-3-36-16 appears to be an effective and well-tolerated hypotensive agent during chronic administration to sodium-depleted primates. The hypotensive response does not seem to be directly related to the inhibition of renin in the plasma.