Cardiopulmonary exercise test indices of respiratory buffering before and after aerobic exercise training in women with pulmonary hypertension: Differentiation by magnitudes of change in six-minute walk test performance.

While aerobic exercise training (AET) has generally been shown to improve 6-min walk test (6MWT) distance (6MWD) in patients with pulmonary hypertension (PH), a substantial number of patients appear to adapt differently, with minimal or even negative changes in 6MWT distance being reported. PURPOSE: To compare post-aerobic exercise training adaptations in cardiorespiratory functional capacity across three groups of patients with PH: those with high (HI), low (LI) and negative (NEG) post-training increases in 6MWD. METHODS: Participants were 25 females (age 54 ± 11 years; BMI 31 ± 7 kg/m2) who completed a vigorous, 10-week, thrice weekly, supervised treadmill walking exercise program. Cardiopulmonary exercise tests (CPET) and 6MWT were completed before and after training. Ten of the 25 participants were classified as HI (range = 47-143 m), 11 were classified as LI (range = 4-37 m) and 4 were classified as NEG (range = -17 to -53 m). RESULTS: Peak CPET duration, WR and time to anaerobic threshold (AT) were significantly higher (p < 0.05) after training in both the LI and HI groups but not in the NEG group. There was a significant improvement in VE/VCO2 (p = 0.042), PETCO2 (p = 0.011) and TV (p = 0.050) in the HI group after training, but not in the NEG or LI group. CONCLUSION: These findings suggest that sustained ventilatory inefficiency and restricted respiratory buffering may mediate exercise intolerance and impede the ability to adapt to exercise training in some patients with PH.

Estimate of absorbed dose based on two-dimensional autoradiographic information in internal radionuclide therapy.

In radiation therapies using radionuclides emitting short-range particles, such as radioimmunotherapy or boron neutron capture therapy, the biological effects are strongly affected by the heterogeneity of the absorbed dose distribution delivered to tumor cells. The three-dimensional (3D) information of the source distribution at the cellular level is required to accurately determine the absorbed dose distribution to the individual tumor cells. Two-dimensional distribution of cell and nuclide with a resolution of 1 microm can be obtained from individual tissue sections by microautoradiography. To obtain such information in 3D, an ideal approach would be to align the serial tissue sections from a block and analyze all of them. This is straightforward in theory, but extremely difficult in practice. Furthermore, every section in the block has to be processed and analyzed, and the usage of the data from this laborious work is very inefficient. An approach presented here is to estimate the absorbed dose based on individual sections without 3D reconstruction. It is realistically workable since it avoids the most difficult task of alignment for the serial tissue sections. In addition, the absorbed dose can be estimated based on a limited number of noncontiguous sections. The validity of this approach has been tested by a Monte Carlo simulation for two representative radionuclide configurations: (a) a uniform distribution of sources and (b) a cell membrane bound source distribution. With only a limited number of sampling sections, the uncertainties in the dose estimation were estimated to approximately 15% for short-range particles.

A direct approach for the determination of absorbed dose from electron beams using non-water phantoms.

Non-water solid phantoms are often used in the determination of absorbed dose to water for electron beams. Protocols have been established and widely accepted. In these procedures, several assumptions in addition to the Spencer-Attix conditions are required, and several correction factors are needed. A direct approach, in which the conversion is carried out in a single step using a modified Spencer-Attix formula, is studied in this paper. The approach is consistent with the protocols for water phantom, and the conversion factors can be calculated using Monte Carlo simulation. The behavior of the conversion factors is described by comparing the results from the AAPM protocol and experiment data for three electron energies (6, 12, and 16 MeV). This study demonstrates that for beam calibration at dmax, the results from the new approach agree with those from the protocol with a maximum discrepancy of 1% for PMMA and 1.3% for polystyrene. For the depth dose measurement from near the surface to R80, the agreement is within 1.5% for PMMA, 2.5% for polystyrene, and 2.8% for electron solid water. It also demonstrates that for electron solid water, the new approach provides better agreement with experiment data for the beam calibration at d(max).

Real-time, in vivo measurement of radiation dose during radioimmunotherapy in mice using a miniature MOSFET dosimeter probe.

This report presents the first real-time measurement of absorbed radiation dose during radioimmunotherapy in mice. Dose rate and total dose at the center of the tumor were measured after administration of 90Y-labeled antibodies using a miniature metal oxide semiconductor field-effect transistor radiation dosimeter probe which was inserted into the center of the tumor volume. Continuous real-time measurements were made for as long as 23 h after injection of the radiolabeled antibodies. Comparison of the real-time dose-rate measurements with estimates based on the MIRD formalism indicates good agreement. The real-time measurements are further compared to measurements made in a second experiment in which groups of mice were sacrificed at individual times after injection of the same radiolabeled antibodies. The real-time measurements agree well with the measurements in excised tumors. The real-time measurements have greater time resolution and are much more efficient than traditional uptake measurements.

The spatial accuracy of cellular dose estimates obtained from 3D reconstructed serial tissue autoradiographs.

In order to better predict and understand the effects of radiopharmaceuticals used for therapy, it is necessary to determine more accurately the radiation absorbed dose to cells in tissue. Using thin-section autoradiography, the spatial distribution of sources relative to the cells can be obtained from a single section with micrometre resolution. By collecting and analysing serial sections, the 3D microscopic distribution of radionuclide relative to the cellular histology, and therefore the dose rate distribution, can be established. In this paper, a method of 3D reconstruction of serial sections is proposed, and measurements are reported of (i) the accuracy and reproducibility of quantitative autoradiography and (ii) the spatial precision with which tissue features from one section can be related to adjacent sections. Uncertainties in the activity determination for the specimen result from activity losses during tissue processing (4-11%), and the variation of grain count per unit activity between batches of serial sections (6-25%). Correlation of the section activity to grain count densities showed deviations ranging from 6-34%. The spatial alignment uncertainties were assessed using nylon fibre fiduciary markers incorporated into the tissue block, and compared to those for alignment based on internal tissue landmarks. The standard deviation for the variation in nylon fibre fiduciary alignment was measured to be 41 microns cm-1, compared to 69 microns cm-1 when internal tissue histology landmarks were used. In addition, tissue shrinkage during histological processing of up to 10% was observed. The implications of these measured activity and spatial distribution uncertainties upon the estimate of cellular dose rate distribution depends upon the range of the radiation emissions. For long-range beta particles, uncertainties in both the activity and spatial distribution translate linearly to the uncertainty in dose rate of < 15%. For short-range emitters (< 100 microns), such as alpha particle sources, the magnitude of the uncertainty in serial section alignment is comparable with the particle track length. Under these circumstances, dosimetric errors are introduced in proportion to the serial section alignment inaccuracy.

A miniature MOSFET radiation dosimeter probe.

Prototype miniature dosimeter probes have been designed, built, and characterized employing a small, radiation sensitive metal oxide semiconductor field effect transistor (MOSFET) chip to measure, in vivo, the total accumulated dose and dose rate as a function of time after internal administration of long range beta particle radiolabeled antibodies and in external high energy photon and electron beams. The MOSFET detector is mounted on a long narrow alumina substrate to facilitate electrical connection. The MOSFET, alumina substrate, and lead wires are inserted into a 16 gauge flexineedle, which, in turn, may be inserted into tissue. The radiation dosimeter probe has overall dimensions of 1.6 mm diam and 3.5 cm length. The MOSFET probe signals are read, stored, and analyzed using an automated data collection and analysis system. Initially, we have characterized the probe's response to long range beta particle emission from 90Y sources in solution and to high energy photon and electron beams from linear accelerators. Since the prototype has a finite substrate thickness, the angular dependence has been studied using beta particle emission from a 90Sr source. Temperature dependence and signal drift have been characterized and may be corrected for. Measurements made in spherical volumes containing 90Y with diameters less than the maximum electron range, to simulate anticipated geometries in animal models, agree well with Berger point kernel and EGS4 Monte Carlo calculations. The results from the prototype probes lead to design requirements for detection of shorter range beta particles used in radioimmunotherapy and lower photon energies used in brachytherapy.

Image analysis for the study of radionuclide distribution in tissue sections.

UNLABELLED: Tissue section autoradiographs are often prepared to review the precise spatial locations of a radiolabeled molecule relative to cells, such as in the study of radiolabeled antibody distribution. The objective of this work was to develop and evaluate a method to automatically detect both grains and cell nuclei from stained tissue autoradiographs using a microscope and an image analyzer. METHOD: Using a sequence of morphological image operations, the densely stained regions of the section, representing the cell nuclei are identified first, and then subtracted from the original image. This enables the identification of autoradiographic grains under conditions of variable contrast, by separation of the grains overlapping the cell nuclei from the extracellular spaces, permitting a more accurate and robust automatic segmentation routine. RESULTS: The accuracy of the method to detect grains has been evaluated at different threshold levels. The highest accuracy obtained was approximately 90%. The accuracy in the detection of cell nuclei was histology-dependent. As examples, we have estimated accuracies of approximately: 86%, 81% and 77% for kidney, EL-4 lymphoma and pneumonocyte sections, respectively. CONCLUSION: This method was tested using specimens designed to study radiolabeled antibody distribution, but it should be applicable with comparable accuracy to other radiolabeled compounds for which quantitative information on the heterogeneity of distribution is required.

Internal dosimetry using data derived from autoradiographs.

Cancer therapies based on administered radionuclides require accurate information on tumor dose. One of the major factors influencing the distribution of absorbed-dose characteristics is the uniformity of the radiolabel distribution in tissue. To study the effect of nonuniformities, we used image analysis techniques to measure automatically the coordinates of autoradiographic grains (sources) and cell nuclei in cut sections from three different tumors, following treatment with radiolabeled antibodies. The spatial distribution data of sources and cell nuclei from these tumor sections were assessed and the pattern of energy deposition in the cell nuclei calculated, assuming that each autoradiograph grain corresponded to a source of the alpha emitter astatine-211 (211At) or the beta emitter yttrium-90 (90Y). The distribution of deposited energy obtained for the real grain distributions was compared to the distribution assuming a locally uniform source distribution, i.e., simulating grain count averaging as produced by a microdensitometric method within a 100 x 100 microns 2 frame size (frame averaging), and a uniform distribution across the entire section (section averaging). The results show first that when the grain distribution is uniform, the average dose within the section is an adequate estimate of the dose to the cell nuclei. Second, when the grain distribution is nonuniform, the distribution of doses to the cell nuclei is significantly less when calculations use the measured grain coordinates, or frame averaging, than when section averaging is used. Third, when the sources are located on or in the cells, both frame and section averaging produce underestimates of the dose to the cell nuclei.

The influence of air cavities on interface doses for photon beams.

PURPOSE: As the quantification of dose in homogeneous media is now better understood, it is necessary to further quantify effects from heterogeneous media. The most extreme case is related to air cavities. Although dose corrections at large distances beyond a cavity are accountable by attenuation differences, perturbations at air-tissue interfaces are complex to measure or calculate. These measurements helps understand the physical processes that govern these perturbations. METHODS AND MATERIALS: A thin window parallel-plate chamber and a special diode were used for measurements with various air cavity geometries (layer, channel, cubic cavity, triangle) in x-ray beams of 4 and 15 MV. RESULTS: Underdosing effects occur at both the distal and proximal air cavity interfaces. The magnitude depends on geometry, energy, and field sizes. As the cavity thickness increases, the central axis dose at the distal interface decreases. Increasing field size remedied the underdosing, as did the introduction of lateral walls. Following a 2.0 cm wide air channel for a 4 MV, 4 x 4 cm2 field there was an 11% underdose at the distal interface, while a 2.0 cm cubic cavity yielded only a 3% loss. Measurements at the proximal interface showed losses of 5% to 8%. For a 4 MV parallel opposed beam irradiation the losses at the interfaces were 10% for a channel cavity (in comparison with the homogeneous case) and 1% for a cube. The losses were slightly larger for the 15 MV beam. Underdosage at the lateral interface was 4% and 8% for the 4 MV and 15 MV beams, respectively. CONCLUSION: Although reports suggest better clinical results using lower photon energies with the presence of air cavities, there is no reliable dose calculation algorithm to predict interface doses accurately. The measurements reported here can be used to guide the development of new calculation models under nonequilibrium conditions. This situation is of clinical concern when lesions such as larynx carcinoma beyond air cavities are irradiated.

Verification of lung attenuator positioning before total body irradiation using an electronic portal imaging device.

PURPOSE: We report the first clinical experience with an electronic portal imaging device for lung attenuator positioning before delivery of total body irradiation. We demonstrate a technique for lung attenuator placement which reduces the dose to the patient during setup, reduces the patient setup time, and increases the accuracy of lung attenuator positioning. METHODS AND MATERIALS: Patients are treated with total body irradiation using a dedicated dual source irradiation facility prior to receiving bone marrow transplantation. The dose rate to the patient's midline is limited to 0.10 Gy/min, and partial transmission lung blocks are used to minimize radiation induced pneumonitis while delivering adequate dose to the regions under the blocks. Lung blocks are placed on the patient's back and chest wall, and portal images are used to verify proper block placement before the remaining treatment dose is delivered. RESULTS: We report the use of a liquid ionization chamber matrix electronic portal imaging device for imaging total body irradiation patient setups. CONCLUSION: The dose to the patient using the EPID for portal imaging is a factor of 7.5 lower than that needed for film. Image quality is superior to that of film due to digital processing. Since less time and dose are needed for imaging, it is demonstrated that better and more efficient final placement of the lung blocks can be achieved.

Dosimetry of 125I sources in a low-density material using scaling.

One may apply O'Connor's scaling theorem to dose measurements with brachytherapy sources in order to overcome the difficulties associated with the need for high spatial accuracy. This possibility has been evaluated by measuring the dose distribution around 125I sources in a low-density styrofoam phantom and comparing it with the dose distributions in water and solid water. Some generalization of the scaling theorem is proposed to allow for the minor differences in atomic composition between styrofoam and water, and the distances are scaled according to the ratio of the linear attenuation coefficients, instead of the physical densities, of the two media. The validity of this application of the scaling theorem has also been tested using Monte Carlo calculations. The results indicate that the scaling of the styrofoam measurements to water is a useful approximation in brachytherapy dosimetry.

A model of cell inactivation by alpha-particle internal emitters.

Tumor-associated antibodies labeled with 131I and 90Y have been used in the treatment of malignant disease with some success. The use of alpha-particle-emitting radionuclides as radiolabels offers potential advantages over beta-particle sources. The short range in tissue (< 100 microns) and the high linear energy transfer associated with alpha-particle emitters will result in a more concentrated deposition of energy at the site of radionuclide decay. Thus, if radiolabeled antibodies can be bound to malignant cells specifically, a high differential cell killing can be achieved between the malignant and the normal cells. However, the energy deposition pattern will be strongly dependent upon the configuration of alpha-particle sources relative to the cells, and will consequently impact upon the dose-response characteristics. The purpose of this paper is to study distributions of energy deposition from alpha-particle-emitting radioimmunoconjugates distributed uniformly and nonuniformly around cells through theoretical modeling. Energy deposition spectra for cell nuclei are calculated and used to estimate the survival fraction by a simple biological model. We show that survival curves resulting from nonuniform distributions of alpha-particle-emitting radiolabeled antibodies can depart significantly from the classical exponential survival model applied to external alpha-particle beams. The survival curves may have initial slopes much steeper than those produced by a uniform distribution of sources, and they may also depart from linearity. Furthermore, the results of the modelling indicate how survival curves are dependent on the cell and radiolabel spacing. The results from our model compare reasonably well with published experimental data and can be used to facilitate the design and interpretation of radiobiological experiments.

Sampling techniques for the evaluation of treatment plans.

Sampling techniques using randomly distributed points and regular Cartesian grids were compared for the evaluation of volume, dose-volume histogram, tumor control, and normal tissue complication probabilities in radiation treatments. Particularly, the uncertainties associated with each sampling technique in estimating the dose-volume histograms for several dose distributions are analyzed in detail. It is found that the estimation of these parameters using sampling points on a regular Cartesian grid is, in general, significantly more efficient than using random points. This finding is different from other published results. The choice of grid size for sampling was analyzed according to the AAPM recommended uncertainty on the dose delivered to the patient. It was concluded that when grid sampling is used, a grid size of 0.5 cm is adequate for most plans to meet the guidelines.

Three-dimensional dose distribution of total body irradiation by a dual source total body irradiator.

This study describes the three-dimensional dosimetric characteristics of total body irradiation by our dedicated irradiation unit, which consists of two modified 4-MV linear accelerators mounted opposite each other, providing a field size of 220 cm x 80 cm at the midplane. Our dose calculation algorithm considers the three-dimensional contour of the patient to evaluate the primary and scatter doses. The data base for the calculation includes tissue-to-maximum ratios measured for the large fields. The lung dose correction was calculated using the methods of Batho or ratio of TMR. The accuracy of the calculated dose distributions was verified by measurements with ionization chambers in a humanoid phantom. We also describe and verified a technique to achieve desirable midline lung doses using lead shields. The flexibility and the accuracy of the planning system offers the potential in optimizing the therapeutic ratio for total body treatments.

Automated data collection and analysis system for MOSFET radiation detectors.

Metal oxide semiconductor field effect transistors (MOSFET) have been used as radiation dosimeters. Because of their small detector size, minimal power requirements, and signal integration characteristics, they offer unique possibilities as real-time dose monitors in radiotherapy. An automated data collection and analysis system for use with MOSFET radiation dosimeters has been designed and built. The objective was to design a system which can acquire and process the MOSFET signals in real time, in any radiation field encountered in radiotherapy. In particular, major problems have been solved arising from the intrinsic drifts of the MOSFET signal during low dose rate measurements. These signal drifts are significant when the MOSFET detector is used in applications such as on-line monitoring of radiation dose delivery in brachytherapy or radioimmunotherapy. The data collection and analysis system includes a portable IBM-compatible personal computer fitted with digital-to-analog and analog-to-digital converter boards. A single-chip programmable current supply is used to power the MOSFET dosimeters. Intrinsic and extrinsic drifts in signal due to ion diffusion and electron tunneling are corrected by deconvolution of the collected data in real time or after data collection. The data acquisition system and signal-processing methodologies are described.

Monte Carlo calculations of scatter to primary ratios for normalisation of primary and scatter dose.

The separation of total absorbed dose into primary and scatter components is a commonly used technique in photon dose calculations. The primary dose component can be characterised by a measured narrow beam attenuation coefficient and a single normalisation value which establishes the relative proportion of the primary to the total dose at some reference depth and field size. The determination of this normalisation value from measured data requires an extrapolation of measured values for finite field sizes to obtain a zero field size value. We have used Monte Carlo simulations to score primary and scatter dose for photon beams of 4, 6, 10, 15 and 24 MV and report values of the scatter to primary ratio at the depth of dose maximum for the circular equivalent of a 10 cm x 10 cm field. These values have an uncertainty of less than 1% and can be used in lieu of extrapolation of measured data to establish the relative magnitude of the primary dose for a wide range of photon beam energies.

Three-dimensional photon dose distributions with and without lung corrections for tangential breast intact treatments.

The influence of lung volume and photon energy on the 3-dimensional dose distribution for patients treated by intact breast irradiation is not well established. To investigate this issue, we studied the 3-dimensional dose distributions calculated for an 'average' breast phantom for 60Co, 4 MV, 6 MV, and 8 MV photon beams. For the homogeneous breast, areas of high dose ('hot spots') lie along the periphery of the breast near the posterior plane and near the apex of the breast. The highest dose occurs at the inferior margin of the breast tissue, and this may exceed 125% of the target dose for lower photon energies. The magnitude of these 'hot spots' decreases for higher energy photons. When lung correction is included in the dose calculation, the doses to areas at the left and right margin of the lung volume increase. The magnitude of the increase depends on energy and the patient anatomy. For the 'average' breast phantom (lung density 0.31 g/cm3), the correction factors are between 1.03 to 1.06 depending on the energy used. Higher energy is associated with lower correction factors. Both the ratio-of-TMR and the Batho lung correction methods can predict these corrections within a few percent. The range of depths of the 100% isodose from the skin surface, measured along the perpendicular to the tangent of the skin surface, were also energy dependent. The range was 0.1-0.4 cm for 60Co and 0.5-1.4 cm for 8 MV. We conclude that the use of higher energy photons in the range used here provides lower value of the 'hot spots' compared to lower energy photons, but this needs to be balanced against a possible disadvantage in decreased dose delivered to the skin and superficial portion of the breast.

The effect of differences in data base on the determination of absorbed dose in high-energy photon beams using the American Association of Physicists in Medicine protocol.

Exposure rates were adjusted at the National Institute of Standards and Technology (NIST) on January 1, 1986 to take into account more recent values for some physical parameters, mainly in electron stopping power ratios. Exposure calibration factors for 60Co gamma rays Nx will therefore be lowered by 1.1%. Consequently, absorbed dose determinations in high-energy photon beams will be reduced by the same amount if the values for these physical parameters remain unchanged in the American Association of Physicists in Medicine (AAPM) protocol. If the same data base as used at NIST is applied in the AAPM protocol, then Ngas/Nx values, water-air stopping power ratios, and Pwall values will be different. The overall change in absorbed dose determinations using a consistent set of data will be a reduction of 0.8% for 60Co gamma rays and 1.5% for a 20-MV x-ray beam compared to the values before January 1, 1986. Since the net effect is small when different sets of data are applied, the new NIST exposure calibration factors may be used in combination with the AAPM protocol without significant error.