Thomas J. Farrell

A dynamic model for ALA-PDT of skin: simulation of temporal and spatial distributions of ground-state oxygen, photosensitizer and singlet oxygen

Singlet oxygen (¹O₂) direct dosimetry and photosensitizer fluorescence photobleaching are being investigated and applied as dosimetric tools during 5-aminolevulinic acid (ALA)-induced protophorphyrin IX (PpIX) photodynamic therapy (PDT) of normal skin and skin cancers. The correlations of photosensitizer fluorescence and singlet oxygen luminescence (SOL) emission signals to ¹O2 distribution and cumulative ¹O₂dose are difficult to interpret because of the temporal and spatial variations of three essential components (light fluence rate, photosensitizer concentration and oxygen concentration) in PDT. A one-dimensional model is proposed in this paper to simulate the dynamic process of ALA-PDT of normal human skin in order to investigate the time-resolved evolution of PpIX, ground-state oxygen (³O₂and ¹O₂ distributions. The model incorporates a simplified three-layer semi-infinite skin tissue, Monte Carlo simulations of excitation light fluence and both PpIX fluorescence and SOL emission signals reaching the skin surface, ¹O₂-mediated photobleaching mechanism for updating PpIX, ³O₂ and ¹O₂ distributions after the delivery of each light dose increment, ground-state oxygen supply by diffusion from the atmosphere and perfusion from blood vessels, a cumulative ¹O₂-dependent threshold vascular response, and the initial non-uniform distribution of PpIX. The PpIX fluorescence simulated using this model is compared with clinical data reported by Cottrell et al (2008 Clin. Cancer Res. 14 4475-83) for a range of irradiances (10-150 mW cm⁻²). Except for the vascular response, one set of parameters is used to fit data at all irradiances. The time-resolved depth-dependent distributions of PpIX, ³O₂ and ¹O₂ at representative irradiances are presented and discussed in this paper, as well as the PDT-induced vascular response at different depths. Tissue hypoxia and shutdown of oxygen supply occur in the upper dermis, where PpIX is also preserved at the end of treatment.

Measurement of fluorophore concentrations and fluorescence quantum yield in tissue-simulating phantoms using three diffusion models of steady-state spatially resolved fluorescence

Steady-state diffusion theory models of fluorescence in tissue have been investigated for recovering fluorophore concentrations and fluorescence quantum yield. Spatially resolved fluorescence, excitation and emission reflectance Carlo simulations, and measured using a multi-fibre probe on tissue-simulating phantoms containing either aluminium phthalocyanine tetrasulfonate (AlPcS4), Photofrin meso-tetra-(4-sulfonatophenyl)-porphine dihydrochloride The accuracy of the fluorophore concentration and fluorescence quantum yield recovered by three different models of spatially resolved fluorescence were compared. The models were based on: (a) weighted difference of the excitation and emission reflectance, (b) fluorescence due to a point excitation source or (c) fluorescence due to a pencil beam excitation source. When literature values for the fluorescence quantum yield were used for each of the fluorophores, the fluorophore absorption coefficient (and hence concentration) at the excitation wavelength (mu(a,x,f)) was recovered with a root-mean-square accuracy of 11.4% using the point source model of fluorescence and 8.0% using the more complicated pencil beam excitation model. The accuracy was calculated over a broad range of optical properties and fluorophore concentrations. The weighted difference of reflectance model performed poorly, with a root-mean-square error in concentration of about 50%. Monte Carlo simulations suggest that there are some situations where the weighted difference of reflectance is as accurate as the other two models, although this was not confirmed experimentally. Estimates of the fluorescence quantum yield in multiple scattering media were also made by determining mu(a,x,f) independently from the fitted absorption spectrum and applying the various diffusion theory models. The fluorescence quantum yields for AlPcS4 and TPPS4 were calculated to be 0.59 +/- 0.03 and 0.121 +/- 0.001 respectively using the point source model, and 0.63 +/- 0.03 and 0.129 +/- 0.002 using the pencil beam excitation model. These results are consistent with published values.

Quantification of bioluminescence images of point source objects using diffusion theory models.

A simple approach for estimating the location and power of a bioluminescent point source inside tissue is reported. The strategy consists of using a diffuse reflectance image at the emission wavelength to determine the optical properties of the tissue. Following this, bioluminescence images are modelled using a single point source and the optical properties from the reflectance image, and the depth and power are iteratively adjusted to find the best agreement with the experimental image. The forward models for light propagation are based on the diffusion approximation, with appropriate boundary conditions. The method was tested using Monte Carlo simulations, Intralipid tissue-simulating phantoms and ex vivo chicken muscle. Monte Carlo data showed that depth could be recovered within 6% for depth 4-12 mm, and the corresponding relative source power within 12%. In Intralipid, the depth could be estimated within 8% for depth 4-12 mm, and the relative source power, within 20%. For ex vivo tissue samples, source depths of 4.5 and 10 mm and their relative powers were correctly identified.

Quantitative fluorescence imaging of point-like sources in small animals.

A planar imaging approach is described for the in vivo quantitative reconstruction of fluorescent point sources in small animals. The method uses the diffusion approximation as a forward model of light propagation from a point source in a homogeneous tissue to find source depth and strength. The tissue optical properties obtained from video reflectometry measurements were used to compensate for the effects of tissue heterogeneity. The method was evaluated on images of fluorescent sources implanted 2-8.5 mm deep in the thigh and abdomen of rats post mortem. In more than 70% of the total number of implants the source depth was retrieved with an error of less than 1 mm. The largest absolute error was 1.9 mm. In retrieving source strength, the errors ranged from 0.4% to 89% generally increasing with increased source depth.

Bioluminescence imaging of point sources implanted in small animals post mortem: evaluation of a method for estimating source strength and depth

The performance of a simple approach for the in vivo reconstruction of bioluminescent point sources in small animals was evaluated. The method uses the diffusion approximation as a forward model of light propagation from a point source in a homogeneous tissue to find the source depth and power. The optical properties of the tissue are estimated from reflectance images obtained at the same location on the animal. It was possible to localize point sources implanted in mice, 2-8 mm deep, to within 1 mm. The same performance was achieved for sources implanted in rat abdomens when the effects of tissue surface curvature were eliminated. The source power was reconstructed within a factor of 2 of the true power for the given range of depths, even though the apparent brightness of the source varied by several orders of magnitude. The study also showed that reconstructions using optical properties measured in situ were superior to those based on data in the literature.

Investigation of light propagation models to determine the optical properties of tissue from interstitial frequency domain fluence measurements

Four models, standard diffusion approximation (SDA), single Monte Carlo (SMC), delta-P1, and isotropic similarity (ISM), are developed and evaluated as forward calculation tools in the estimation of tissue optical properties. The inverse calculation uses the ratio of the fluences and phase difference at two locations close to an intensity modulated isotropic source to recover the reduced scattering coefficient mus and the absorption coefficient mua. Diffusion theory allows recovery of optical properties (OPs) within 5% for media with musmua>10. The performance of the delta-P1 model is similar to SDA, with limited enhanced accuracy. The collimation approximation may limit the use of the delta-P1 model for spherical geometry, and/or the fluence may not be accurately calculated by this model. The SMC model is the best, recovering OPs within 10% regardless of the albedo. However, the necessary restriction of the searched OPs space is inconvenient. The performance of ISM is similar to that of diffusion theory for media with musmua>10, and better for 1<musmua<10, i.e., determines absorption within 5% and reduced scattering within 20%. In practice, satisfactory estimates (within 5 to 10%) can be achieved using SDA to recover mus and ISM to recover mua for media with musmua>5.

Integrating spheres for improved skin photodynamic therapy.

The prescribed radiant exposures for photodynamic therapy (PDT) of superficial skin cancers are chosen empirically to maximize the success of the treatment while minimizing adverse reactions for the majority of patients. They do not take into account the wide range of tissue optical properties for human skin, contributing to relatively low treatment success rates. Additionally, treatment times can be unnecessarily long for large treatment areas if the laser power is not sufficient. Both of these concerns can be addressed by the incorporation of an integrating sphere into the irradiation apparatus. The light fluence rate can be increased by as much as 100%, depending on the tissue optical properties. This improvement can be determined in advance of treatment by measuring the reflectance from the tissue through a side port on the integrating sphere, allowing for patient-specific treatment times. The sphere is also effective at improving beam flatness, and reducing the penumbra, creating a more uniform light field. The side port reflectance measurements are also related to the tissue transport albedo, enabling an approximation of the penetration depth, which is useful for real-time light dosimetry.

2D/3D registration algorithm for lung brachytherapy

PURPOSEnA 2D∕3D registration algorithm is proposed for registering orthogonal x-ray images with a diagnostic CT volume for high dose rate (HDR) lung brachytherapy.nnnMETHODSnThe algorithm utilizes a rigid registration model based on a pixel∕voxel intensity matching approach. To achieve accurate registration, a robust similarity measure combining normalized mutual information, image gradient, and intensity difference was developed. The algorithm was validated using a simple body and anthropomorphic phantoms. Transfer catheters were placed inside the phantoms to simulate the unique image features observed during treatment. The algorithm sensitivity to various degrees of initial misregistration and to the presence of foreign objects, such as ECG leads, was evaluated.nnnRESULTSnThe mean registration error was 2.2 and 1.9 mm for the simple body and anthropomorphic phantoms, respectively. The error was comparable to the interoperator catheter digitization error of 1.6 mm. Preliminary analysis of data acquired from four patients indicated a mean registration error of 4.2 mm.nnnCONCLUSIONSnResults obtained using the proposed algorithm are clinically acceptable especially considering the complications normally encountered when imaging during lung HDR brachytherapy.

SU-E-T-34: Time Series Analysis of Skin Reactions during Heck and Neck IMRT

Purpose: To quantitatively characterize the time sequence of skin erythema in head and neck patients undergoing intensity modulated radiation therapy(IMRT)treatments using optical reflectance spectroscopy. The overall goal is to identify patients who will develop extreme skin responses earlier than is possible by visual inspection alone. Methods: Ten (10) patients undergoing IMRT for the treatment of head and neck cancers were followed throughout the course of their intervention. Daily spectralskin reflectance measurements were made in order to track changes in the tissue optical properties. Weekly thermoluminescent detector(TLD) readings were performed in the measurement area to verify the dose calculated by the treatment planning system. Patients also completed a weekly questionnaire on factors that may have affected their skin reaction, and were visually inspected by a radiation oncologist.Results: The data were fit by a 2‐component principle component analysis (PCA) model. The preliminary results show that absorbed dose is the largest contributor to changes in the spectral reflectance and that those changes are seen primarily at wavelengths above 600 nm. Differences among patient skin responses were seen and accounted for in the model Conclusions: The PCA model indicates that it may be possible to predict a patients spectralskin reflectance measurement on the final day of treatment given an initial spectrum and the dose. Therefore, further analysis of the data may yield a method of determining patient reactions before visible signs are detected. Partial funding through Varian, Inc. and the Natural Sciences and Engineering Research Council of Canada.

Hyperspectral Imaging and Classification for Grading Skin Erythema

Erythema is an inflammatory condition of the skin that is commonly used as a feature to monitor the progression of cutaneous diseases or treatment induced side effects. In radiation therapy, skin erythema is routinely assessed visually by an expert using standardized grading criteria. However, visual assessment (VA) is subjective and commonly used grading tools are too coarse to score the onset of erythema. Therefore, an objective method capable of quantitatively grading early erythema changes may help identify patients at higher risk for developing severe radiation induced skin toxicities. The purpose of this study is to investigate the feasibility of using hyperspectral imaging (HSI) for quantitative assessment of early erythema and to characterize its performance against VA documented on conventional digital photographic red-green-blue (RGB) images. Erythema was induced artificially on 3 volunteers in a controlled pilot study; and was subsequently measured using HSI, color imaging, and reflectance spectroscopy. HSI and color imaging data was analyzed using linear discriminant analysis (LDA) to perform classification. The classification results, including accuracy and precision, demonstrated that HSI is superior to color imaging in skin erythema assessment.