Dwayne J. Dickey

Light dosimetry using the P3 approximation

In earlier work, we demonstrated that radiance, calculated using the P3 approximation in a plane wave geometry, could be used to accurately predict the optical parameters of an Intralipid/methylene blue phantom. Plane wave geometry is impractical for clinical use but the results of this work encouraged us to further develop the P3 approximation for a spherical geometry, described in this paper. Radiance predicted by this model for a defined Intralipid/methylene blue phantom was compared with radiance measured in this phantom. The results demonstrate that the spherical derivation of the P3 approximation will reproducibly predict optical parameters of a tissue phantom as effectively as the slab geometry derivation of the P3 approximation. In a similar protocol, the P3 approximation was used to estimate the optical parameters of ex vivo human prostate. Radiance in this case was measured in the prostate samples using an after loading technique. Three prostate samples tested were found to be surprisingly optically homogeneous. The after loading protocol described in this paper could form the basis of a minimally invasive and effective clinical method to optically characterize human prostate.

Fractionated versus Standard Continuous Light Delivery in Interstitial Photodynamic Therapy of Dunning Prostate Carcinomas

Purpose: The study aims to compare the standard/continuous light delivery with fractionated light delivery for interstitial photodynamic therapy (PDT) of prostate cancer. Experimental Design: Dunning R3327 prostate tumor models were established in male syngeneic rats. When tumors reached ∼3,000 mm3, animals were randomized to various treatment groups. Three hours after QLT0074 injection, tumors were illuminated by 690-nm light delivered by a computer-controlled switch, which sequentially directed light to one of the seven optical fibers in cycles. For comparison, tumors were treated with continuous illumination. Tumors treated with light-only served as control. Dynamic contrast-enhanced magnetic resonance imaging was used to monitor tumor perfusion changes before and after PDT. Results: Tumor response (animal survival) to PDT with fractionated light delivery was PDT dose dependent in both tumor models. Rats bearing anaplastic tumor treated by fractionated light (PDT dose: 1.5 mg/kg QLT0074, 900 J light) had a median survival of 51 days with 25% tumor cures compared with that of 26 days with no tumor cure by continuous illumination (P = 0.015) and 14 days by light-only (P = 0.0001). Rats bearing well-differentiated tumor treated by fractionated light had a median survival of 82 days compared with 65 days by continuous illumination (P = 0.001) and 37 days by light-only. PDT with fractionated light generated a perfusion reduction of 80% compared with 52% for continuous illumination in well-differentiated tumors. Conclusions: Fractionated light delivery is more effective than continuous light delivery in PDT of prostate cancer (solid tumors). These results warrant further investigation in clinical trials.

Radiance modelling using the P3 approximation

Light dosimetry is an essential component of effective photodynamic therapy (PDT) of tumours. Present PDT light dosimetry techniques rely on fluence-based models and measurements. However, in a previous paper by Barajas et al, radiance-based light dosimetry was explored as an alternative approach. Although successful in demonstrating the use of Monte Carlo (MC) simulations of radiance in tissue optical characterization, the MC proved time consuming and impractical for clinical applications. It was proposed that an analytical solution to the transport equation for radiance would be desirable as this would facilitate and increase the speed of tissue characterization. It has been found that the P3 approximation is one such potential solution. Radiance and fluence expressions based on the P3 approximation were used to optically characterize an Intralipid-based tissue phantom of varying concentration of scatterer (Intralipid) and absorber (methylene blue) using a plane wave illuminated, semi-infinite medium geometry. The results obtained compare favourably with the Grosjean approximation of fluence (a modified diffusion theory) using the same optical parameters (mu(a), mu(s), g). The results illustrate that radiance-based light dosimetry is a viable alternative approach to tissue characterization and dosimetry. It is potentially useful for clinical applications because of the limited number of invasive measurements needed and the speed at which the tissue can be characterized.

Photodynamic Therapy of the Canine Prostate: Intra-arterial Drug Delivery

PurposeInterstitial photodynamic therapy (PDT) selectively destroys tissue targeted with a photosensitizer and then exposed to light of a specific wavelength. We report a novel delivery method—intra-arterial drug delivery for PDT of the prostate—in a canine model.MethodsTo evaluate drug distribution, the prostatovesical artery was selectively cannulated and photosensitizers alone or in conjunction with 99m-technetium-labeled macro-aggregated albumin (99mTc-MAA) were injected via a 3 Fr microcatheter in 8 animals. One dog was followed for 3 months to determine tolerance and toxicity. The remaining animals were euthanized and imaged with whole-body single photon emission CT and gamma counting for radioactivity distribution. Photosensitizer distribution was further analyzed by fluorescence confocal microscopy and tissue chemical extraction. To evaluate PDT, the photosensitizer QLT0074 was infused in 3 animals followed by interstitial illumination with 690 nm laser light.ResultsIntra-arterial infusion selectively delivered drugs to the prostate, with both radioactivity and photosensitizer levels significantly higher (up to 18 times) than in the surrounding organs (i.e., rectum). With unilateral injection of 99mTc-MAA, only the injected half of the prostate showed activity whereas bilateral administration resulted in drug delivery to the entire prostate. PDT resulted in comprehensive damage to the prostate without severe complications or systemic toxicity.ConclusionInjection of radiolabeled MAA into the prostatovesical artery results in distribution within the prostate with negligible amounts reaching the adjacent organs. PDT also demonstrates selective damage to the prostate, which warrants clinical application in targeted prostate therapies.

Dosimetric considerations of interstitial photodynamic therapy of the canine prostate mediated by intra-arterially administered hypocrellin derivative

Interstitial photodynamic therapy (iPDT) is a promising minimally invasive treatment modality for locally confined prostate cancer. Therapeutically excited at 635nm, the photophysical properties of SL-052 (a novel hypocrellin derivative photosensitizer) lend themselves uniquely to iPDT, facilitating real-time monitoring. Under 635nm excitation, SL-052 exhibits near infrared fluorescence, allowing both photosensitizer fluorescence and tissue transmissivity to be continuously monitored. The absorption and fluorescence characteristics of SL-052 in vivo and in vitro are first illustrated. SL-052 mediated iPDT of canine prostate was performed with a novel switched light delivery system and novel intra-arterial drug delivery method. A preliminary examination of the dosimetric properties of intra-arterial iPDT is presented, focusing on transmissivity dynamics. Spectrofluorimetry results relating specifically to the unique photophysical properties of SL-052 iPDT are also included.

Fractionated PDT light delivery system based on fiber optic switching technology

Photodynamic Therapy, PDT, promises to be an effective and minimally invasive modality for the treatment of this early stage disease. Typically PDT of solid tumours is performed using an array of interstitial fibreoptic light sources implanted in the tumour, illuminated continuously with light from a single laser until the required lethal dose of light is delivered. The literature teaches that PDT is dose rate independent so that the illumination intensity of the sources will not influence the therapeutic outcome. Recent work, however, suggests that this teaching should be qualified. PDT will saturate when the cellular oxygen is depleted, consumed by the photo-oxidation of the photosensitizer. This implies that time fractionated light delivery should increase the lethality of treatment. In this paper we describe a computer controlled time fractionated fibre optic light delivery/detection system that may be used to synchronize treatment and tissue perfusion. Two laser diodes are each coupled to a computer controlled fibreoptic switch. The switch couples the laser sequentially to an array of interstitial fibre optic light sources. The dose delivered to each source is time moderated so that a non-uniform dose distribution may be delivered across the tumour. We describe preliminary results of this light delivery system and the photo-toxin QLT0074 for the treatment of rats with AT an -H flank tumours. We also compare tissue response to both time-fractionated and continuous light delivery.

Large-area slab gas laser discharge

A technique for eliminating electrical standing waves from the electrodes of a large area CO2 Slab laser is described. This method is general and may be used to smooth the electric field distribution over planar electrodes of arbitrary dimensions and coaxial electrodes.

Predicting fluence measurements from a cylindrical diffusing tip using the P3-approximation

Photodynamic Therapy (PDT) is becoming a popular treatment modality for many superficial cancers and several non-malignant diseases. The use of PDT to treat solid tumors has been limited because there is currently is no clinically acceptable method of either characterizing the optical parameters of a target tissue or of determining dose delivered to the target tissue volume as delivered by a fibreoptic terminated in a cylindrical diffusing tip. Accurate light dosimetry methods, such as the Monte Carlo method, are of limited clinical utility. In this paper we describe the use of the P3-Approximation to optically characterize a light scattering and absorbing medium. Tissue characterization calculations made using the P3-Approximation are analytical and may be performed much faster than with numerical modeling. The process time needed to estimate the dose distribution is sufficiently short to permit iterative adjustment of the light source distribution to account for tissue inhomogeneities, in real time. P3-Approximation based optical dosimetry should be sufficiently fast to be incorporated into an iterative feedback control algorithm for the distribution of light across an interstitial source array. With the optical coefficients furnished by the P3-Approximation, the light dose delivered to the medium from a cylindrical fibreoptic source can be accurately calculated using a novel formulation of Diffusion Theory. The cylindrical fibreoptic diffuser is modeled as a Huygens array: a finite yet continuous array of isotropic point sources. The predicted light fluence distribution from the Huygens array compares favorably with experimental fluence measurements.