Linda R. Jones

The Science of Phototherapy: An Introduction

1: An Overview of Phototherapy. 2: Optical Physics and Biotechnology. 3: Phototherapy light sources. 4: Quantum Description of Light Interactions with Matter. 5: Tissue Optics. 6: Photochemical Damage to Biological System. 7: Optical Methods of Imaging and Diagnosis. 8: Light Dosimetry Modeling for Phototherapy. 9: Laser Interactions with Tissues. 10: Photodynamic Therapy: Science and Technology. 11: Photodynamic Therapy: Clinical Aspects. 12: Phototherapy of Skin Disease: Science and Technology. 13: Phototherapy of Neonatal Jaundice.

Singlet oxygen generation by Photofrin® in homogeneous and light-scattering media

The singlet oxygen quantum yield (phi delta) for Photofrin solubilized by Triton X-100 was measured in homogeneous and light-scattering media using the photosensitized inactivation of lysozyme as an internal actinometer. Higher values of phi delta at 630 nm than at 514 nm are attributed to the formation of a far-red-absorbing photosensitizing photoproduct.

Pilot study on light dosimetry variables for photodynamic therapy of Barrett's esophagus with high-grade dysplasia.

Purpose: Photodynamic therapy (PDT) is used to treat Barretts esophagus with high-grade dysplasia and mucosal carcinoma. Outcomes are variable with some patients having persistent disease, whereas others develop strictures. The aims of this study were (a) to compare porfimer sodium tissue uptake, light dose, and esophageal thickness with clinical outcomes and (b) to determine the selectivity of porfimer sodium uptake in diseased and normal epithelium. Experimental Design: Forty-eight hours after porfimer sodium infusion, patients underwent mucosal biopsy for quantification of the porfimer sodium. Laser light was delivered at 48 hours and again 24 or 48 hours later. Porfimer sodium was extracted from the biopsy samples and quantified using fluorescence spectroscopy. The enhanced photodynamic dose was determined as [porfimer sodium content * light dose/esophageal thickness]. PDT efficacy was determined 6 to 8 weeks later based on persistence or complete ablation of dysplasia or carcinoma. Results: Mean porfimer sodium content of 6.2 mg/kg (range, 2.6-11.2 mg/kg) and mean total light dose of 278 J/cm (range, 225-360 J/cm) resulted in a complete treatment. Mean porfimer sodium tissue content of 3.9 mg/kg (range, 2.1-8.1 mg/kg) and mean total light dose of 268 J/cm (range, 250-350 J/cm) resulted in an incomplete treatment. The total esophageal thickness (range, 1.7-6.0 mm) and enhanced photodynamic dose were correlated with treatment outcome. Conclusions: Esophageal thickness is the strongest predictor of treatment outcome. The porfimer sodium content of Barretts and normal tissue is not significantly different. “Photodynamic dose” for esophageal PDT should incorporate the esophageal thickness.

Performance evaluation of fiber optic probes for tissue lifetime fluorescence spectroscopy

The design of fiber-optic probes plays an important role in optical spectroscopic studies, including fluorescence spectroscopy of biological tissues. It can affect the light delivery and propagation into the tissue, the collection efficiency (total number of photons collected vs. total number of photons launched) and the origin of collected light. This in turn affects the signal to noise ratio (SNR) and the extend of tissue interrogation, thus influencing the diagnostic value of such techniques. Three specific fiber-optic probe designs were tested both experimentally and computationally via Monte Carlo simulations. In particular, the effects of probe architecture (single-fiber vs. two bifurcated multifiber probes), probe-to-target distance (PTD), and source-to-detector separation (SDS) were investigated on the collected diffuse reflectance of a Lambertian target and an agar-based tissue phantom. This study demonstrated that probe architecture, PTD, and SDS are closely intertwined and considerably affect the light collection efficiency, the extend of target illumination, and the origin of the collected reflected light. Our findings can be applied towards optimization of fiber-optic probe designs for quantitative fluorescence spectroscopy of diseased tissues.

Monte Carlo Model of Stricture Formation in Photodynamic Therapy of Normal Pig Esophagus

Photodynamic therapy (PDT) is FDA‐approved for use in patients with Barrett’s esophagus using porfimer sodium (2 mg per kg) and a recommended light dose of 130 J cm−1 for high grade dysplasia. Despite uniform drug and light doses, the clinical outcome of PDT is variable. A significant number of PDT cases result in esophageal strictures, a side effect related to excessive energy absorption. The purpose of this project was to model esophageal stricture formation with a Monte Carlo simulation. An original multilayer Monte Carlo computer simulation was developed for esophageal PDT. Optical absorption and scattering coefficients were derived for mucosal and muscle layers of normal porcine esophagus. Porfimer sodium was added to each layer by increasing the absorption coefficient by the appropriate amount. A threshold‐absorbed light dose was assumed to be required for stricture formation and ablation. The simulation predicted irreversible damage to the mucosa with a 160 J cm−1 light dose and damage to the muscle layer with an additional 160 J cm−1 light dose for a tissue porfimer sodium content of 3.5 mg kg−1. The simulation accurately modeled photodynamic stricture formation in normal pig in vivo esophageal tissue. This preliminary work suggests that the absorbed light threshold for stricture formation may be between 2 and 4 J per gram of tissue.

Effects of Photofrin® on in vivo skin reflectivity

Skin reflection spectra were measured before and 24 h after administration of Photofrin to nevoid basal-cell carcinoma syndrome patients. The presence of the drug reduced the reflectivity of uninvolved skin and increased the reflectivity of erythematous basal cell cancers. Data analysis with diffusion approximation and Monte Carlo simulation were employed to estimate the optical constant changes and localized drug concentration.

Variables in photodynamic therapy for Barrett's esophagus

Photodynamic therapy with porfimer sodium (PS) is a treatment option for high grade dysplasia associated with Barretts esophagus. This study sought to investigate the optical properties of Barretts dysplasia that may be useful in light dosimetry planning and to determine the effect of PS on tissue absorption and scattering. Fiber optic reflectance spectra were collected before and 48 hours after administration of 2 mg/kg PS. Mucosal biopsies were collected at the same locations. According to Monte Carlo analysis, the fiber optic probe sampled only the mucosal layer. A mathematical fit of the reflectance spectra was performed as a function of blood volume fraction, oxygen saturation and scattering. The average calculated blood volume was 100% higher in Barretts tissue than normal esophageal tissue. The average scattering slope from 620 to 750 nm was 26% higher for Barretts dysplasia than normal esophageal tissue, indicating an increase in the size of scattering particles. The difference in the scattering amplitude was not statistically significant, suggesting no significant increase in the number of scattering particles. PS tissue content was determined with extraction methods. Changes in the scattering slope due to PS sensitization were observed; however they were not proportional to the extracted PS concentration.

Light dosimetry calculations for esophageal photodynamic therapy using porfimer sodium

Background: Photodynamic therapy using porfimer sodium (Ps-PDT) is approved for use in patients with Barretts highgrade dysplasia and esophageal carcinoma. Ps-PDT light dosimetry, however, is critically important to treatment outcomes since insufficient ablation results in residual dysplasia and carcinoma while excessive treatment results in stricture formation. Aim: The aim of this study was to model esophageal PDT with optical absorption and scattering coefficients derived from an ex-vivo porcine multilayer esophagus model. Methods: Optical coefficients were derived for the mucosal and muscle layers of normal pig esophagus. The mucosal layer (mucosa, muscularis mucosa and submucosa) was separated from the muscle layer. Diffuse reflectance and transmittance were measured with an integrating sphere spectrophotometer. Absorption and reduced scattering coefficients were determined with the inverse adding doubling method. (Table not available in abstract, see pdf of paper) Multilayer Monte Carlo simulation and single-layer mathematical dosimetry equations were employed to model esophageal PDT with the derived coefficients. Porfimer sodium addition was modeled with an increase in both absorption and scattering. Depth of injury, assumed to require a threshold light dose, was estimated for various light doses commonly used in clinical practice. Depth of injury was then compared to clinical outcomes reported in the literature for various light doses.