Clive J. Kelty

The History of Photodetection and Photodynamic Therapy

Abstract Light has been employed in the treatment of disease since antiquity. Many ancient civilizations utilized phototherapy, but it was not until early last century that this form of therapy reappeared. Following the scientific discoveries by early pioneers such as Finsen, Raab and Von Tappeiner, the combination of light and drug administration led to the emergence of photochemotherapy as a therapeutic tool. The isolation of porphyrins and the subsequent discovery of their tumor-localizing properties and phototoxic effects on tumor tissue led to the development of modern photodetection (PD) and photodynamic therapy (PDT). This review traces the origins and development of PD and PDT from antiquity to the present day.

Barrett's oesophagus: Intestinal metaplasia is not essential for cancer risk

Objective. Barretts oesophagus is the main identifiable risk factor for oesophageal adenocarcinoma. It has been suggested that only patients with intestinal metaplasia are at risk of cancer, but the British Society of Gastroenterology (BSG) guidelines suggest that glandular mucosa is all that is needed. The aim of this study was to quantify the risk of adenocarcinoma in columnar-lined lower oesophagus, with or without specialized intestinal metaplasia. Material and methods. All patients who had endoscopic biopsies of the lower oesophagus between 1980 and 1994 in a single-centre teaching hospital were included in the study. All histological specimens were re-examined and reported according to whether they contained columnar epithelial-lined lower oesophagus, glandular mucosa, with or without intestinal metaplasia. The primary outcome measure was the development of adenocarcinoma. Results. In total, 712 patients were identified. Of these, 379 (55.1%) were found to have specialized intestinal metaplasia (SIM), and the remaining 309 (44.9%, p=NS) were reported as having glandular mucosa (GM). The median follow-up for patients was 12 years (range 8–20 years). Twenty-eight patients went on to develop adenocarcinoma (4.1%) during the follow-up period – 17 in the SIM group (4.5%) and 11 in the GM group (3.6%, p=NS). The oesophageal malignancy rate was 0.34% per year (SIM 0.37%, GM 0.30%; p=NS). Conclusions. Patients who have glandular mucosa on biopsy without intestinal metaplasia have a similar cancer risk to those with specialized intestinal metaplasia.

Endoscopic ablation of Barrett's oesophagus: a randomized‐controlled trial of photodynamic therapy vs. argon plasma coagulation

Background : Barretts oesophagus is the major risk factor for oesophageal adenocarcinoma. 5‐Aminlevulinic acid‐induced photodynamic therapy and argon plasma coagulation have been shown to be effective for ablating Barretts oesophagus, but a comparative trial of these two modalities has not been reported.

The use of 5-aminolaevulinic acid as a photosensitiser in photodynamic therapy and photodiagnosis

Photodynamic therapy (PDT) is a treatment for cancer and pre-malignant conditions, which involves the administration of a photosensitising agent followed by exposure of the tissue to light. 5-Aminolaevulinic acid (ALA) is a naturally occurring compound in the haem biosynthetic pathway, which is metabolised to a photosensitive product, protoporphyrin IX (PpIX). The major advantage of ALA when compared to synthetic photosensitisers is the rapid metabolism, which significantly reduces the period of cutaneous photosensitivity. This review focuses on the development of ALA as a photosensitiser in photodynamic therapy and photodiagnosis, and the wide range of clinical applications in which ALA is now being used as a therapeutic modality.

Comparison of high- vs low-dose 5-aminolevulinic acid for photodynamic therapy of Barrett's esophagus.

Background: Barrett’s esophagus is the major risk factor for esophageal adenocarcinoma, the incidence of which is increasing rapidly in the Western world. Aminolevulinic acid for photodynamic therapy (ALA-PDT) is effective in the treatment of Barrett’s esophagus, but controversy exists regarding optimum ALA dosage. The aim of this study was to establish the optimum dosage regime for ALA-PDT for Barrett’s esophagus. Methods: Twenty-five patients with Barrett’s esophagus were randomized to receive 30 (low-dose) or 60 (high-dose) mg/kg oral ALA at 4 or 6 h or 30 mg/kg in two fractions 4 and 6 h before PDT. PDT was standardized using red (635 nm) light. Biopsy specimens were taken for protoporphyrin IX (PpIX) quantification. Endoscopy was repeated 4 weeks later. Results: All patients showed a macroscopic response, with squamous re-epithelialization. This response was greatest in the 30 mg/kg and fractionated ALA groups. There was no significant difference in response between dosing 4 or 6 h prior to PDT. Tissue levels of PpIX were similar for all dosage groups and were not predictive of clinical response. Side effects were more common with the higher dose of ALA. Conclusion: Low-dose ALA-PDT appears to be a safe protocol for the ablation of Barrett’s esophagus.

Light dosimetry measurements during ALA-PDT of Barrett's oesophagus

A fibre optic probe and compact light detection system has been used to monitor the fluence-rate at the tissue surface during 5-aminolaevulinic acid based photodynamic therapy (PDT) of Barretts oesophagous. The contributions from three specific wavelengths were recorded, corresponding to the combination of therapeutic laser light and fluorescence emission from protoporphyrin IX (635nm), the fluorescence from an oxidation product of the photosensitiser (670nm), and the protoporphyrin IX fluorescence alone (705nm). We have found that light scattering results in an enhancement of the therapeutic fluence-rate, and hence light dose, by approximately 70%. At the onset of therapy the fluorescence provides a 10% contribution to the overall fluence-rate at 635nm. The dynamics of photosensitiser bleaching could be extracted from the depletion in light signals. By defining a bleaching dose as the 635nm light fluence delivered over the period during which the photosensitiser fluorescence decays to 1/e(3) of its initial value, we find that the average ratio of bleaching to total dose is 33%. Further, the fluorescence contributes approximately 5% of the bleaching light dose. These results suggest that the prescribed period of therapeutic light exposure may be reduced with no loss in clinical efficacy, but with a consequent improvement in patient tolerance to this therapy.