Ronan Valentine

Monte Carlo simulations for optimal light delivery in photodynamic therapy of non-melanoma skin cancer

The choice of light source is important for the efficacy of photodynamic therapy (PDT) of non-melanoma skin cancer. We simulated the photodynamic dose (PDD) delivered to a tumour during PDT using theoretical radiation transfer simulations performed via our 3D Monte Carlo radiation transfer (MCRT) model for a range of light sources with light doses up to 75 J cm(-2). The PDD delivered following superficial irradiation from (A) non-laser light sources, (B) monochromatic light, (C) alternate beam diameters and (D) re-positioning of the tumour within the tissue was computed. (A) The final PDD deposited to the tumour at a depth of 2 mm by the Paterson light source was 2.75, 2.50 and 1.04 times greater than the Waldmann 1200, Photocure and Aktilite, respectively. (B) Tumour necrosis occurred at a depth of 2.23 mm and increased to 3.81 mm for wavelengths 405 and 630 nm, respectively

Monte Carlo modelling of daylight activated photodynamic therapy

The treatment of superficial skin lesions via daylight activated photodynamic therapy (PDT) has been explored theoretically with three dimensional (3D) Monte Carlo radiation transfer simulations. For similar parameters and conditions, daylight activated PDT was compared to conventional PDT using a commercially available light source. Under reasonable assumptions for the optical properties of the tissue, protoporphyrin IX (PpIX) concentration and a treatment dose of 75 J cm(-2), it was found that during a clear summer day an effective treatment depth of over 2 mm can be achieved after 30 min of daylight illumination at a latitude of 56 degrees North. The same light dose would require 2.5 h of daylight illumination during an overcast summer day where a treatment depth of about 2 mm can be achieved. For conventional PDT the developed model suggests that 15 min of illumination is required to deliver a light dose of 75 J cm(-2), which would result in an effective treatment depth of about 3 mm. The model developed here allows for the determination of photo-toxicity in skin tissue as a function of depth for different weather conditions as well as for conventional light sources. Our theoretical investigation supports clinical studies and shows that daylight activated PDT has the potential for treating superficial skin lesions during different weather conditions.

Mathematical modeling of the optimum pulse structure for safe and effective photo epilation using broadband pulsed light

The objective of this work is the investigation of intense pulsed light (IPL) photoepilation using Monte Carlo simulation to model the effect of the output dosimetry with millisecond exposure used by typical commercial IPL systems. The temporal pulse shape is an important parameter, which may affect the biological tissue response in terms of efficacy and adverse reactions. This study investigates the effect that IPL pulse structures, namely free discharge, square pulse, close, and spaced pulse stacking, has on hair removal. The relationship between radiant exposure distribution during the IPL pulse and chromophore heating is explored and modeled for hair follicles and the epidermis using a custom Monte Carlo computer simulation. Consistent square pulse and close pulse stacking delivery of radiant exposure across the IPL pulse is shown to generate the most efficient specific heating of the target chromophore, whilst sparing the epidermis, compared to free discharge and pulse stacking pulse delivery. Free discharge systems produced the highest epidermal temperature in the model. This study presents modeled thermal data of a hair follicle in situ, indicating that square pulse IPL technology may be the most efficient and the safest method for photoepilation. The investigation also suggests that the square pulse system design is the most efficient, as energy is not wasted during pulse exposure or lost through interpulse delay times of stacked pulses. PACS number: 87.10.Rt

Development of a handheld fluorescence imaging device to investigate the characteristics of protoporphyrin IX fluorescence in healthy and diseased skin

BACKGROUND Topical Photodynamic therapy (PDT) is an effective treatment for superficial non-melanoma skin cancers (NMSC) and dysplasia. During PDT light activates the photosensitiser (PpIX), metabolised from a topical pro-drug. A combination of PpIX, light and molecular oxygen results in inflammation and cell death. However, the outcomes of the treatment could be better. Insufficient biosynthesis of PpIX may be one of the causes of incomplete response or recurrence. Measuring surface fluorescence is usually employed as a means of studying PpIX formation. The aim of this work was to develop a device and a method for convenient fluorescence imaging in clinical settings to gather information on PpIX metabolism in healthy skin and NMSC with a view to improving PDT regimes. METHODS A handheld fluorescence camera and a time course imaging method was developed and used in healthy volunteers and patients diagnosed with basal cell carcinoma (BCC) and actinic keratosis (AK). The photosensitiser (precursor) creams used were 5-aminolaevulinic acid (ALA; Ameluz(®)) and methyl aminolevulinate (MAL; Metvix(®)). Pain was assessed using a visual analogue score immediately after the PDT. RESULTS Fluorescence due to PpIX increases over three hours incubation in healthy skin and in lesional BCC and AK. Distribution of PpIX fluorescence varies between the lesion types and between subjects. There was no significant correlation between PpIX fluorescence characteristics and pro-drug, diagnosis or pain experienced. However, there was a clear dependence on body site. CONCLUSION The device and the method developed can be used to assess the characteristics of PpIX fluorescence, quantitative analysis and time course. Our findings show that body site influences PpIX fluorescence which we suggest may be due to the difference in skin temperature at different body sites.

Laser-induced autofluorescence spectroscopy: Can it be of importance in detection of bladder lesions?

BACKGROUND Non-muscle invasive bladder cancer can be missed during white light endoscopy in up to 50% of cases. We aimed to test whether or not we could find a difference between benign and cancerous tissue wavelengths using laser induced autofluorescence spectroscopy can increase cancer detection. MATERIALS AND METHODS We analysed 67 tissue samples using spectral analysis. The WavSTAT (Spectra Science) optical biopsy device was used to record fluorescence spectra from biopsied tissue enabling calculation of an AUC for each spectrum, a measure of the mean spectral wavelength (λ¯ (nm)) and a dimensionless fluorescence ratio. Mann-Whitney test was used to compare the two groups. RESULTS We found that 49.3% (33/67) of the tissue was benign, 44.8% (30/67) was CIS/cancerous tissue, and the remaining 4/67 samples were atypia (2) and dysplasia (2). The median AUC for the benign tissue was 19.53 (interquartile range [IQR]: 5.35-30.39) and that for CIS/cancerous tissue was 7.05 (IQR: 2.89-14.24) (P=0.002). The median wavelengths for the benign tissue and malignant tissue were 502.4nm (IQR: 500.3-504.3nm) and 505.2nm (IQR: 502.1-513.2nm), respectively (P=0.003). The median fluorescence ratio was 0.080 (IQR: 0.070-0.088) for benign tissue and 0.096 (IQR: 0.079-0.221) for CIS/cancerous tissue (P=0.002). CONCLUSIONS We found statistical differences between the median AUC calculations and median wavelengths for the benign and cancerous tissue. We also found a statistical difference between the fluorescence ratios between the two tissue types. There seems to be a role for optical spectroscopy in verifying bladder lesions.

Is the pain of topical photodynamic therapy with methyl aminolevulinate any different from that with 5-aminolaevulinic acid?

Topical photodynamic therapy (PDT) using 5‐aminolaevulinic acid (ALA) or methyl aminolevulinate (MAL) is widely used in dermatology. It is commonly stated that MAL PDT is less painful than ALA PDT, although published data are conflicting. We report our experience of the use of ALA (4–6 h) (n = 20) and MAL (3 h) (n = 20) in 40 consecutive patients with Bowens disease or superficial basal cell carcinoma, treated with PDT using an identical irradiation regime. Although there was a trend to higher pain scores with ALA PDT [visual analogue scale (VAS)score, median 4.50], this was not significantly different from that of MAL PDT (VAS score, median 3.55; P = 0.98), nor considered to be clinically important. Importantly, both ALA and MAL PDT regimes were fairly well tolerated in this patient cohort, supporting the use of these prodrugs in dermatological PDT.

A multi-wavelength (u.v. to visible) laser system for early detection of oral cancer

A multi-wavelength (360nm – 440nm), real-time Photonic Cancer Detector (PCD) optical system based on GaN semiconductor laser technology is outlined. A proof of concept using blue laser technology for early detection of cancer has already been tested and proven for esophageal cancer. This concept is expanded to consider a wider range of wavelengths and the PCD will initially be used for early diagnosis of oral cancers. The PCD creates an image of the oral cavity (broad field white light detection) and maps within the oral cavity any suspicious lesions with high sensitivity using a narrow field tunable detector.

Porphyrin profile in four human cell lines after supplementation with 5-aminolaevulinic acid and its methyl ester

Multiple factors can affect the synthesis of the prodrugs aminolaevulinic acid and its methyl ester to protoporphyrin. These may ultimately influence the efficacy of ALA-induced porphyrin as a photosensitiser for photodynamic therapy or fluorescence diagnosis. This study demonstrates the variation in total amount of porphyrin produced and cellular porphyrins synthesised in four different human cell lines after supplementation with these prodrugs. A non-invasive optical biopsy system was able to detect spectral changes associated with the more carboxylated porphyrins accumulating in oesophageal (OE19) and bladder (HT1197) carcinoma cells, and to a lesser extent neuroblastoma (SH-SY5Y) cells after a 24h incubation with the prodrugs. If the porphyrin profile changes during disease progression, or between normal and cancerous cells clinically, then the demonstrated non-invasive spectral analysis may be exploitable in distinguishing between normal, dysplastic and tumour tissue. Finally, the OE19 cell line was insensitive to photo-inactivation under the experimental conditions used, despite accumulating more porphyrin than the other cells lines.

3D Monte Carlo radiation transfer modelling of photodynamic therapy

The effects of ageing and skin type on Photodynamic Therapy (PDT) for different treatment methods have been theoretically investigated. A multilayered Monte Carlo Radiation Transfer model is presented where both daylight activated PDT and conventional PDT are compared. It was found that light penetrates deeper through older skin with a lighter complexion, which translates into a deeper effective treatment depth. The effect of ageing was found to be larger for darker skin types. The investigation further strengthens the usage of daylight as a potential light source for PDT where effective treatment depths of about 2 mm can be achieved.

The effect of 222‐nm UVC phototesting on healthy volunteer skin: a pilot study

Frequent topical antiseptic use to hands is now common in healthcare and other work environments. Inevitably, the use of such antiseptics will present an occupational risk for irritancy and allergic dermatitis. New, less irritant and even non‐chemical antimicrobial approaches are under investigation.