Laser and Non-laser Light Sources for Photodynamic Therapy

. Photodynamic therapy (PDT) is an anticancer combination therapy, which requires a photosensitiser, which tends to accumulate preferentially in the tumour, and light. Historically large, complex lasers have been used to carry out PDT treatment. Nowadays there is a wide range of coherent and non-coherent sources that can be used. This paper considers the important characteristics of light sources for PDT, including dye lasers pumped by argon or metal vapour lasers and frequency-doubled Nd:YAG lasers. Non-laser sources including tungsten filament, xenon arc, metal halide and fluorescent lamps are also discussed. New exiciting developments such as LEDs and femtosecond lasers are also reviewed. The relative merits of laser and non-laser sources are critically examined. Paper received 18 June 2001; accepted 6 December 2001.     

Histological Examination of Bronchial Mucosa after Photodynamic Therapy Showing no Selectivity of Effect between Tumour and Normal Mucosa

.After the treatment for early stage bronchogenic carcinoma including carcinoma in situ with photodynamic therapy (PDT), the degree of bronchial mucosal damage was studied histologically. The influence of treatment modality on bronchial mucosa was also examined. Few studies of histological changes of bronchial mucosa caused by PDT have been done. The histological specimens of bronchial mucosa in patients who received PDT and had a complete response were reviewed retrospectively. Twenty-three patients with 24 carcinomas including six carcinomas in situ had been treated with PDT using argon dye laser, excimer dye laser with or without additional radiotherapy. The degree of epithelial and subepithelial changes was classified as normal, hyperplasia, metaplasia and as mild, moderate and marked fibrosis, respectively. Subepithelial fibrosis was seen after PDT in almost all cases even when the tumour was entirely superficial to this layer. As a whole, epithelial change was found to be hyperplastic in three and metaplastic in 13 cases. Subepithelial fibrosis were found to be mild in four, moderate in 13, and marked in four cases. No differences were seen between the effects with the excimer and argon dye lasers. As used at present, PDT in the bronchi has no selectivity between normal and tumour tissue but may have advantages over other techniques due to the lack of cumulative toxicity and the excellent healing. Received for publication 15 September 1997; accepted following revision 23 February 1998     

A Fibreoptic Light Distributor for the Preventative Photodynamic Therapy of Secondary Cataract

. A device for the preventative photodynamic therapy of secondary cataract has been developed. Disturbance of the epithelial cells of the crystalline lens during the primary cataract surgery and/or their migration thereafter can frequently generate secondary cataract. This can generally be prevented by destroying these epithelial cells. One approach is to expose them to a phototoxic dye which is then activated by selective exposure to light. For this purpose we designed a light distributor furnishing a torus-shaped light intensity profile, allowing for selective destruction of these epithelial cells, while preventing any potentially damaging exposure to other parts of the eye. The size and geometry of the device are adapted to the eye's anatomy, providing a relatively homogeneous irradiation of the treated zone of up to about 2.7 J/cm² in 1 min. The device is easy to handle and is sterilisable with ethylene oxide gas. Paper received 17 August 1999; accepted after revision 24 March 2000.     

Optimisation of Illumination for Photodynamic Therapy With mTHPC on Normal Colon and a Transplantable Tumour in Rats

. Recent reports suggest that the effect of photodynamic therapy (PDT) can be enhanced by fractionating the light dose or reducing the light fluence rate. We assessed these options on two tissues in rats (normal colon and a transplanted fibrosarcoma) using the photosensitiser meta-tetrahydroxyphenylchlorin (mTHPC). Animals were sensitised with 0.3 mg/kg mTHPC, 3 days prior to illumination with red light (652 nm) using a single fibre touching the target tissue and killed 1–3 days later for quantitative measurement of the extent of PDT necrosis. Results were similar for both tissues, although the differences between illumination regimens were less marked in tumour tissue. Using continuous illumination and a fixed low energy in colon, the extent of necrosis was up to almost three times larger with 5 mW than with 100 mW, although the maximum attainable necrosis was independent of power. The long treatment time using 5 mW could be halved without loss of effect by increasing the power during treatment. Dividing the light into two equal fractions at 100 mW increased the lesion size by up to 20% in colon (independent of the timing of the dark interval), but by only 10% in tumour and had no effect at 20 mW. Previous studies using 5-aminolaevulinic acid (ALA) showed a much larger effect of fractionation that was critically dependent on the timing of the dark interval. We postulate that enhancement of PDT by fractionation is due to improved oxygen supply to the treated area which may be due to reversal of temporary vascular occlusion (more likely with ALA) or less rapid photochemical consumption of oxygen (more likely with mTHPC). At lower fluence rates, the oxygen consumption rate is not fast enough to be improved by fractionation. We conclude that fractionated or low power light delivery can enhance PDT with mTHPC. Although the effects are not large, this may be of value for interstitial treatment of solid tumours when multiple sites are treated simultaneously. Paper received 9 April 2001; accepted after revision 28 September 2001.     

Damage to Tumour and Brain by Interstitial Photodynamic Therapy in the 9L Rat Tumour Model Comparing Intravenous and Intratumoral Administration of the Photosensitiser

Summary In the 9L rat brain tumour model the damage to tumour and normal brain by photodynamic therapy after intratumoural photosensitizer administration (intratumoural PDT) was studied. Twenty four rats received an intratumoural injection of 4 or 40 mm³ haematoporphyring deriative (HpD, 5 mg ml^–1), followed by interstitial irradiation with 20 Joule (J) (630 nm) 5 h later. For comparison, seven rats were treated with 20 Joule 24 h after an intravenous injection of 10 mg kg^–1 HpD (intravenous PDT). With the chosen PDT parameters there was no important difference between the damaged areas produced by intratumoural PDT or intravenous PDT. No selective tumour kill was observed. Even though normal brain tissue was heavily damaged, vital tumour parts were still present. Intravenous PDT caused extensive diffuse damage to small blood vessels in tumour and surrounding normal brain. Intratumoural PDT was characterised by an infiltration of polymorphonuclear cells into damaged tissue, dilatation of larger blood vessels and gross haemorrhage. These results suggest an immediate vascular shutdown in the intravenous approach, while in the intratumoural approach the vasculature remained patent initially. Because of the severe side effects observed, the use of HpD seems not advisable for intratumoural PDT of brain tumours.     

Photodynamic Therapy (PDT) of Gastrointestinal Tumours: A New Light Delivery System

The Paterson lamp is a convenient, low cost, portable, alternative light source to lasers for photodynamic therapy (PDT). A multiwavelength capability enables the clinician to vary the photosensitiser used. The Paterson lamp has been applied in the field of dermatology using a liquid light guide with distal optics for surface application. We now describe distal optics suitable for use with this light guide for intraluminal applications in the oesophagus and colorectum. The geometry of the site (oesophagus and colorectum) requires distal optics such as a cylindrical diffuser or a side-fire diffuser. We have designed new probes that diffuse light radially from the guide axis (cylindrical diffusion). The tips have a frosted glass surface that scatters and effectively couples light radially into the tissue. An acrylic spacer is placed over the diffuser to position the tissue at a constant diameter from the probe. This is held in position by a silicone sheath placed over the distal one metre. For use in the oesophagus, a channel, to facilitate intubation over a guide wire, is included. The diameter of the entire probe is 8.4 mm and the power output can be adjusted from 0–500 mW. Pilot PDT of tubulovillous adenomas of the rectum and Barrett's oesophagus using this light delivery system is currently underway and has shown good early response in the treated area. Paper received 6 October, 1997; accepted in final form 13 January 1998.     

Light dose fractionation versus single-dose irradiation in photodynamic therapy of tumours

The effect of photoirradiation fractionation on photodynamic therapy of Sarcoma 180 in mice was investigated. Photofrin II (10 mg/kg bodyweight) and different schedules of light dose fractionation were used. The inhibition of tumour growth was comparable when a dose of 1×300 J/cm² or 2×150 J/cm² was applied. However, the skin photoreaction and the normal tissue reactions in the irradiated area were weaker with the second schedule of irradiation. The best effect was reached with 6×50 J/cm², doses being given at 5-hour intervals between the 24th and 48th hours after drug administration. Despite the small total dose in the case of irradiation with 6×35 J/cm², the effect on the tumour was comparable with that reached using the first two schedules of treatment (total irradiation dose 300 J/cm²). With multiple photoirradiation fractionation the photodynamic therapeutic effect is considerably greater than with a single or double fractionation of irradiation using the same total dose. With the multiple light dose fractionation the normal tissue reactions in the irradiated areas are more weakly expressed than with a single or double fractionation of irradiation using the same total dose. The multiple photoirradiation fractionation allows a reduction in the total light dose necessary to achieve the same biological effect as with single or double irradiation.     

Aminolaevulinic Acid-induced Photodynamic Therapy in the Treatment of Dysplastic Barrett's Oesophagus and Adenocarcinoma

. Photodynamic therapy (PDT) may have a role in the prevention of oesophageal cancer. Ten patients with Barrett's oesophagus, three with low-grade dysplasia (LGD), four with high-grade dysplasia (HGD), one with carcinoma in situ and two with invasive carcinoma, were treated with PDT. All received 30 mg/kg aminolaevulinic acid (ALA) followed 4 h later by laser endoscopy. Half were treated with red light (630 nm; 100 mW/cm² for 1000 s) and half with green light (514 nm; 100 mW/cm² for 500 s). Columnar epithelial regression was seen in all patients with dysplasia (mean area decrease 44%; range 10–100%), with apparent elimination of dysplasia in all cases. In patients with in situ or invasive carcinoma, no response was seen. ALA-induced PDT, using either red or green light, produces effective ablation of dysplastic Barrett's oesophagus, hence may have a role in the prevention of oesophageal carcinoma, but has little effect on in situ or invasive adenocarcinoma. Paper received 3 January 1999; accepted after revision 12 April 1999.     

In vitro fluorescence measurements and Monte Carlo simulation of laser irradiation propagation in porcine skin tissue

In dermatology, the in vivo spectral fluorescence measurements of human skin can serve as a valuable supplement to standard non-invasive techniques for diagnosing various skin diseases. However, quantitative analysis of the fluorescence spectra is complicated by the fact that skin is a complex multi-layered and inhomogeneous organ, with varied optical properties and biophysical characteristics. In this work, we recorded, in vitro, the laser-induced fluorescence emission signals of healthy porcine skin, one of the animals, which is considered as one of the most common models for investigations related to medical diagnostics of human cutaneous tissues. Differences were observed in the form and intensity of the fluorescence signal of the porcine skin, which can be attributed to the different concentrations of the native fluorophores and the variable physical and biological conditions of the skin tissue. As the light transport in the tissue target is directly influencing the absorption and the fluorescence emission signals, we performed Monte Carlo simulation of the light distribution in a five-layer model of human skin tissue, with a pulsed ultraviolet laser beam.     

应用蒙特卡罗模拟优化肾功能亢进患者万古霉素给药方案的研究

目的根据万古霉素在肾功能亢进(ARC)和肾功能正常患者中的药物代谢动力学/药物效应动力学(PK/PD)原理,应用蒙特卡罗模拟优化ARC和肾功能正常患者万古霉素对常用革兰阳性菌的初始给药方案。方法使用文献公开发表的ARC及肾功能正常患者中的群体PK模型,收集2017至2019年南京医科大学附属苏州医院甲氧西林耐药金黄色葡萄球菌(MRSA)、甲氧西林耐药表皮葡萄球菌(MRSE)、粪肠球菌、屎肠球菌的最小抑菌浓度(MIC)分布。采用蒙特卡罗模拟计算不同万古霉素日剂量的目标获得概率(PTA)和累积反应分数(CFR),以预测达到与PK/PD参数指标AUC0~24 h/MIC的万古霉素给药剂量,推荐最佳给药方案。结果蒙特卡罗模拟结果显示,MIC=0.5时ARC患者对革兰阳性菌万古霉素日剂量2.0 g/d的PTA为97.30%,而肾功能正常患者只需要1.5 g/d,PTA即可达99.16%。MIC=1时,肾功能正常患者需要万古霉素2.5 g/d,PTA可达92.91%,而ARC患者需要万古霉素3.5 g/d,PTA才可达88.71%。当MIC≥2时,万古霉素常规推荐的给药剂量(2.0~4.0 g/d)很难达到理想的PTA值。对于常见革兰阳性菌,肾功能正常患者需要万古霉素3.0 g/d,CFR可达91.36%,而ARC患者需要万古霉素4.5 g/d,CFR可达90.60%。MRSA和屎肠球菌的MIC≤1的占比分别为97.25%和94.50%。肾功能正常患者MRSA感染给予万古霉素2.5 g/d,CFR可达93.95%,屎肠球菌给予万古霉素3.0 g/d,CFR可达94.46%;而ARC患者MRSA感染给予万古霉素3.5 g/d,CFR可达91.42%,屎肠球菌给予4.0 g/d,CFR可达93.07%。MRSE的MIC=1和2占比分别为64.64%和27.44%,粪肠球菌为77.09%和20.13%。肾功能正常患者粪肠球菌感染给予万古霉素4.0 g/d,CFR可达92.55%,MRSE需要万古霉素4.5 g/d,CFR可达92.79%,而ARC患者MRSE和粪肠球菌需要万古霉素6.0 g/d,CFR才可达88.35%和92.03%。当革兰阳性菌MIC≤0.5时ARC患者给予万古霉素2.0 g/d和肾功能正常者予1.5 g/d,PTA均可≥90%。MIC=1时肾功能正常患者推荐万古霉素3.0 g/d,ARC患者推荐万古霉素4.5 g/d,PTA和CFR可达90%以上。MIC≥2的革兰阳性菌万古霉素常规给药日剂量(2.0~4.0 g/d)对于ARC和肾功能正常患者均很难达到目标的PTA及CFR。结论与肾功能正常患者相比,ARC患者万古霉素需要更大的日剂量才可达目标PTA和CFR。MIC≥2的革兰阳性菌感染,建议改用其他敏感性更好的抗革兰阳性菌药物治疗。     

Development of an alternative light source to lasers for photodynamic therapy: 2. Comparative in vivo tumour response characteristics

The performance of a low cost, table-top/portable light source was tested against an argon ion pumped dye laser for in vivo photodynamic therapy (PDT). The prototype delivers up to 1 W via a 4 mm flexible lightguide within a 30 nm bandwidth centred at any wavelength from 300 nm to 1200 nm at fluence rates of up to 8 W cm^–2. An in situ bioassay using regrowth delay of tumour T50/80 was used to quantify the relative efficacy of the prototype with a laser. The tumours were sensitized with haematoporphyrin derivative (HpD) and externally irradiated. There was no significant difference in the response of the tumour to treatment between the two light sources (p = 0.69). Mean growth delays ranged from 2 days (light dose 10 J cm^–2) to 20 days (light dose 100 J cm^–2). The estimate for the difference in means (laser minus prototype growth delay) was only 0.66 days and was not statistically significant. This in vivo study demonstrates that the prototype is equivalent to a laser in PDT effect. The device has low capital/running cost, is simple to use and is one of the most powerful, spectrally efficient non-laser PDT sources available.     

Photodynamic Therapy with 5-aminolevulinic Acid 10% Gel and Red Light for the Treatment of Actinic Keratosis,Nonmelanoma Skin Cancers,and Acne: Current Evidence and Best Practices

Photodynamic therapy (PDT) can be an effective treatment for actinic keratosis (AK) as well as selected non-melanoma skin cancers (NMSCs), such as Bowen''s disease and superficial basal cell carcinoma. PDT has also demonstrated effectiveness in the management of acne vulgaris. Results from controlled clinical trials have shown the safety and efficacy of PDT for these conditions with the use of different photosensitizers and a wide range of light sources. PDT has been employed effectively as monotherapy and in combination with other topicals and alternate light or laser energy therapies. This article provides expert practical guidance for the use of the newest 5-aminolevulinic acid (ALA) product (ALA 10% gel) plus red light as monotherapy for AKs, NMSC, and acne. Here, information from clinical guidelines and a summary of supporting evidence is provided for each cutaneous condition. The authors also provide detailed guidance for employing ALA 10% gel, a photosensitizer precursor, for each of these applications.