Light delivery to tumour tissue through implanted optical fibres during photodynamic therapy

The maximum rate at which the light dose may be delivered during interstitial photodynamic therapy (PDT) has been measured for several types of delivery fibre. Measurements of light irradiance at the skin surface overlying subcutaneous experimental tumours were made during interstitial irradiation by 200m core diameter fibres whose output ends were either plane-cut or 5 mm long cylindrical diffusers. For plane-cut fibres, a rapid fall in light transmission, due to blood coagulation at the fibre tip, was observed at output powers greater than 229 mW and 104 mW in tumours with and without photosensitizer, respectively. Such a rapid fall was not observed with cylindrical diffusing fibres at output powers up to 1 W.In the clinical use of PDT the fibre output power is held constant at a level below which thermal effects may occur. In a second study, therefore, the irradiance at the skin surface was monitored for this treatment regime. A decrease in light transmission during treatment was observed. Plane-cut fibres showed a greater decrease than cylindrical diffusing fibres and for a given fibre type, non-photosensitized tumours showed a greater decrease than photosensitized tumours. For cylindrical diffusing fibres at output powers of 150 mW or less there was a 9% decrease in irradiance measured at the skin surface during the first 1000 s of treatment. The decrease was larger (30–40%) for fibre output powers in the range 200–300 mW.     

Construction,quality assurance and calibration of spherical isotropic fibre optic light diffusers

Spherical isotropic fibre optic light diffusers are used in photodynamic therapy either as a light source or as a light detector. The construction of light diffusers using different materials is described, viz. an optical method involving local polymerization of a dental fissure sealant, which is referred to as the Henderson method, and a second method using plastic or ceramic pre-fabricated spheres. Quality tests necessary for reliable clinical use are presented for the mechanical strength, output power and isotropy. The maximum pull-off force and blow-off output power for the different kinds of diffusers were determined. The calibration procedures are given for measurement of the output power and wavelength of the light emitted by a diffuser and for measurement of the fluence rate by a light-detecting diffuser, using a compact integrating sphere device. With all types of diffusers described, an isotropy can be obtained of better than ± 20% measured over a 320° angle for spheres as small as 1 mm. Larger ceramic diffusers are particularly suitable for delivering high output powers. A 3-mm-diameter ceramic diffuser mounted on a 600-m-core fibre can emit up to 5 W of continuous wave (CW) visible light in air. Diffusers used for light detection can measure the light fluence rate in tissue with 15% accuracy or better if calibration factors are determined for each individual probe.     

Interstitial photodynamic therapy in the Dunning R3327-AT6 prostatic carcinoma

Interstitial photodynamic therapy (PDT) could be an alternative radical treatment for prostate cancer. The ability to predict the depth of necrosis is necessary for light treatment planning using multiple optical fibres. The extent of PDT necrosis was studied in subcutaneously implanted R3327-AT6 Dunning prostate tumours which had similar optical characteristics to human prostate. Tumour-bearing subjects were given 20 mg kg^–1 Haematoporphyrin esters (HPE) and irradiated 24 h later with 630 nm laser light. Five subjects per group were treated with increasing light doses (50–450 J cm^–1) delivered interstitially via a single 2 cm long cylindrical diffuser. After 450 J cm^–1 of irradiation, 4.3±0.8 cm³ [standard error of the mean (s.e.m.)] of tumour tissue was necrosed to a depth of 10.5±0.8 mm around the diffuser. There was an approximately linear correlation between the volume of PDT necrosis around the fibre and prescribed light dose. The mean threshold light dose for PDT effect was 18±2 J cm^–2. In this tumour with a mean photosensitizer concentration of 16±1.5g g^–1, low light doses produced tumour necrosis. PDT using multiple diffusers could destroy a relatively large tumour volume and the diffusion theory model reliably predicted the depth of necrosis.     

Coagulation of blood at the tip of optical fibres used for light delivery in photodynamic therapy

Optimal delivery of light to the tumour is of considerable importance in photodynamic therapy. The most effective way of delivering laser light to the tumour tissue is through an implanted optical fibre. In order to investigate the possible effects taking place at the tips of fibres implanted in tissue, fibres were used to deliver light to human blood and the transmission of light by the blood was measured at different power levels. The maximum power level which could be delivered without charring or coagulation at the fibre tip was measured for five different fibres. Three plane cut fibres and two with 1.5 cm long diffusing tips were studied. Charring and coagulation, which resulted in practically no light being delivered more than 0.5 mm from the fibre tip, were observed at relatively low-output powers (70-130 mW) for all the plane-cut fibres. This is less than the level required to deliver a clinically useful dose in a reasonable time. In contrast, neither charring nor coagulation was observed at the diffusing tips for output powers up to 1.1 W and consequently these should be the fibres of choice for interstitial photodynamic therapy. Observed changes in light transmission through the blood with increasing output power indicate that, for accurate light dosimetry, a means of monitoring delivered light in vivo during photodynamic therapy is essential.     

In vitro Alexandrite laser angioplasty: A study on fibre conduction and tissue effects

Pulsed ultra-violet excimer laser radiation is capable of tissue ablation with only minimal thermal injury of adjacent tissue structures. Since difficult fibre optic coupling of energy was observed, alternative Q-switched laser sources capable of ablation of atherosclerotic plaque are under current investigation. To evaluate tissue effects of Alexandrite laser radiation, 160 arterial segments with macroscopic evidence of atherosclerotic disease were treated. The laser light was transmitted via silica based quartz fibres with different diameters. Using the Q-switched Alexandrite laser at the fundamental wavelength (748 nm) with a pulse duration of 300 ns the energy density threshold for tissue ablation was found to be in the range of 63 to 126 J cm^–2 using a 300m fibre. On macroscopic examination only limited thermal and acoustic injury was found in crater adjacent tissue structures. Crater edges were even and did not reveal signs of crater charring or debris in the crater lumen. However, the histological cross-sections revealed thermal injury extending from 100 up to 200m lateral into adjacent tissue. The crater margins revealed fissuring as a result of shock wave injury. Thermal damage was most evident if irradiation of atherosclerotic tissue was performed in blood.     

X-Ray- and catheter-guided intracardial laser photocoagulation of arrhythmogenic substrates

Cardiac arrhythmias resistant to drug treatment and correlated to an arrhythmogenic anatomic structure can be treated in several cases by surgical intervention. A further method of treatment is the percutaneous, ECG mapping-guided catheter ablation with either direct current (DC) or radio frequency (RF) ablation of localized arrhythmogenic foci. These methods overcome some complications inherent to open surgery to the heart; DC ablation, however, often induces further arrhythmias or ventricular or auricular fibrillation, while RF ablation shows only little success. In the method presented here disturbing electric effects are avoided by laser photocoagulation via a transcatheter quartz fibre. An electrode/laser catheter recently developed simultaneously allows for a mapping-guided localization of arrhythmogenic substrates and their percutaneous transluminal and intracardial deactivation. An anchoring mechanism at the catheter's tip keeps it in place during the treatment. This mechanism also prevents contact of the quartz fibre to the endomyocardium in order to avoid destruction of the fibre tip due to local overheating of the myocardium. A Nd-YAG laser (wavelength 1.064m) delivers pulses of 5–10 s and a power of 10–15 W at the tip of a quartz fibre with a core diameter of 400m. The corresponding parameter or irradiation of the myocardium are power densities of 700–1500 W cm^–2 and energy densities of 8–15 kJ cm^–2. In dog hearts lesions 2–10 mm in diameter and up to 11 mm in depth were obtained. Simultaneously registered electrocardiograms show that primarily induced arrhythmias lasted only for about 3 min but could not again be observed during the 2–3 months follow-up. Crater formation or perforation of the myocardium always could be avoided by an ECG-controlled laser irradiation. This indicates the safety and efficacy of the laser method for intracardial intervention in arrhythmogenic substrates. Clinical tests have been started recently.     

Clinical recording of laser-induced fluorescence spectra for evaluation of tumour demarcation feasibility in selected clinical specialities

Laser-induced autofluorescence spectra from humans were recorded in vivo at three different clinics in a study aimed at investigating the capability of this method to discriminate between malignant tumours and normal surrounding tissues. For the recordings a mobile trolley with the necessary equipment was constructed for use in an examination room or in an operating theatre environment. Laser light was guided through a 600m optical fibre to the target tissue. The fluorescence from the excited tissue was collected with the same fibre and was fed to an optical multichannel analyser. Two excitation wavelengths were used (337 and 405 nm) in order to optimize the fluorescence signals in two interesting wavelength regions (380–500 and 550–700 nm). Oral and oropharyngeal tumours excited with 405 nm light contained detectable endogenous porphyrins and were in this way discriminated from the normal mucosa. Astrocytoma grade III–IV fluorescence different from that of normal brain tissue, while tumours in the bronchial tree were not detectable using the spectral shape of the pure tissue autofluorescence.     

Comparison of continuous-wave and pulsed excitation for interstitial neodymiurn-YAG laser-induced hyperthermia

To investigate the effect of pulsing on neodymium-YAG laser-induced hyperthermia we have exposed rat liver to low-power Nd-YAG laser light delivered via an interstitially inserted fibre. This was either continuous wave excitation or pulsed excitation at 10 or 40 Hz (pulse duration 100s) with an average power of 1W and exposure durations of 400 s. No differences were seen with respect to overall diameter of the histological damage, diameter of the central cavitation, or intrahepatic temperatures, as measured by an embedded array of microthermocouples. We conclude that with 100-s pulses, within the range of parameters studied, the pulsing rate does not influence the nature or the extent of damage seen after low-power interstitial Nd-YAG laser hyperthermia.     

The use of a modular skills center for the maintenance of laparoscopic skills

Background: A reliable method supplying graduated experience and practice is needed to develop and refine laparoscopic skills. The laparoscopic surgeon, like the microvascular surgeon, must have ongoing training to refine and maintain his or her skills. Methods: The authors describe a new modular training unit. The unit consists of a box with a built-in television camera, a light source, and a rotating platform. A videotape recorder with a timing device documents the actual operating time required for the various exercises. The first phase of training consists of a basic skills board. This initial phase enhances the use of dominant and nondominant hand motor activity. Results: The surgeon then progresses to lifelike models (biliary, suturing, hernia, gynecologic) to simulate the human operative setting. Ten surgeons spent 5 h each working with the module. The specific exercises were recorded and timed. Their progress is described. Conclusions: The modular laparoscopic skills center is an integral part of any laparoscopic educational program. It facilitates the acquisition and maintenance of laparoscopic skills.     

Photodynamic therapy of oesophageal cancer

Twenty-three patients, 12 males and 11 females aged 42–86 years (mean age 69.6), with inoperable oesophageal cancer were treated by endoscopic photodynamic therapy. Inoperability in 20 patients was due to extent of tumour and existence of metastases, in two because of poor general condition and in one patient due to recurrence at the site of previous anastomosis. Prior to treatment, patients' degree of dysphagia and their functional status were recorded. Using barium contrast studies and endoscopy, the extent and location of the tumour within the lumen of the oesophagus were mapped out. Treatment protocol consisted of intravenous administration of the photosensitizer, Polyhaematoporphyrin, followed 24–48 h later by illumination of the tumour with 630 nm light produced by a copper vapour pumped-dye laser and delivered via a 400m internal diameter optical fibre with a cylindrical diffusing end. All treatments were undertaken under general anaesthesia as day case procedures. There was no treatment-related mortality nor was there any complication apart from a mild skin photosensitivity reaction in one case. Every patient's swallowing and functional status was improved at 6 weeks post-treatment. Ten patients needed more than one treatment: five required oesophageal dilatation. Thirteen patients survived a mean period of 6.2 months. Two needed oesophageal intubation 3–4 weeks before their death. Ten patients are alive at 6–14 months. This study suggests photodynamic therapy in inoperable oesophageal cancer to be a useful treatment method and in suitable cases an alternative to other forms of palliation. Its value lies in the fact that it can be used to treat cancer at any level of the oesophagus irrespective of histology.     

A Comparative Optical Analysis of Cylindrical Diffuser Fibres for Laser Therapy Using Fluorescence Imaging

. Cylindrical light diffusers are commercially available for clinical applications such as photodynamic therapy (PDT) and interstitial laser photocoagulation (ILP). A fluorescence imaging technique has been used to quantify the light distribution produced by each of six different diffuser fibres. The light distribution produced by each device was found to depend on the distance the light propagated in the fluorescent dye solution. At a distance of 1 mm from the diffuser midline, the measured profiles were found to be consistent with published results obtained in air at a similar distance. The three devices intended for PDT utilised scattering particles and reflectors in their construction. The profiles produced by these applicators revealed peaks that were attributed to the reflectors located at their distal tips. By comparison, the two etched ILP fibres displayed either a strong modulation in the profile due to non-uniform etching or a predominant forward peak associated with the conical shape of the tip. We conclude that it is important to take into account the forward-directed light emitted by the diffusers when considering clinical applications using these devices. Paper received 12 January 1999; Accepted after revision 12 April 1999.     

Development of cylindrical diffusing fibres suitable for interstitial photodynamic therapy

The development of suitable optical fibres, especially cylindrical diffusing fibres, has enabled the application of photodynamic therapy (PDT) in hollow organs such as the bronchus, oesophagus or the bladder. Although cylindrical diffusing fibres are commercially available, these are expensive and therefore many pre-clinical investigations are performed with institutionally-made fibres. We describe the production process of a plastic cylindrical diffusing fibre with good light distribution qualities and very low costs. To identify the permitted tolerances on fibre parameters, fibres with varying light distribution patterns were tested in an in vivo tumour model for growth delay after PDT. No significant difference in growth delay was found between these fibres using an energy of 100J cm⁻¹ at 24h after injection with Photofrin. These results indicate that by cheap, simple means, fibres can be made which are suitable for interstitial PDT and that small differences in light distribution patterns do not affect the in vivo response.     

Genetic manipulation of mammary epithelium by transplantation

Genes can be introduced into mammary epitheliumin vivo by the tissue reconstitution method. Primary cultures of mammary epithelial cells are prepared, a gene introduced using retrovirus vectors, and the cells transplanted into a mammary fat pad from which the normal epithelium has been removed. The cells reform an epithelium in which some cells express the introduced gene. The technique is reviewed and compared with the mammary-specific expression of genes in transgenic mice. To model the development of neoplasia, particularly the preneoplastic changes caused by a single oncogene alone, several oncogenes have been expressed this way—myc, Ha-ras, erbB, erbB2,Wnt-1, andhst/FGF-4. Each caused a different alteration to the growth pattern of the epithelium, such as altered branching, premature alveolus development, distorted duct structure, or altered hormone sensitivity. Insights into normal development have also been obtained by inappropriate expression of genes such asWnt-4.     

Diffusion theory of isotropic light dosimetry probe response

For the measurements of light energy fluence rate in tissues in vitro and in vivo we have developed an isotropic probe. The response of such a probe depends on the refractive index (n) of the medium. This has been measured in a collimated light beam with the probe in air, water (n=1.33), ehtylene glycol (n=1.43) and glycerin (n=1.46). The response as a function of n has also been calculated using diffusion theory, taking into account reflection at the boundaries. Simple formulas are proposed which very well approximate Fresnel reflection of unpolarized light, facilitating mathematical calculations. For a probe of 3.2 mm diameter with little light absorption the theoretical result depends only on n and differs from the experimental data by not more than 6 %. For a probe of 0.8 mm diameter with some light absorption excellent agreement between theory and experiment could be obtained by adjusting the (unknown) absorption and scattering coefficients ( _a, _s) of the probe material. However, a good fit was only possible within certain limits for _a, i.e. 0.35 mm^–1< _a<0.40 mm^–1, whereas _s (1-g) could be varied between at least 5 and 20 mm^–1 (g is the asymmetry parameter of the scattering function).     

Contact laser-assisted neuroendoscopy can be performed safely by using pretreated 'black' fibre tips: experimental data

BACKGROUND AND OBJECTIVE: Laser-assisted endoscopic neurosurgery by using conventional fibres requires the use of high-power laser light. Because this is potentially hazardous, we developed a pretreated fibre tip and evaluated tissue effects in vitro and in vivo. STUDY DESIGN/MATERIALS AND METHODS: By applying a highly absorbing coating to the front of the ball tip, almost all laser light is transformed into thermal energy, instantly producing ablative temperatures at the tip itself. The temperature distribution was examined by using an in vitro thermal imaging technique. The in vivo effect on rabbit cerebral tissue was examined macroscopically and histologically. RESULTS: By using a conventional fibre tip, ablation was not observed, despite the use of high energy and power (20 W for 10 seconds), whereas histology and thermal imaging demonstrated deleterious effects deeply into the cerebral tissue. By using the coated fibre tip, ablation was observed at low energy and power (1 W for 1 second) with thermal effects restricted to superficial structures. CONCLUSIONS: We show that laser-assisted neuroendoscopy can only be considered to be safe when pretreated "black" fibre tips are used, as laser light damages deep structures.     

Comparison of fibre tips for percutaneous interstitial laser photocoagulation

This paper seeks to optimize the parameters of interstitial laser photocoagulation, and clarify controversies regarding the effect of three types of fibre tips used in percutaneous application on the size of thermal lesions produced. Bare-cut, pre-charred and conical diffused tips of 600 μm silica core fibre were compared using a diode laser (805 nm) applied in vitro using fresh porcine livers. Continuous wave laser radiation at 805 nm was applied at 1.0, 1.5, 2.0 and 2.5 W for 5, 10 and 15 min. The sizes of the resultant lesion, cavity and char were measured and analysed using the method of analysis of variance for statistical significance. It is concluded that the fibre tips do not significantly affect the lesion size (p> 0.05). Conical fibre tips produced less char when applied for 10 min or more at 2–2.5 W. Laser power and irradiation time affect the lesion size significantly (p< 0.05), and the size of the lesion produced depends on both laser power and irradiation time, not merely on the total laser energy applied.     

The BrainIT group: concept and core dataset definition

Summary ¶Introduction. An open collaborative international network has been established which aims to improve inter-centre standards for collection of high-resolution, neurointensive care data on patients with traumatic brain injury. The group is also working towards the creation of an open access, detailed and validated database that will be useful for post-hoc hypothesis testing. In Part A, the underlying concept, the group coordination structure, membership guidelines and database access and publication criteria are described. Secondly, in part B, we describe a set of meetings funded by the EEC that allowed us to define a Core Dataset and we present the results of a feasibility exercise for collection of this core dataset. Methods. Four group meetings funded by the EEC have enabled definition of a Core Dataset to be collected from all centres regardless of specific project aim. A paper based pilot collection of data was conducted to determine the feasibility for collection of the core dataset. Specially designed forms to collect the core dataset demographic and clinical information as well as sample the time-series data elements were distributed by both email and standard mail to 22 BrainIT centres. A deadline of two months was set to receive completed forms back from centres. A pilot data collection of minute by minute physiological monitoring data was also performed. Findings. A core-dataset was defined and can be downloaded from the BrainIT web-site (go to Core dataset link at: www.brainit.org). Eighteen centres (82%) returned completed forms by the set deadline. Overall the feasibility for collection of the core data elements was high with only 10 of the 64 questions (16%) showing missing data. Of those 10 fields with missing data, the average number of centres not responding was 12% and the median 6%. An SQL database to hold the data has been designed and is being tested. Software tools for collection of the core dataset have been developed. Ethics approval has been granted for collection of multi-centre data as part of a pilot data collection study. Interpretation. The BrainIT network provides a more standardised and higher resolution data collection mechanism for research groups, organisations and the device industry to conduct multi-centre trials of new health care technology in patients with traumatic brain injury.Published online July 23, 2003     

Experience with a new solid phase enzyme immunoassay for prostatic acid phosphatase

Summary In recent years, the value of prostatic acid phosphatase (PAP) as a tumor marker for early prostatic cancer (CaP) has been the subject of controversial discussion. Investigation of sera from patients with pathohistologically proven localized CaP and from those with benign prostatic hyperplasia (BPH) has demonstrated a lack of discrimination between these groups of patients. Earlier investigations have demonstrated that the turnover rate of PAP in a conventional enzyme immunoassay (EIA) was limited by the release of the phosphate from the active center of the enzyme. However, a transfer of the activated phosphate on n-butanol or n-pentanol could increase the turnover rate to about 150%. Based on these observations 1-butanol was added to a solid-phase direct EIA in order to increase the sensitivity. PAP was assayed in 177 healthy male donors, 33 patients with benign prostatic hyperplasia and 33 patients with CaP. In 10 out of 21 patients with localized CaP (T1-3N0M0), the tumor stage was based on pathohistological examination. The upper limit of discriminative normal value was set at 0.65 g/l. The values of normal donors ranged between 0.07 and 0.6 g/l (mean 0.27 g/l), while the values for patients with BPH were slightly higher (mean 0.5 g/l). Only one patient with BPH had an elevated serum level (0.7 g/l). Out of 33 patients with CaP, 31 were found to have PAP values higher than 0.65 g/l. In one patient with CaP, pT2pN0M0 and one other patient with CaP T1N0M0, serum PAP levels were slightly lower than 0.65 g/l. This study indicates that an increase in the sensitivity of PAP determination might yield a valuable tool even in the diagnosis of early CaP.     

Studies of Er-YAG laser interactions with soft tissue

The ablation efficiency and depth of secondary thermal damage have been determined for a range of cadaveric soft tissues on exposure to radiation from a pulsed Er-YAG laser operating at 2.94m. The tissues investigated included brain, small intestine, stomach, liver, heart, spleen, lung, aorta, cornea, kidney, skin and uterus. The results obtained are compared to those predicted by a simple one-dimensional model of the interaction. The amount of tissue damage varied between tissues. In cellular tissues it was approximately 20m in extent on either side of the slot and at its base. In acellular tissues (aorta, cornea, etc.) the alteration in protein structure was more variable and was dependent upon the nature of the connective tissue fibres. Corneal collagen showed changes in protein structure up to 30m from the edge of the slot, whereas aortic elastic fibres were little affected by the laser energy, apparently melting to form a coagulum that lined the slot.     

Non-PDT Uses of lasers in oncology

The use of therapeutic lasers depends on four basic laser-tissue interactions; photothermal, photochemical (PDT), mechanical and ablative. There is no place for mechanical and ablative interactions in oncology; PDT will be the subject of a further review and the subject of this review is therefore the photothermal reaction. Thermal lasers have been in routine use in oncology for the last 10–15 years. These lasers, emitting in the visible or infra-red parts of the spectrum, are used to produce three basic effects; hyperthermia, coagulation and vaporization. Other energy sources beside lasers can also be used to produce these tissue effects but lasers seem to possess certain basic advantages. In comparison with monopolar or bipolar diathermy and heater probes, lasers can deliver more power, more accurately at the target tissue with better control of damage and a wider range of effects. In comparison with microwave and ultrasound therapy, lasers are again more precise and can be used with more compact and accurate delivery devices. In gastroenterological surgery (as opposed to endoscopy), neurosurgery and gynaecology, laser light can be delivered via a handpiece to cut and coagulate. In ENT and also some applications of gynaecology lasers can also be used via a microscope. In endoscopic surgery laser light is delivered through an optical fibre within the endoscope—this for the time being precludes the use of the CO₂ laser for these applications. More recently, the laser fibre can be placed directly within tumour tissue for interstitial thermal therapy of liver metastases, pancreatic tumours and brain tumours. The future use of thermal lasers in oncology depends very much on the results of properly controlled comparative studies against PDT and non-laser thermal devices; in addition their use may well be widened to include some curative procedures; up until now their use has very much been restricted to palliative therapy except where they are used as an adjunctive cutting device alongside conventional curative surgery.This paper is a revised and updated version of a talk given at Lasers in Medicine: Facing 1992, the final meeting of the European Community Concerted Action Programme on Medical Laser Development, in Amsterdam 29 November–1 December 1991.