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(Chest. 1999;115:502-510.)
© 1999 American College of Chest Physicians

Fine-Needle Interstitial Photodynamic Therapy of the Lung Parenchyma*

Photosensitizer Distribution and Morphologic Effects of Treatment

David I. Fielding, MD; Giovanni A. Buonaccorsi, PhD; Alexander J. MacRobert, PhD; Andrew M. Hanby, FRCPath; Martin R. Hetzel, MD and Stephen G. Bown, MD

* From the National Medical Laser Centre (Drs. Fielding, Buonaccorsi, MacRobert, and Bown), Department of Surgery, University College London Medical School; Department of Thoracic Medicine (Drs. Fielding and Hetzel), University College London Hospitals; and Hedley Atkins/Imperial Cancer Research Fund Breast Pathology Laboratory (Dr. Hanby), Guy's Hospital, London, UK.


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: To look at the effect of interstitial photodynamic therapy (PDT) in normal lung parenchyma to assess its potential for treating localized, peripheral lung tumors.

Design: Studies were performed on normal Wistar rats using the photosensitizer meso-tetrahydroxyphenyl chlorine. Drug distribution was measured by fluorescence microscopy on tissue sections. Light was delivered to the lungs via a single fiber inserted percutaneously under x-ray control and the PDT effect studied in animals killed at times up to 6 months later.

Results: Fluorescence studies showed that the drug was initially distributed throughout the lung, but was later predominantly in the vasculature, bronchi, and macrophages. PDT produced sharply defined zones of hemorrhagic necrosis up to 12 mm in diameter that healed with regeneration of bronchial epithelium and local fibrosis. Different histologic effects were seen between drug light intervals of 1 and 3 days. Treatment was well tolerated, there was a low incidence of pneumothorax, and as long as the fiber tip was within the lung parenchyma, there was no damage to adjacent tissues.

Conclusion: Interstitial PDT produces zones of necrosis in normal lung that heal safely by a percutaneous technique without affecting adjacent areas of untreated lung. If the lesion size can be increased by using multiple fibers, this could be a promising new technique for treating localized, peripheral lung cancers in patients who are unfit for surgery.

Key Words: image-guided therapy • non-small cell lung cancer • photodynamic therapy


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Photodynamic therapy (PDT) is a technique for the localized destruction of tissue with low-power red light after prior administration of a photosensitizing drug.1 ,2 ,3 It is a photochemical rather than a thermal effect that has remarkably little effect on connective tissues like collagen and elastin. As a result, many tissues heal with less scarring than after thermal damage and hollow organs like airways and major blood vessels maintain their mechanical integrity. There is also no cumulative toxicity, so treatment can be repeated, although there is the disadvantage that the whole patient may be rendered sensitive to bright lights for anything from a few hours to several weeks, depending on which photosensitizing drug is used. Thus, PDT offers the chance of necrosing tumors with minimal effects on the structure of the organ in which the tumor develops.

Most applications of PDT to date have been to tumors of hollow organs, and good results have been reported for early tumors of the major airways.4 ,5 ,6 ,7 However, more recently, there has been increasing interest in interstitial applications in tumors of solid organs such as the prostate and pancreas.8 ,9 The potential in the lungs would be to treat peripheral tumors by passing one or more laser fibers into the lesion through needles positioned percutaneously under radiologic guidance, in the manner of a fine-needle aspiration biopsy. Patients with small peripheral tumors (primary or isolated metastases10 ), who refused or were unfit for surgery, particularly because of poor lung function or borderline operable status, might be offered the technique as an alternative to radiotherapy.11 The aim could be palliative or potentially curative. Compared with radiotherapy, it would be easier to localize the effect and minimize damage to adjacent normal tissue, although it would be necessary to treat a rim of normal tissue around a tumor.

It is well known that PDT can produce zones of necrosis within solid tumors.9 This article describes experiments on rats designed to study the nature and healing of lesions produced by interstitial PDT in the normal, air-filled lung to assess whether it is likely to be safe to apply this technique to lesions within the lung parenchyma.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The photosensitizer chosen for these experiments was meso-tetrahydroxyphenyl chlorin (mTHPC),12 which has been shown to produce the largest PDT lesions in a solid organ (lesion diameter up to 24 mm around a single fiber in the canine prostate)8 and requires lower light doses than other drugs, reducing treatment times.5 ,13 All experiments were carried out on normal Wistar rats weighing 300 to 400 g under inhalational general anesthetic using halothane and oxygen. All experimental procedures and animal care were approved by the British Home Office under the Animals (Scientific Procedures) Act 1986.

Pharmacokinetics
The first part of the study was designed to assess the distribution of mTHPC in lung parenchyma using fluorescence microscopy on tissue sections. Tissue concentrations measured by this technique correlate well with those measured by chemical extraction.14 mTHPC (temoporphin, Foscan) was supplied by the manufacturer (Scotia Quanta Nova; Guildford, UK) as a crystalline solid and dissolved in a solution composed of 20% ethanol, 30% polyethylene glycol 400, and 50% distilled water. This was injected slowly via a tail vein (1 mg/kg), after which the rats were protected from direct light to prevent skin photosensitivity. Rats were killed after 1, 3, 4, 6, and 8 days (three rats at each time). Samples of lung parenchyma were removed at postmortem examination and immediately frozen in liquid nitrogen for preparation of 6-µm-thickness cryosections for study.

An inverted microscope (IMT-2; Olympus America; Huntington Station, NY) with epifluorescence and phase-contrast attachments was used.15 Fluorescence excitation was carried out with an 1.8-mW helium-neon laser operating at 543 nm with the output directed through a liquid light guide (via a 10-nm bandpass filter to remove extraneous light) onto a dichroic mirror in the epifluorescence microscope that incorporated phase-contrast attachments. Fluorescence was detected in the range 630 to 680 nm using a combination of bandpass (Omega Optical Inc; Brattleboro, VT) and longpass (RG595; Schott; Marlborough, MA) filters. The charge-coupled device (CCD) sensor 578 x 385 pixels (model P8603; EEV Ltd; Elmsford, NY) was cryogenically cooled and imaging operations and processing were carried out by a clone (IBM AT/PC; Rochester, MN). The values of mean fluorescence intensities were calculated by image processing software (Wright Instruments; Cambridge, UK) within rectangular areas of variable size corresponding to sites of interest. No fluorescence photobleaching was evident under the conditions used. The sections used for fluorescence microscopy were subsequently stained with hematoxylin-eosin (H & E) for later visual comparison using light microscopy and photography. The amount of photosensitizer was quantified from the CCD images of at least two large areas on each slide. Two sections were analyzed for each animal so at each time point there were four separate recordings from each of three different animals giving a mean of at least 12 measurements for each time point.

The first results suggested a nodular pattern of tissue fluorescence due to concentration of mTHPC in macrophages. To check this, immunocytochemistry was performed on frozen sections using a monoclonal antibody (FA11, macrosialin) specific for rat macrophages (gift of Dr R. De Silva, William Dunn School of Pathology, Oxford).16 Fluorescence imaging was performed first with the CCD camera and the images stored, then the macrophage stain was used on the same slide that allowed direct correlation.

Photodynamic Therapy
The dose of mTHPC used for PDT studies was 0.3 mg/kg, prepared and injected as for the pharmacokinetic studies. After the appropriate time interval, the left side of the chest was shaved and sterilized topically. The rat was placed in a stereotactic frame and the optimum site for placement of the laser fiber into the left lung chosen using fluoroscopy. A small incision was made and the 19G introducer needle passed into the lung parenchyma. The laser fiber within the introducer needle was then held stationary while the introducer needle itself was retracted a short distance leaving the bare fiber tip exposed in the lung parenchyma. The light source used was a copper vapor pumped dye laser (Oxford Lasers; Oxford, UK), tuned to deliver light at 652 nm. The laser power used in all experiments was 100 mW as control experiments in unsensitized animals showed that this power used for light doses of 80 to 100 J did not produce any thermal necrosis on histology 3 days after treatment. The laser fiber was a 0.4-mm core diameter bare-tipped glass fiber with Silastic cladding.

The animals were allowed to recover after the procedure and then killed by CO2 inhalation at a range of times after PDT. The lungs were removed and gently inflated via the trachea until all pleural surfaces were smooth. Then the trachea was ligated and the lungs allowed to fix in formaldehyde for a further 24 h after which they were sectioned perpendicular to the line of fiber entry into the lung. The largest diameter of necrosis seen macroscopically (black tissue) was measured.

In the first set of experiments, animals were treated at drug-light intervals of 1, 3, and 6 days (six animals at each time interval) to determine the interval at which PDT damage was greatest as measured 3 days after treatment and to compare the histology using these different drug-light intervals. From these experiments and also from previous reports from another group that showed that the best ratio of mTHPC between tumor and normal tissue was seen 3 days after sensitization,17 3 days was chosen as the most suitable drug-light interval for the subsequent experiments. In these, two further aspects were studied. First, the light dose was varied between 20 and 300 J and the lesion size measured 3 days after PDT (at least three animals treated at each point). Second, animals were treated with a fixed light dose of 80 J and killed at times from a few minutes to 6 months later for measurements of the size of the lesions produced and for histologic examination (at least five animals treated at each point). In selected sections, reticulin staining was used to demonstrate collagen fibers and Gram's stain to exclude the presence of bacteria as a cause of inflammation in the treated area.

Fluoroscopy was used to check for pneumothorax immediately after treatment in all animals. Conventional chest radiographs were used postmortem to exclude a late pneumothorax at each time point up to 6 months.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Pharmacokinetics
Figure 1 shows the mean tissue fluorescence in the lung parenchyma at times from 1 to 8 days after IV administration of mTHPC. The highest level was seen at the earliest time point studied, 1 day, followed by a gradual decline. At the early time points, there was diffuse uptake of the drug across the lung parenchyma and vessels. Bronchioles did not stand out from the surrounding areas. However, by 3 days, it was clear that the vessels and bronchi were retaining more of the mTHPC and stood out from the background (Fig 2 ). This was most obvious at 6 days. In the first 2 days, fluorescence was seen in the intima of larger vessels, but at 3 to 6 days, it was in the muscular layer of these vessels. In the bronchi, fluorescence was diffusely distributed through the bronchial wall and epithelium.



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  		Figure 1. Average concentration of mTHPC measured by fluorescence microscopy (arbitrary units) in untreated lung at times up to 8 days after IV injection of 1 mg/kg.

 


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  		Figure 2. Top: false color coded image of mTHPC fluorescence in lung parenchyma 3 days after injection of 1 mg/kg showing high levels of fluorescence (blue and white) in bronchi, in a small blood vessel (arteriole), and in numerous small nodular areas. Bottom: H & E stain on the same section (original magnification x 25).

 
At times from 2 days onwards, in addition to the uptake in blood vessels and bronchioles, there was a more nodular distribution of fluorescence that did not conform to underlying lung structures. The fluorescence intensity from these nodules was typically 10 to 20 times as high as in the adjacent background tissue. Immunohistochemistry showed that these bright nodules were macrophages (Fig 3 ). The pattern was still present, although less intense, at 8 days.



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  		Figure 3. Top: false color-coded image of mTHPC fluorescence in lung parenchyma 3 days after injection of 1 mg/kg at high power. Bottom: immunohistochemical stain for macrophages on the same section. The correlation between the two demonstrates that the nodules containing high levels of mTHPC are macrophages (original magnification x 75).

 
Photodynamic Therapy
Macroscopic: All experimental animals tolerated the PDT procedure well. On lung sections taken perpendicular to the line of the laser fiber 3 days after PDT (the time of maximum necrosis), the lesion was a circular, uniformly dark area centered around the site of the tip of the fiber. There was a clear demarcation between lesions and the surrounding unaffected parenchyma (Fig 4 ). Some lesions were visible on the adjacent lung surface, although the surface had a normal contour in all cases. The effect was always confined to the lung and visceral pleura and no effects were seen on the parietal pleura. The remainder of the lung appeared normal in virtually all cases apart from some rats treated with a drug-light interval of 1 day when there was evidence of vascular congestion on the lung surface.



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  		Figure 4. PDT on normal lung with 100 J light, 3 days after 0.3 mg/kg mTHPC. Macroscopic appearance of the zone of necrosis 3 days after light delivery in the plane perpendicular to the line of laser fiber entry.

 
From 3 weeks after PDT, mild, localized indrawing of the pleural surface was seen. This appeared to be maximal by 2 months and was still evident at 6 months. No adhesions were seen between the visceral and parietal pleura. At these later times, there was a localized area of pale fibrous tissue on the cut surface of the lung that had replaced the zone of hemorrhagic necrosis seen in the sections taken at earlier times after PDT. There was no cavitation. Where the lesion was adjacent to major structures, there was no obvious effect on these, in particular, no evidence of localized stenosis in major bronchi or occlusion of major blood vessels.

The lesion sizes were highly reproducible; with a 3-day drug light interval and a light dose of 80 J, the mean lesion diameter in 10 specimens was 9.8 mm, with a SD of only 1 mm. The effect on lesion size of changing the drug-light interval is shown in Figure 5 , top, and that of increasing the light dose with a 3-day drug-light interval is shown in Figure 5 , center. These animals were all killed 3 days after PDT. Figure 5 , bottom, shows how 80-J lesions with a 3-day drug-light interval healed over a period of 6 months. The largest lesion seen was 12 mm in diameter (200 J, 3 days after sensitization).



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  		Figure 5. Top: lesion size 3 days after PDT using different drug light time intervals. All treatments were with 0.3 mg/kg mTHPC and a light dose of 80 J. Each bar is the mean (SD) of at least six animals. Center: lesion size 3 days after PDT using different light doses. All treatments were with a 3-day drug light interval after 0.3 mg/kg mTHPC. Each bar is the mean (SD) of at least three animals. Bottom: lesion size at times up to 6 months after PDT. All treatments were with a 3-day drug light interval after 0.3 mg/kg mTHPC and a light dose of 80 J. Each bar is the mean (SD) of at least five animals.

 
A pneumothorax was seen on fluoroscopy immediately after PDT in 7 of the 60 animals. No tension pneumothorax was seen and no animal died as a result of a pneumothorax. All rats with a pneumothorax were killed at 3 days for the assessments outlined above. Radiographs performed postmortem at times from 3 weeks to 6 months after treatment did not show a pneumothorax in any animal, indicating that no delayed pneumothorax occurred.

Mediastinal structures like the great vessels and esophagus were not damaged by PDT in the immediately adjacent lung with the exception of two cases in which the laser fiber had inadvertently been placed through the medial surface of the visceral pleura. It had come into direct contact with the esophagus, which led to esophageal perforation with mediastinitis in both cases, necessitating killing of the animals. The zone of necrosis in these animals was centered on the esophagus itself with PDT effects seen on the mediastinal aspect of the pleura of both lungs. Microscopic examination showed necrosis and hemorrhage, and reticulin and elastin van Gieson stains at the site of perforation showed marked disruption of the collagen architecture. Such changes are not typical of PDT necrosis.18 ,19 It is known that even with a laser power as low as 100 mW, it is possible to get a 1 to 2-mm zone of necrosis around a bare fiber tip in the GI tract in unsensitized animals due to thermal effects.18 ,20 The esophagus of rats is so thin (< 1 mm) that if the fiber tip happened to be exactly on the esophageal wall during PDT, there could have been a localized thermal effect enough to cause a perforation. From the 60 rats treated, these two esophageal perforations were the only serious adverse events. In all the other treatments, the fiber tip had been correctly placed in the lung parenchyma and no effects were seen on the esophagus.

Histology
Three-Day Drug Light Interval: Sections from animals killed a few minutes after PDT did not show the zones of parenchymal necrosis that developed in animals killed longer after PDT, but did show extravasation of RBCs through the walls of larger vessels, both arteries and veins, together with endothelial damage and occasional thrombosis (Fig 6 ).



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  		Figure 6. Histology of lung vessel 2 min after PDT (3-day drug light interval, light dose 80 J) showing endothelial damage with extravasation of RBCs through the vessel wall. At this time, no PDT necrosis is evident in the surrounding parenchyma (H & E, original magnification x 25).

 
Three days after treatment, histologic sections showed a well-demarcated circular zone of hemorrhagic necrosis (Fig 7 , top) corresponding to the lesion seen macroscopically. This area had a uniform, bland eosinophilic appearance. At high magnification, RBCs could be seen leaking from damaged alveolar capillaries and alveoli contained fibrin and fluid. Although there was uniform cell death, the tissue architecture was not disturbed. Ghost outlines of alveolar walls, blood vessels, and bronchi were still easily identifiable (Fig 7 , center). Reticulin stains showed that collagen was undisturbed with no damage to the supporting tissue in alveolar walls, blood vessel walls, or bronchi (Fig 7 , bottom). Necrosis was seen in the bronchial epithelium and smooth muscle and in the endothelium and muscular layers of blood vessels. Some vessels also showed intraluminal thrombosis. Surrounding the zone of PDT necrosis was a rim of acute inflammatory cells, including neutrophils and lymphocytes as seen at 1 day.



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  		Figure 7. Top, A: histology of lesion 3 days after PDT (3-day drug light interval, light dose 80 J) showing homogenous necrosis of all structures in the treated area with no effect on adjacent structures apart from a small rim of inflammation around the lesion (H & E; original magnification x 4). Center, B: high-power view of center of necrotic lesion showing residual outline of bronchiole and arteriole. Acute inflammatory cells are infiltrating and there is capillary engorgement (H & E, original magnification x 10). Bottom, C: reticulum stain of lesion 3 days after PDT (3-day drug light interval, light dose 80 J), showing preservation of tissue architecture (original magnification x 25).

 
Sections taken 10 days after PDT performed with a 3-day drug light interval showed resorption of RBCs from the central part of the zone of PDT necrosis. By 3 weeks, there was replacement of necrotic tissue by early granulation tissue. The bronchi and blood vessels within the treated zone remained structurally intact and by this time had regrown normal epithelium and endothelium (Fig 8 ). By 2 months, the initial PDT lesion had become a small, scarred zone with residual bronchi and vessels within it. Despite the initial severity of the PDT necrosis, adjacent structures such as large bronchi and vessels remained histologically normal. There was no residual scarring or architectural disruption of any surrounding tissue, including zones that may have shown alveolar edema and hemorrhage initially. The changes at 6 months were the same as those seen at 2 months, indicating that healing was complete by 2 months.



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  		Figure 8. Histology of lesion 3 weeks after PDT (3-day drug light interval, light dose 80 J). Fibrosis has replaced the alveolar necrosis, but the bronchial wall is unaffected and normal bronchial epithelium has regenerated (H & E, original magnification x 4).

 
One-Day Drug Light Interval: About one third of sections taken from rats treated with a 1-day drug light interval showed intra-alveolar edema, perivascular cuffing, hemorrhage, and marked neutrophil infiltration in viable lung surrounding the PDT damaged zone. These changes were most marked where the lesion had been made close to the hilum of the lung causing proximal obstruction to pulmonary venous drainage leading to edema and hemorrhage in the periphery of the lung. Sections that showed neutrophil infiltration were counterstained with Gram's stain but no bacteria were seen. None of the rats from which these sections were taken showed any evidence of ill health.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
These studies have shown that it is possible to produce focal areas of PDT necrosis in normal lung parenchyma that heal safely, using a minimally invasive, percutaneous technique. The unique nature of PDT means that the basic integrity of connective tissue, airways, and blood vessels is preserved. Necrosis was truly localized with no effect on immediately adjacent tissue and collagen and elastin were largely preserved in the treated area. While only normal tissue was assessed in this study, in other organs, tumors have always been at least as sensitive to PDT as the normal tissue in which the tumor arose5 ,20 ,21 ,22 and one would anticipate the same in the lungs. Previous reports show that there is more collagen in bronchial carcinomas than in adjacent normal bronchi,23 which suggests that treated tumors should maintain their mechanical integrity. Clinically, it would be necessary to treat peripheral tumors with a rim of surrounding normal tissue. The volume of necrosis produced around a single fiber would not be large enough to do this, but the volume of the PDT effect can be increased by using multiple fibers placed at separations of about 1 cm.8

At least part of the mechanism of PDT is endothelial injury leading to tissue ischemia, edema, and accumulation of acute inflammatory cells.24 This was most marked with a 1-day drug light interval, probably due to more drug being present in the endothelium than at 3 days, as shown in the CCD studies. However, despite the concentration of mTHPC in lung 1 day after injection being five times greater than after 3 days, the size of PDT lesions made at these two times using the same light doses was virtually the same. Other authors using mTHPC have recognized the same pattern with a comparable extent of necrosis but less florid vascular effects using a longer drug light interval (>= 3 days).25 ,26 ,27 They also showed no difference between the histologic appearance of PDT-treated tumors with 4- and 8-day drug light intervals. In tumor treatments with mTHPC, there is often marked damage of tumor vessel walls as well as intraluminal thrombosis.28 Clinical applications in other organs now typically use a 3-day or longer drug light interval4 as others have shown that this is the time at which the highest drug levels are seen in tumors.17 Also, this avoids the edema and congestion seen with the 1-day interval.

To our knowledge, this is the first description of mTHPC uptake into macrophages in tissues. Concentration in macrophages is an important mechanism for localization of photosensitizers in tumors29 ,30 and may be particularly relevant in lung tumors that often contain large numbers of macrophages.31 ,32 Our fluorescence microscopy studies showed that drug was still present in both small vessels and macrophages up to 6 to 8 days after injection of the drug, so drug in either or both of these compartments could have been involved in producing the still moderate-sized lesions observed at this time point when the total quantity of drug in the lung was low. Even if macrophages contribute only partly to the PDT process, this is to be welcomed as lung tumors contain large numbers of macrophages that could potentially improve the selectivity of treatment.33 Previous studies in vitro have shown that macrophages release cytokines such as tumor necrosis factor alpha when stimulated with PDT.34

Pelton et al35 described the effects of PDT using photofrin on thoracic organs during surface treatments of the pleura in rats. They reported changes in the lung just under the pleura suggestive of diffuse alveolar damage, similar to our findings using interstitial light delivery. In addition to these vascular effects, in vitro studies have demonstrated the effectiveness of PDT in causing direct cellular necrosis of human lung cancer cells.36 ,37 ,38 It is likely that both vascular and cellular effects are involved in PDT necrosis in the lung. The ability of bronchial epithelium to regenerate is also typical of PDT,23 probably regrowing from the unaffected parts of the bronchus outside the treated zone. This regeneration should make bronchial scarring and bronchial stenosis unlikely.

Light distribution within lungs is dominated by scattering,39 but even so, 70% of the light is absorbed within 3 to 4 mm of the source,40 which explains the plateau effect seen in the lesion size with no increase using a treatment time of > 1,000 to 1,500 s. An important finding related to light distribution was the absence of any deleterious effects on surrounding structures when the needles were placed within the lung parenchyma. This appears to be due largely to light reaching the visceral pleura from the lung parenchyma being reflected back into the lung rather than being transmitted into adjacent structures. Therefore, this could be a relatively painless procedure due to the absence of any effect on the parietal pleura. Also, it suggests that tumors within the lung adjacent to vital mediastinal structures could be treated safely. Although esophageal perforation occurred in 2 animals, this was thought to be because the rat esophagus is so thin and the laser fiber had been inadvertently placed directly on the esophageal wall leading to a small thermal lesion. In experimental and clinical studies of pleural PDT using surface light applicators at thoracotomy for the treatment of mesotheliomas, there has been no esophageal perforation.28 ,41

The incidence of pneumothorax was consistent with that associated just with fine-needle aspiration biopsy.42 It did not appear that there was an additive effect of the necrotic lesion, particularly in view of the preservation of bronchial connective tissue on histology.

These experimental results are encouraging. They suggest that it is feasible to produce PDT lesions in lung in a specific location that heal safely. Prior to clinical studies, further work is required to produce more extensive lesions using multiple fibers in a larger animal and to be sure that these also heal safely.


   Acknowledgements
 
ACKNOWLEDGMENT: Thanks to Dr. Andrew Cheuston, Department of Pathology, Princess Alexandra Hospital, Brisbane, Australia, for photomicrographs in Figure 7 .


   Footnotes
 
The drug mTHPC used in this research was provided by Scotia Quanta Nova, Guildford, UK.

Correspondence to: David I. Fielding, Department of Respiratory Medicine, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia

Abbreviations: CCD = charge coupled device; H & E = hematoxylin-eosin; mTHPC = meso-tetrahydorxyphenyl chlorin; PDT = photodynamic therapy

Received for publication May 18, 1998. Accepted for publication August 19, 1998.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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