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Although photodynamic therapy (PDT) has been studied intensively for the past decade, there are relatively few data on the effects on normal tissue. PDT is used predominantly to treat solid, localized tumors, the photosensitizer being activated by light from a laser. The potential for PDT in the bladder is to treat multifocal carcinoma in situ or dysplasia. The major problem that has been encountered clinically is the level of complications, in particular, the reduction in bladder capacity and compliance, most likely owing to some fibrosis in normal muscle. The mechanical strength of soft tissues is maintained predominantly by collagen, and structural integrity is vital if safe healing is to occur after tumor destruction. The effects of PDT on a range of normal tissues have been studied to ensure that safe healing is possible. Histological studies of the healing of tissues after PDT and thermal damage have demonstrated differences.

Photodynamic therapy (PDT) is a technique for producing localized necrosis with light after prior administration of a photosensitizing agent. This study investigates the nature, safety, and efficacy of PDT for image-guided treatment of primary breast cancer. We performed a phase I/IIa dose escalation study in 12 female patients with a new diagnosis of invasive ductal breast cancer and scheduled to undergo mastectomy as a first treatment. The photosensitizer verteporfin (0.4 mg/kg) was administered intravenously followed by exposure to escalating light doses (20, 30, 40, 50 J, 3 patients per dose) delivered via a laser fiber positioned interstitially under ultrasound guidance. MRI (magnetic resonance imaging) scans were performed prior to and 4 days after PDT. Histological examination of the excised tissue was performed. PDT was well tolerated, with no adverse events. PDT effects were detected by MRI in 7 patients and histology in 8 patients, increasing in extent with the delivered light dose, with good correlation between the 2 modalities. Histologically, there were distinctive features of PDT necrosis, in contrast to spontaneous necrosis. Apoptosis was detected in adjacent normal tissue. Median follow-up of 50 months revealed no adverse effects and outcomes no worse than a comparable control population. This study confirms a potential role for PDT in the management of early breast cancer.

Primary breast cancer while increasing in incidence has been successfully treated with a combination of surgery and adjuvant therapies in the majority of patients. Novel treatments for primary breast cancer need to show additional benefits to existing treatments with equivalent or improved efficacy for niche groups. Photodynamic therapy (PDT) is a potential novel treatment and a Phase I/IIA, open label, non-randomised, single site trial of photodynamic therapy for the treatment of primary breast cancer was conducted. The primary aim was to identify the light dose required for 12 mm of tumour necrosis (or a plateau of necrosis) assessed by histopathology. Post-dose MRI correlation with histopathology findings in treated tumours and in normal breast tissue was sought. In addition adverse events were recorded and comparison of outcome made with matched controls. Results of the first human clinical trial with 12 patients with median follow-up of 39 months showed PDT was well tolerated, with no adverse effects and comparable outcome to control populations. Tumour necrosis increased with incremental increases in light dose, however some patients showed a poor response even at the highest light dose. Analysis suggests that there may be predictive factors for good and poor response. PDT in primary breast cancer requires further investigation to identify which patients would most benefit from this therapy.

India has one of the highest rates of oral cancer incidence in the world, with an estimated 80,000 new cases per year, accounting for 30% of reported cancers. In rural areas, a lack of adequate medical infrastructure contributes to unchecked disease progression and dismal mortality rates. PDT emerges as a potential modality which can be implemented in resource limited settings, while photosensitizer fluorescence can be leveraged for treatment guidance. Here, as part of an ongoing clinical study evaluating low-cost technology for ALA PDT treatment, we evaluated the capability of a simple smartphone-based device for imaging ALA-induced PpIX fluorescence. The imaging device itself consists of an annulus of 405nm LEDs for PpIX excitation with emission filter in the center mounted over the phone camera. 18 subjects having

Background and objective: Pancreatic cancer has long been a leading cause of cancer death. Few patients are suitable for surgery and for those who are not, the response to treatment is generally poor. No more than about 10% survive for more than a year. Recent research has focused on focal treatment for local disease control. This review covers the development of one of the most promising options, photodynamic therapy (PDT). Methods: This review covers pre-clinical and clinical studies. Laboratory work was designed to understand the effect of PDT on the normal pancreas and surrounding tissues and on transplanted cancers in the hamster pancreas to ensure safety prior to clinical application. Essentially all clinical studies have been undertaken in University College Hospital, London. Phase-I studies used the photosensitisers mTHPC and verteporfin in patients with localised but inoperable cancers. Results: Laboratory results showed that normal pancreas, bile duct, liver, stomach and major blood vessels could tolerate PDT without any unacceptable effects on the structure and function of these organs. Necrosis that healed safely was documented in transplanted cancers. The clinical trials showed that focal necrosis could be produced in inoperable cancers with acceptable levels of complications, but considerable refinements of treatment delivery and monitoring are required before the technique will be ready for assessment in controlled clinical trials. Conclusions: PDT is showing promise for the minimally invasive treatment of localised pancreatic cancers, but it is still at an early stage of development. Much more work will be necessary to optimise techniques for applying PDT to these cancers and for combining it with other therapeutic options such as chemotherapy.

Significance: India has one of the highest rates of oral cancer incidence in the world, accounting for 30% of reported cancers. In rural areas, a lack of adequate medical infrastructure contributes to unchecked disease progression and dismal mortality rates. Photodynamic therapy (PDT) has emerged as an effective modality with potential for treating early stage disease in resource-limited settings, while photosensitizer fluorescence can be leveraged for treatment guidance. Aim: Our aim was to assess the capability of a simple smartphone-based device for imaging 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence for treatment guidance and monitoring as part of an ongoing clinical study evaluating low-cost technology for ALA-based PDT treatment of early oral cancer. Approach: A total of 29 subjects with

Sentinel lymph node biopsy is a standard diagnosis procedure to determine whether breast cancer has spread to the lymph glands in the armpit (the axillary nodes). The metastatic status of the sentinel node (the first node in the axillary chain that drains the affected breast) is the determining factor in surgery between conservative lumpectomy and more radical mastectomy including axillary node excision. The traditional assessment of the node requires sample preparation and pathologist interpretation. An automated elastic scattering spectroscopy (ESS) scanning device was constructed to take measurements from the entire cut surface of the excised sentinel node and to produce ESS images for cancer diagnosis. Here, we report on a partially supervised image classification scheme employing a Bayesian multivariate, finite mixture model with a Markov random field (MRF) spatial prior. A reduced dimensional space was applied to represent the scanning data of the node by a statistical image, in which normal, metastatic, and nonnodal-tissue pixels are identified. Our results show that our model enables rapid imaging of lymph nodes. It can be used to recognize nonnodal areas automatically at the same time as diagnosing sentinel node metastases with sensitivity and specificity of 85% and 94%, respectively. ESS images can help surgeons by providing a reliable and rapid intraoperative determination of sentinel nodal metastases in breast cancer.

This study investigated the photophysical and photobiological properties of a new amphiphilic chlorin photosensitiser, disulfonated tetraphenylchlorin (TPCS(2a)), for photochemical internalisation (PCI). The absorption and fluorescence spectra of TPCS(2a) were examined in a range of solvents together with fluorescence lifetime measurements. The fluorescence lifetime of TPCS(2a) was found to be 8.5 ns in methanol, whereas non-exponential decays were observed in distilled water due to sensitiser dimerisation. The singlet oxygen quantum yield of TPCS(2a) was determined as 0.62 in deuterated methanol by direct observation of singlet oxygen phosphorescence. In a human oral squamous carcinoma (HN5) cell line, intracellular co-localisation of TPCS(2a) and Alexa488-labelled saporin, a macromolecular toxin, was observed corresponding predominantly to a lysosomal distribution. Intracellular fluorescence redistribution of TPCS(2a) and Alexa488-saporin was observed after 405 nm irradiation. Using two-photon confocal microscopy at 840 nm, and fluorescence lifetime imaging (FLIM), the lifetime was measured as 6 ns in HN5 cells. PCI using TPCS(2a) was shown to be very effective, and a synergistic increase in saporin toxicity was achieved in HN5 cells where viability was significantly reduced after light exposure compared to saporin (25 nM) treatment alone. The results demonstrate the favourable photophysical and photobiological properties of TPCS(2a) for PCI, which induces the relocalisation of a macromolecular anti-cancer toxin inside cells and significantly enhances cell death.

Photofrin photodynamic therapy (PDT) is a licenced treatment for Barrett’s oesophagus (BE) with high-grade dysplasia (HGD) but causes strictures and photosensitivity and complete reversal of dysplasia (CR-HGD) by 50 % at 5 years. 5-Aminolaevulinic acid (ALA) is an alternative treatment with non-randomised data suggesting 85 % CR-HGD and a low risk of side effects. We aimed to compare efficacy and side effect profile between the drugs. A single-centre randomised controlled trial was conducted. Presence of HGD was confirmed on three occasions by two specialist GI pathologists. Stratification was by length of BE and extent of dysplasia. Standard protocols for ALA and Photofrin-PDT were followed. Endoscopic follow-up with 2-cm four-quadrant biopsy was at 6 weeks, 4 months, and then annually. All adverse event data were collected. Sixty four patients were randomised, 34 ALA and 30 Photofrin-PDT. Median follow-up is 24 months. On intention-to-treat analysis, CR-HGD was 16/34 (47 %) with ALA-PDT and 12/30 (40 %) with Photofrin-PDT. The overall cancer incidence was 14 % (9/64). On sub-group log-rank analysis, for BE ≤6 cm, CR-HGD was significantly higher with ALA-PDT than Photofrin-PDT (χ2 = 5.39, p = 0.02). Strictures and skin photosensitivity were significantly more common after treatment with Photofrin-PDT than ALA-PDT (33 vs. 9 % and 43 vs. 6 %, respectively, p

Since the first report of the use of photodynamic therapy (PDT) for prostate cancer in 1990 it has been investigated as a primary and a salvage treatment, using either whole gland or focal approaches. Since 1990 advances in the transperineal approach to the prostate, coupled with photosensitizers which have a short drug-light interval and minimal skin phototoxicity, have resulted in major advances in the field. This review will look at the work done to date, and the ongoing studies which help to define the place of PDT as a useful treatment modality for organ-confined prostate cancer. Lasers Surg. Med. 43:768-775, 2011. (C) 2011 Wiley-Liss, Inc.

Most techniques for measuring tissue concentrations of drugs are invasive, time-consuming, and often require the removal of tissue or body fluids. Optical pharmacokinetics (OP) is a minimally invasive alternative giving an immediate result. Pulses of white light are directed at the tissue of interest using a fiber optic probe. Scattered light is detected by a second fiber immediately adjacent to the first in the same probe (separation 1.7 mm). Using the photosensitizer disulfonated aluminium phthalocyanine ( AlS2Pc ), OP measurements were made in phantoms and on the mouth, stomach, colon, skin, and liver of normal rats 1 and 24 h after intravenous AlS2Pc administration. AlS2Pc concentration was determined by calculating the area under the curve (AUC) in the spectral region around the peak drug absorption or measuring the height of the peak. Spectral baseline interpolation removed the need for pre-drug, control optical measurements. OP measurements correlated well with values from alkali chemical extraction (CE) of the corresponding tissues, (R2 0.87–0.97). OP measurements in the mouth also correlated with CE of less accessible internal organs (R2 0.77–0.88). In phantoms, the lowest detectable concentration was 0.1 μg/g. In vivo, results were limited by the lower accuracy in the CE measurements but were almost certainly comparable. An incidental finding was a 12–15 nm red shifted component in the spectra observed 1 h after drug administration, suggesting partitioning of the drug in different microenvironment compartments, which could prove to be of considerable interest in future studies. In conclusion, OP shows promise for real-time measurement of concentrations of drugs with suitable absorption peaks.

Photochemical internalisation (PCI) is a delivery technology that employs a sub-lethal form of photodynamic therapy (PDT) in which a photosensitiser is activated by light to break down intracellular membranes and release macromolecules into the cytosol where they can be biologically active. Although PCI does enhance the PDT killing of transplanted tumours in mice after local injection of the cytotoxic agent, gelonin, the redistribution of gelonin from intracellular organelles into the cytosol has only previously been demonstrated in vitro. This study is designed to understand the factors controlling the efficacy of PCI in vivo and to document the mechanism of action. Using the photosensitiser AlS(2)Pc in studies on normal rat liver, we have demonstrated in vivo that gelonin is initially taken up into lysosomes, but can be released into the cytosol using PCI. Furthermore, PCI enhances the PDT effect after systemic administration of gelonin (volume of necrosis increased x2.5 when gelonin is given one hour before light), with the remarkably low dose of 5 microg/kg (10,000 times lower than the LD50); in the absence of light, there is no effect with 500 microg/kg. These results suggest that PCI may have a useful role to play in the site specific activation of cytotoxic agents like gelonin, given at a dose level that has no effect in the absence of light.

In some applications of diffuse reflectance spectroscopy there may be substantial variability between the spectra from replicate measurements of what is nominally the same sample. A method called error reduction by orthogonal subtraction (EROS) is proposed to ameliorate the effects of this. The first step is to use principal component analysis (PCA) to identify the structure in the variability of replicate measurements. This is followed by subtraction of the modelled effects from the original spectral data matrix X by projection onto the subspace orthogonal to factors derived from the PCA. An application to the clinical diagnosis of colon lesions is presented, in which pre-treatment of spectra using the proposed method is successful in reducing the complexity and increasing both the accuracy and interpretability of the subsequent classification model. Copyright © 2008 John Wiley & Sons, Ltd.

Over the last 20 years, the Brixen meetings on “Photodynamic Therapy and Photodiagnosis in Clinical Practice” brought together many scientists and clinicians from all over the world in a convivial and stimulating environment. Younger researchers had the opportunity to meet established experts in order to discuss projects and new ideas in an informal atmosphere. However, much of the clinical work presented was at a relatively early stage of development, and the clinicians at the meeting were those with major commitments to photodynamic therapy (PDT) rather than those who see PDT as one option amongst a range of possible techniques for treating patients in their particular specialty. This chapter looks at how the broader cancer research community sees PDT and links the Brixen meetings to the potential of PDT in routine clinical practice. It is based on a workshop held in London in July 2014, convened by the major funders of cancer research in the UK in order to review the current status of PDT. The aim was to identify which new studies would be most likely to establish where PDT could find a place in routine clinical practice in oncology.

Objectives The palliation of patients with malignant bile duct obstruction using metal or plastic biliary stents may be limited by stent occlusion. The aim of this study was to determine the safety and efficacy of endoscopically delivered meso-tetrahydroxyphenyl chlorin photodynamic therapy in the treatment of irresectable malignant biliary strictures and recurrent stent occlusion. Methods Thirteen patients with malignant biliary obstruction owing to carcinoma of the biliary tract (n=9), pancreas (n=3) or stomach (n=1), were studied. All had been initially palliated with metal (n=10) or polyethylene (n=3) biliary stents, but presented with recurrent obstructive jaundice because of local tumour progression. Patients received meso-tetrahydroxyphenyl chlorin 0.15 mg/kg intravenously 72 h before endoluminal light activation with an endoscopically placed optical fibre, followed by polyethylene stent insertion.Methods Thirteen patients with malignant biliary obstruction owing to carcinoma of the biliary tract (n=9), pancreas (n=3) or stomach (n=1), were studied. All had been initially palliated with metal (n=10) or polyethylene (n=3) biliary stents, but presented with recurrent obstructive jaundice because of local tumour progression. Patients received meso-tetrahydroxyphenyl chlorin 0.15 mg/kg intravenously 72 h before endoluminal light activation with an endoscopically placed optical fibre, followed by polyethylene stent insertion.Results Before photodynamic therapy, patients had a median of three (range 0-5) stent occlusions in the preceding 11 (2-22) months, with a median patency of plastic stents placed inside metal bile duct stents for recurrent stent occlusion of 3.5 (0.5-13) months. After photodynamic treatment, tumour necrosis and/or metal stent recanalization was seen in all patients, with a median of 0 (0-3) stent occlusions during 7 (1-43) months follow-up. The median patency of plastic stents placed inside metal stents; after photodynamic therapy was 5 (1-43) months. The median survival after diagnosis and photodynamic therapy administration was 21 (10-56) and 8 (1-43) months, respectively. Photodynamic therapy was generally well tolerated but two patients developed cholangitis within the first week, complicated in one by a fatal liver abscess and two developed haemobilia within 4 weeks of treatment, one of whom died with a gall bladder empyema.Conclusion In patients with malignant biliary obstruction, endoscopically delivered meso-tetrahydroxyphenyl chlorin photodynamic therapy causes efficient tumour necrosis and recanalization of blocked metal stents, but there is a significant risk of complications. Eur J Gastroenterol Hepatol 19:479-485 (C) 2007 Lippincott Williams & Wilkins.

The utilization of macromolecules in the therapy of cancer and other diseases is becoming increasingly important. Recent advances in molecular biology and biotechnology have made it possible to improve the targeting and design of cytotoxic agents, DNA complexes and other macromolecules for clinical applications. In most cases the targets of macromolecular therapeutics are intracellular. However, degradation of macromolecules in endocytic vesicles after uptake by endocytosis is a major intracellular barrier for the therapeutic application of macromolecules having intracellular targets of action. Photochemical internalization (PCI) is a novel technology for the release of endocytosed macromolecules into the cytosol. The technology is based on the activation by light of photosensitizers located in endocytic vesicles to induce the release of macromolecules from the endocytic vesicles. Thereby endocytosed molecules can be released to reach their target of action before being degraded in lysosomes. PCI has been shown to stimulate intracellular delivery of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane, including type I ribosome-inactivating proteins (RIPs), RIP-based immunotoxins, DNA delivered as gene-encoding plasmids or by means of adenoviruses or adeno-associated viruses, peptide–nucleic acids and chemotherapeutic agents such as bleomycin. The efficacy and specificity of PCI of macromolecular therapeutic agents have been improved by combining the macromolecules with targeting moieties, such as the epidermal growth factor. Several animal models have been used for in vivo documentation of the PCI principle. Recent results also indicate that PCI may reverse doxorubicin resistance or be utilized to circumvent multidrug resistance. In general, PCI can induce efficient light-directed delivery of macromolecules into the cytosol, indicating that it may have a variety of useful applications for site-specific drug delivery, as for example in gene therapy, vaccination and cancer treatment.

Background Biopsy and polypectomy frequently are performed for lesions that carry a low risk of malignant transformation in the colon. Elastic scattering spectroscopy (ESS) is a novel optical biopsy technique that can distinguish, almost instantaneously, between normal and abnormal tissue in vivo, without the need to remove tissue. We assessed the diagnostic potential of ESS in the colon to differentiate normal colonic mucosa, chronic colitis, hyperplastic polyps, adenomatous polyps (with dysplasia), and adenocarcinoma. Methods ESS spectra were obtained from 138 sites in 45 patients at colonoscopy. They were then compared with conventional biopsy specimens taken from the same site, including normal colonic mucosa, hyperplastic polyps, adenomatous polyps, chronic colitis, and colon cancer. Spectral analysis was carried out with a validated computerized model that used principal component analysis followed by linear discriminant analysis. Cross validation was carried out by using 60% of the data as a "training set" and the remaining 40% of the data as a "test set." Results A total of 483 spectra were analyzed (290 normal, 19 hyperplastic, 69 adenomatous polyps, 74 chronic colitis, and 31 colorectal cancer). The sensitivity and the specificity of differentiating adenomas from hyperplastic polyps was 84% and 84%, respectively; for cancer from adenomatous polyps, 80% and 75%, respectively; for colitis from normal tissue, 77% and 82%, respectively; and for dysplastic mucosa (from polyps) from colitis, 85% and 88%, respectively. Conclusions ESS holds promise for differentiating colonic lesions with good accuracy and, therefore, is a potentially useful tool to make an instantaneous diagnosis during colonoscopy. It could prove a valuable aid for targeting biopsies in dysplasia surveillance in inflammatory bowel disease and for deciding which small polyps should be removed.

Background and Objectives: Enhancement of photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) has been demonstrated experimentally using light dose fractionation or CP94 iron chelation. This study extends this research.Study Design/Materials and Methods: In normal rat colon, CP94 administration and light dose fractionation were independently and concurrently employed to enhance ALA-PDT. In colonic rat tumors, the most successful enhancement regimes were employed separately.Results: Independent use of light dose fractionation and iron chelation produced similar results in normal colon (2.4- and 2.9-fold more necrosis than controls, respectively). Using both techniques simultaneously produced fivefold enhancement. In the colonic tumors, light dose fractionation and iron chelation (using different parameters) produced two and five times the volume of necrosis, respectively.Conclusions: Both techniques significantly enhanced ALA-PDT in the normal and neoplastic tissues investigated and produced similar levels of enhancement when comparable parameters were employed. Concurrent use of light dose fractionation and iron chelation in normal colon produced considerably more enhancement than either technique could achieve independently.

present for a photodynamic effect to occur; photosensitizer, light and oxygen. The photosensitizer is administered in a stable form (ground state). It is then promoted to a higher energy state (singlet state) by light of a specific wavelength. The excited photosensitizer is then unstable and can release energy in one of three ways, i.e. emission of heat, emission of light, or conversion to an intermediate energy state (triplet state), before returning to stable ground state. In triplet state the photosensitizer can produce hydroxyl and superoxide radicals (type 1 reaction), or convert molecular tissue oxygen to form singlet oxygen (type 2 reaction). This singlet oxygen in turn reacts with proteins, lipids and nucleic acids in cells, causing functional and structural damage which leads to cell death. Hydroxyl and superoxide radicals are also directly responsible for cell death, although it is thought likely that type 2 reactions are more important for many of the photosensitizers [2]. It is likely that the immune response to PDT plays a part in its action, particularly in the long term. However, although this has been studied in animal models, it requires further study in the clinical setting [3].

The mechanism of tissue damage from photodynamic therapy (PDT) may be cellular, vascular or both, depending on the photosensitising agent and the treatment conditions. Well established photosensitisers like porfimer sodium have an optimum drug light interval of two days and may cause skin photosensitivity lasting several weeks. ATX-S10Na(II) is a new photosensitiser that remains largely in the vasculature after systemic administration and clears from the body within a few hours. The present study looks at the factors controlling the extent of PDT necrosis using ATX-S10Na(II) and correlates these with changes in the circulation after PDT. Normal Wistar rats were sensitised with ATX-S10Na(II), 2 mg/kg. At laparotomy, a laser fibre was positioned just touching the colonic mucosa and 50 J light at 670 nm delivered varying the drug light interval (0.5–24 h) and light delivery regime (100 mW continuous, 20 mW continuous or 100 mW in five fractions). Some animals were killed at three days to document the area of necrosis, others received fluorescein shortly prior to death (from a few minutes to three days after PDT) to outline the zone of PDT induced vascular shutdown. Maximum necrosis was seen with the shortest drug light interval (0.5 h), with no effect by 6 h. Fractionating the light or lowering the power did not increase the necrosis. The area of fluorescein exclusion increased over the first 2 h after PDT (in contrast to the re-perfusion seen with other photosensitisers) and correlated with the area of necrosis. PDT with ATX-S10Na(II) is most effective with a drug light interval of less than one hour. It induces irreversible vascular shutdown that extends after completion of light delivery and which is largely independent of the light delivery regime.

The conventional surgical treatment for women with symptomatic uterine fibroids is a hysterectomy. Hysterectomy guarantees the removal of all uterine fibroids without a risk of recurrence. It also guarantees the cure of symptoms such as menorrhagia and pressure effects and has been shown to be associated with a high degree of patient satisfaction and improved quality of life scores. However, in addition to women who desire fertility, there are a growing number of women who have completed their family who do not wish to undergo a hysterectomy. Uterine conserving surgical methods include myomectomy or fibroid shrinkage either by embolisation/laparoscopic clipping of both uterine arteries or myolysis. This article reviews the surgical alternatives to hysterectomy and analyses the data that is currently available with each method. Laparoscopic interstitial laser photocoagulation of uterine fibroids is a relatively new modality of treatment and is carried out in our centre. Results of this method are presented and discussed in this article. Myomectomy is associated with significant morbidity and difficulty in long term management because of high recurrence rates. Surgical alternatives to myomectomy are still limited to large series in a few centres with a special interest in the procedure developed. Well designed long term studies are required to properly evaluate the efficacy and feasibility of each procedure in normal practice and its effect on infertility.

Background: The aim of therapy for advanced esophageal cancer is relief of dysphagia with minimal treatment-related morbidity. This study assessed the efficacy of endoscopic intratumoral injection of cisplatin/epinephrine gel to relieve obstruction and improve swallowing. The gel is designed to minimize diffusion of active drug away from the tumor injection site. Methods: Patients with inoperable esophageal cancer and dysphagia caused by exophytic esophageal tumor underwent up to 6 weekly endoscopic injections of the gel. Response was documented objectively (exophytic tumor volume, lumen size, dysphagia grade) and subjectively (achievement of treatment goal). Results: Twenty-four patients were treated. Primary evaluation criteria for 18 evaluable patients were as follows: dysphagia grade improved in 4 (duration 30 to 45 days) and stabilized in 11; lumen patency improved in 6 (duration 29 to 56 days) and stabilized in 10; exophytic tumor volume decreased in 8 (duration 29 to 114 days). Eight patients felt that their ability to swallow improved. One patient with intramural and exophytic tumor developed a tracheoesophageal fistula, possibly related to treatment. Other complications were tolerable and self-limited. No nephrotoxicty or severe nausea/vomiting typical of systemic administration of cisplatin occurred. Conclusions: Endoscopic injection of cisplatin/epinephrine gel is a straightforward procedure with standard equipment and techniques, which can provide palliation for patients with exophytic malignant tumors of the esophagus. Assessment of this method in conjunction with other therapeutic options such as brachytherapy is warranted. (Gastrointest Endosc 2002;56:644-51.)

Purpose: Photodynamic therapy, using a photosensitizing drug activated by red light, can destroy localized areas of cancer with safe healing and without the cumulative toxicity associated with ionizing radiation. We used photodynamic therapy in a phase I–II study to treat patients with locally recurrent prostate cancer after radiotherapy.Materials and Methods: Patients with an increasing prostate specific antigen (PSA) and biopsy proven local recurrence after radiotherapy were offered photodynamic therapy. Three days after intravenous administration of the photosensitizer meso-tetrahydroxyphenyl chlorin, light was applied using optical fibers inserted percutaneously through perineal needles positioned in the prostate with imaging guidance. Patients were followed with PSA measurements, prostate biopsies, computerized tomography or magnetic resonance imaging and questionnaires on urinary and sexual function.Results: Photodynamic therapy was given to 14 men using high light doses in 13. Treatment was...

The goal of this study was to determine dominant factors affecting treatment response in pancreatic cancer photodynamic therapy (PDT), based on clinically available information in the VERTPAC-01 trial. This trial investigated the safety and efficacy of verteporfin PDT in 15 patients with locally advanced pancreatic adenocarcinoma. CT scans before and after contrast enhancement from the 15 patients in the VERTPAC-01 trial were used to determine venous-phase blood contrast enhancement and this was correlated with necrotic volume determined from post-treatment CT scans, along with estimation of optical absorption in the pancreas for use in light modeling of the PDT treatment. Energy threshold contours yielded estimates for necrotic volume based on this light modeling. Both contrast-derived venous blood content and necrotic volume from light modeling yielded strong correlations with observed necrotic volume (R² = 0.85 and 0.91, respectively). These correlations were much stronger than those obtained by correlating energy delivered versus necrotic volume in the VERTPAC-01 study and in retrospective analysis from a prior clinical study. This demonstrates that contrast CT can provide key surrogate dosimetry information to assess treatment response. It also implies that light attenuation is likely the dominant factor in the VERTPAC treatment response, as opposed to other factors such as drug distribution. This study is the first to show that contrast CT provides needed surrogate dosimetry information to predict treatment response in a manner which uses standard-of-care clinical images, rather than invasive dosimetry methods.

Interstitial laser photocoagulation (ILP) and interstitial photodynamic therapy (PDT) involve delivery of light to lesions in solid organs using thin fibres passed through needles inserted percutaneously under image guidance. In ILP, the laser energy heats the tissue, whereas in PDT it activates a previously administered photosensitising agent. This study looks at their potential for treating localised, small, peripheral lung cancers in patients unsuitable for surgery. Experiments were undertaken on nine normal pigs, up to four fibres being inserted into the lung parenchyma percutaneously under X-ray guidance (ILP: 2-3 W, 1000 q/fibre, from 805 nm diode laser, PDT, 100-200 J/fibre from 652 nm diode laser at 50-100 W, 3 days after 0.15 mg/kg mTHPC). Animals were killed from 3 days to 3 months later and the treated areas examined macroscopically and microscopically. Both techniques were well tolerated, producing well-defined, localised lesions, typically 3.5 x 2 x 2 cm using four fibres. Histology showed thermal coagulative necrosis after ILP and haemorrhagic necrosis after PDT. Early small haematomas and late cavitation were sometimes seen after ILP, but not after PDT. PDT lesions healed with preservation of larger arteries and bronchi in the treated area. A few small pneumothoraces were seen which resolved spontaneously, probably related to the chest wall puncture. It was concluded that ILP and PDT lesions of a size large enough to cover a small tumour can be made safely in the lung parenchyma, although healing was better after PDT. Pilot clinical studies with both techniques are now justified on carefully selected patients.

We read with interest the recent article by Wang et al, reporting the clinical application of SF1 (Sonoflora 1)—a sensitizer that can be activated by light and ultrasound. SF1 is an analog of chlorophyll in that its macrocycle backbone is porphyrin-based and the center of the porphyrin ring consists of a metal ion. The chlorophyll derivative has light absorption peaks at 402 and 636 nm. A very unusual combination of this investigational agent and various prototype light sources and ultrasound devices was used in the treatment of three patients who suffered from late stages of breast cancer with systemic metastases to multiple organs. The combination of photosensitizer and light illumination is commonly known as photodynamic therapy (PDT) and the combination of drug or sonosensitizer and acoustic activation as sonodynamic therapy (SDT). In theory, the direct tumoricidal effects of these modalities are mediated by cytotoxic agents generated through photochemical or sonochemical reactions inside tumor tissue. The narrow gap between potential benefit and potential risk is determined by intrinsic cellular sensitivity and the sensitizer ratio between tumor and normal tissue. The synergistic effects of sensitizer and low-power ultrasound have been examined in many in vitro studies and to a lesser extent in in vivo models. Although the sonosensitization-induced cytotoxicity might be attributed to the sonochemical reaction, such as sensitizer-mediated energy transfer and free radical generation, data suggest that the mechanism of sonosensitization is probably not governed by a universal mechanism, but may be influenced by multiple factors including the nature of the biological model, sensitizer distribution, ultrasound parameters and acoustic energy distribution. Nevertheless, to date, the correlation between ultrasound parameters and biological effects has not been fully established in preclinical investigation (in vitro or in vivo). There is no convincing data that shows that ultrasound used in this way is effective in the treatment of primary tumor and multiple metastases. Therefore, this article raises a few basic questions. First of all, without those critical safety and efficacy information, it is unjustifiable to test the unproven prototypes in humans, particularly those in terminal stages for any purposes. The authors state that acoustic activation was delivered after intravenous administration of the chlorophyll derivative in two different modes—local and whole body ultrasound activation. A handheld ultrasound transducer was used for two patients, which was associated with a side effect of pain. Another patient was placed in a water tub to receive whole body ultrasound treatment. It was expected that ultrasound could reach deep-seated tumor(s) and sensitizers that are beyond the reach of external light of 630 nm. Although no details were provided in terms of the number of transducers in the water tub, the geometric distribution of acoustic energy within the body, and its accessibility to the multiple tumor sites (e.g., breast, lung, bones, liver, neck, axillary lymph nodes, and abdominal lymph nodes), the authors indicated that high acoustic power (2 W/cm at 1 MHz for 20 minutes) was used in both settings without providing justifications on the selection of those parameters. It is also questionable that sufficient acoustic energy will reach the deep-seated metastases in lung and bone tissues. Second, single high-dose PDT and metronomic PDT (i.e., to deliver photosensitizer and/or light doses at low rates over an extended period) have distinct and complementary therapeutic goals. In contrast to the conventional PDT regimen of single dose drug administration (intravenous or oral), the authors used a repeated lingual delivery of the chlorophyll derivative (a total dose of 30 or 60 mg) for 2 to 3 consecutive days followed by light plus ultrasound treatment daily for 3 days starting at day 3 or day 4 after the onset

We report the results of a prospective study of 23 patients in which interstitial laser photocoagulation (ILP) was used to treat an osteoid osteoma. ILP is a technique in which tumour tissue is destroyed by direct heating using low-power laser light energy delivered by thin (400 μm) optical fibres which are introduced percutaneously into the tumour under image guidance. Pain was evaluated before operation and at the latest follow-up using a visual analogue scale with 0 denoting no pain and 10 the worst pain imaginable. The mean follow-up was for 15 months. The results showed that the mean pain score decreased from 7.5 before operation to 0.95 at the latest follow-up. Fourteen patients had no pain and eight had minor discomfort, not requiring analgesia. One patient required a second procedure because placement of the fibre had not been accurate enough and one developed recurrent symptoms eight months after treatment. All patients were satisfied with the operation because of the rapid resolution of pain, the minimally invasive nature of the procedure, and the fact that there was no postoperative restriction of activity.

This article reviews current knowledge on the biology of photodynamic therapy on normal and diseased tissues in the gastrointestinal tract. There is little effect on connective tissue, so the mechanical integrity of the luminal gut is well preserved, even with full thickness damage. This makes photodynamic therapy suitable for treating small tumors, but strictures may occur after circumferential treatment of conditions like Barrett's esophagus unless a muscle-sparing photosensitizing agent is used. Animal studies show that the pancreas and surrounding tissues can tolerate photodynamic therapy, justifying pilot clinical trials on percutaneous, interstitial photodynamic therapy for localized, inoperable pancreatic cancers.

Objective: Photodynamic therapy (PDT) uses red light (non-thermal, non-ionising) to activate a previously administered photosensitising drug. This inhibits neointimal hyperplasia in injured arteries in small animals where it appears safe and well tolerated. Our aim was to develop a method for percutaneous application of PDT to iliac and coronary arteries in a large animal model and investigate its influence on the remodeling and intimal hyperplastic response to balloon injury. Methods: Studies were undertaken on 13 juvenile Large White–Landrace crossbred pigs (15–20 kg). After intravenous administration of the photosensitising agent 5-amino laevulinic acid (ALA), the arterial tree was accessed via the left common carotid artery and balloon injuries made by overdistension in both common iliacs (thirteen animals) and one or two main coronary arteries (eight animals). Half the injured sites were then illuminated with red laser light transmitted via the catheter. Animals were culled 28 days later and tissue harvested for histomorphometry. Results: Compared with control injured vessels, PDT treated, balloon injured coronary arteries had a larger lumen (1.4 vs. 0.8 mm2, P =0.002), larger area within the external elastic lamina (2.8 vs. 2.2 mm2, P =0.006) and smaller area of neointimal hyperplasia (0.4 vs. 0.7 mm2, P =0.06), 28 days after intervention. Less neointimal hyperplasia and the absence of negative remodeling resulted in the lumen of PDT-treated, injured segments being the same as that of adjacent reference segments (1.5 vs. 1.6 mm2). Similar trends, but with smaller differences, were seen in the iliac vessels. Conclusions: Intra-arterial, trans-catheter PDT favourably influences the arterial response to balloon injury in both the coronary and peripheral circulations. This technique offers a promising new approach to restenosis after endovascular procedures.

The optical properties, absorption (mua) and reduced scattering coefficient (mu's), of ex vivo human myometrium and leiomyoma (fibroid) have been determined by the Monte Carlo inversion technique over the wavelength range 600-1000 nm. This region is currently of interest for new, minimal-access, surgical laser procedures such as photodynamic therapy (PDT) for abnormalities of the uterus, and interstitial laser photocoagulation (ILP) for the thermal ablation of fibroids. In the region 630-675 nm (corresponding to PDT), the optical coefficients of myometrium are mua = 0.041+/-0.012 mm(-1) and mu's = 1.37+/-0.19 mm(-1). For the wavelength range 800-1000 nm (associated with infrared lasers for ILP), the optical coefficients of fibroid were found to be mua = 0.020+/-0.003 mm(-1) and mu's = 0.56+/-0.03 mm(-1). Overall, the optical properties of fibroid were found to be lower than myometrium, and this was attributed to the differences in both anatomy and vascularity. The results show that PDT for ablation of the uterine endometrium is most unlikely to affect any tissues beyond the myometrium, and that the region around 800 nm is the most effective for ablation of fibroids using ILP as the penetration depth of light is greatest at this wavelength.

5-Aminolevulinic acid (ALA) is an attractive photosensitizing agent for photodynamic therapy (PDT) as its photoactive derivative, protoporphyrin IX, is metabolized within 1-2 days, eliminating prolonged skin photosensitivity. However, at the maximum dose patients can tolerate by mouth, 60 mg/kg, only superficial effects are seen. This paper extends earlier studies on enhancing the effect by light fractionation. Experiments in the normal rat colon looked at the area of necrosis around a single light delivery fiber 3 days after PDT with a range of light-dose fractionation regimes. All animals were given 200 mg/kg ALA intravenously 2 h prior to light delivery (100 mW at 635 nm) and each interruption in illumination was for 150 s. The area of PDT necrosis (total dose 25 J) could be increased by a factor of 3 with a single interval after 5 J, compared with continuous illumination. Alternatively, with this single break, the total light dose could be reduced by 60% to achieve the same area of necrosis as with continuous illumination. This simple modification to PDT with ALA could markedly reduce current treatment times as well as increasing clinical efficacy.

From a medical point of view, lasers are a convenient but sophisticated source of light in the visible, ultraviolet, and infrared parts of the spectrum. They are easy to control, and the light beam (of a single colour) can be focused to a small spot and in many cases can be transmitted via thin flexible fibres, making internal delivery of light feasible. The range of clinical applications is enormous, from the simple carbon dioxide laser, used as a non-contact scalpel or for superficial tissue ablation, to the precision of the excimer laser, used for reshaping corneas, and the flash lamp pumped dye laser, used to close the small blood vessels of disfiguring port wine birthmarks. This review looks at how the precision of light delivery and the predictability of biological response possible with laser therapy is starting to be exploited for the in situ destruction of diseased tissue and how these techniques might be developed in the future. The first requirement for successful clinical use of lasers is to understand how light at the wavelength used can interact with living tissue. Most of the simple applications are thermal, but the effect produced depends on how much heat is delivered, how fast it is delivered, and the volume of tissue in which it is absorbed. Increasingly, however, the new technique of photodynamic therapy (non-thermal effects from combining laser light and a photosensitising drug) is attracting interest. This review considers particularly the effects of low power thermal treatment and photodynamic therapy (see table). The carbon dioxide laser (wavelength 10 600 nm in the far infrared) is well established as a non-contact scalpel in relatively inaccessible areas like the brain and upper airways and for ablating small lesions as on the skin. However, the beam cannot be transmitted via flexible fibres and can …

Photodynamic therapy (PDT) produces local tumor necrosis, on activation of a previously administered sensitizer with non-thermal light of an appropriate wavelength. It is attractive for treating tumors of the mouth as tissue healing is particularly good, We describe the use of the photosensitizing agent meta tetrahydroxyphenyl chlorin (mTHPC, Foscan(R)) for PDT of oral cancer, including patients with field cancerization. Nineteen patients with histologically confirmed oral cancer (8 with field change disease) and one with severe dysplasia, were sensitised with mTHPC intravenously. Activation was carried out 72-96 hr later with laser light at 652 nm using a range of light doses, The results were assessed clinically and histologically. Multiple biopsies were taken during the ulcerative stages to look at the effects of PDT and after healing to assess the overall treatment result, All single lesions up to stage T3 cleared after one PDT treatment (total of 6 patients), Three out of 6 T4 tumours were also cleared. Lesions in patients with field change disease did less well, only 9 of 14 T1 and T2s clearing, including 4 that required extra treatments with a higher light dose, Most healed very well, but tongue tethering was seen in patient and another had necrosis in normal areas due to light scattering within the mouth. PDT using mTHPC is a promising new treatment for patients with oral cancer, (C) 1997 Wiley-Liss, Inc.

It has often been claimed that photodynamic therapy (PDT) produces selective destruction of small cancers without affecting the adjacent normal tissue. The objective of our work was to treat small cancers of the oral cavity with PDT and subsequently excise the treated areas for histological studies of tumour and adjacent normal tissue exposed to the same light dose. Eleven patients with histologically proven T1NO oral squamous-cell carcinomas were treated with PDT, using Photofrin as a sensitiser. The tumours plus a surrounding cuff of normal tissue were exposed to 50 J/cm2 non-thermal laser light at 630 nm delivered by surface illumination and the treated areas subsequently excised. Histological staining and image analysis were used to determine the nature and extent of injury. No macroscopic distinction was evident between tumour and normal tissue exposed to light. Histologically, replacement of superficial epithelium, tumour and connective tissue with a fibrinous necrotic slough was seen. There was also loss of endothelium from small vessels, with haemorrhage and thrombosis. Preservation of subepithelial collagen and elastin was demonstrated with EVG staining. No evidence of selective tumour necrosis was found. Although depth of injury was variable, full thickness mucosal necrosis occurred in all cases.

Photodynamic therapy (PDT) is an evolving technique for localized control of diseased tissue with light after prior administration of a photosensitizing agent and in the presence of oxygen. The biological effect is quite different from surgery, radiotherapy and chemotherapy. With no temperature change during treatment, connective tissues like collagen are largely unaffected, so maintaining the mechanical integrity of hollow organs. PDT is of particular value for pre-cancer and early cancers of the skin (not melanomas) and mouth as the cosmetic and functional results are so good. Another key indication is for small areas of cancer that are unsuitable for or have persisted or recurred after conventional management. It can be applied in areas already exposed to the maximum safe dose of radiotherapy. Outside cancer, in ophthalmology, it is established for age-related macular degeneration, and has considerable potential in arterial disease for preventing restenosis after balloon angioplasty and in the treatment of infectious diseases, where the responsible organisms are accessible to both the photosensitizer and light. New developments on the horizon include techniques for increasing the selectivity for cancers, such as coupling photosensitizers to antibodies, and for stimulating immunological responses, but many further pre-clinical and clinical studies are needed to establish PDT's role in routine clinical practice.

Summary Background Anal Intraepithelial Neoplasia (AIN), a pre-cursor of anal squamous carcinoma, is increasingly detected in individuals with impaired immune function. However, choices for effective, low morbidity treatment are limited. Photodynamic Therapy (PDT) is promising as it is known to ablate more proximal gastrointestinal mucosa with safe healing, without damage to underlying muscle. It can also ablate skin with safe healing and minimal scarring. Methods Pharmacokinetics: Normal rats were sensitised with 200 mg/kg 5-aminolaevulinic acid (ALA) and killed 1–8 h later. Anal tissues were examined by fluorescence microscopy to quantify the concentration of PPIX (protoporphyrin IX, the active derivative of ALA) in anal mucosa and in the underlying sphincter. PDT: Normal rats were sensitised similarly 3 h later, laser light (635 nm) was delivered. Anal canal: 50–150 J/cm using 1 cm diffuser fibre; for peri-anal skin, 50–200 J/cm2, using microlens fibre. In each group, 2 rats were killed 3, 7, 14 and 28 days later and the anal region removed for histological examination. Results Pharmacokinetics: Peak concentration of PPIX in mucosa was at 3 h, peak ratio mucosa: muscle, 6, seen at same time. PDT. Anal canal 50 J/cm: complete mucosal ablation by 3 days, complete regeneration by 28 days. Higher energies caused muscle damage with scarring. Peri-anal skin: 200 J/cm2; complete ablation of skin, including appendages, complete healing by 28 days. Minimal effect with lower energy. Conclusion ALA-PDT can ablate anal mucosa and peri-anal skin with safe healing and no underlying damage. However, over treatment can damage the sphincters. This technique is ready to undergo clinical trials.

New technical advances have made feasible the utilization of laser to destroy deep-seated brain tumors under real-time monitoring. Experience with interstitial laser thermotherapy (ILTT) in animal and clinical studies has been obtained. These studies are summarized and the future potential of ILTT in neurosurgery is discussed. (C) 1996 by Elsevie Science Inc.

BACKGROUND. Premalignant changes in the mouth, which are often widespread, are frequently excised or vaporized, whereas cancers are treated by excision or radiotherapy, both of which have cumulative morbidity. Photodynamic therapy (PDT) is another option that produces local tissue necrosis with light after prior administration of a photosensitizing agent. This heals with remarkably little scarring and no cumulative toxicity. This article describes the use of PDT with the photosensitizing agent 5-aminolevulinic acid (ALA) for premalignant and malignant lesions of the mouth. METHODS. Eighteen patients with histologically proven premalignant and malignant lesions of the mouth were sensitized with 60 mg/kg ALA by mouth and treated with laser light at 628 nanometers (100 or 200 Joules/cm 2 ). The results were assessed macroscopically and microscopically. Biopsies were taken immediately prior to PDT for fluorescence studies, a few days after PDT to assess the depth of necrosis, when healing was complete, and up to 88 weeks later. RESULTS. The depth of necrosis varied from 0.1 to 1.3 mm, but complete epithelial necrosis was present in all cases. All 12 patients with dysplasia showed improvement (repeat biopsy was normal or less dysplastic) and the treated areas healed without scarring. Some benefit was observed in five of six patients with squamous cell carcinoma, but only two became tumor free (one with persistent mild dysplasia). No patient had cutaneous photosensitivity for longer than 2 days. CONCLUSIONS. PDT using ALA for dysplasia of the mouth produces consistent epithelial necrosis with excellent healing and is a simple and effective way to manage these patients. Results in invasive cancers are less satisfactory, mainly because the PDT effect is too superficial with current treatment regimens using ALA as the photosensitizing agent.

Photodynamic therapy (PDT) produces localised necrosis with light after prior administration of a photosensitising drug. Although the technique is promising for small tumours of hollow organs, little work has been done on solid organs like the prostate. We studied the tissue biodistribution and photodynamic effects of meso-tetra-(m-hydroxyphenyl) chlorin (mTHPC), a potent second-generation photosensitiser, on normal canine prostate in vivo. Using quantitative fluorescence microscopy, the highest concentration of mTHPC in the prostate was seen 24-72 hr after intravenous administration. For PDT, red light (650 nm) was delivered to the prostate by laser fibres inserted via the transurethral or transperineal route under transrectal ultrasound guidance. PDT lesions up to 40 mm in diameter (using 4 fibre sites) were produced, characterised by swelling, inflammatory response and extensive glandular destruction. There was persistent glandular atrophy at 90 days, but no disruption of the main stroma and no change in the ultimate size or shape of the gland. Urethral damage sometimes caused temporary urinary retention, but this resolved by 7 days, and no animal became incontinent. Occasional small lesions were seen in the rectum, but these healed without sequelae and there were no fistulae. Since cancer and normal prostate are likely to respond similarly, PDT has considerable promise for treating cancer confined to the gland as large areas of glandular tissue can be necrosed with safe healing. Because the structural integrity of the gland is maintained, PDT is unlikely to be of value in the management of benign prostatic hypertrophy.

Background: Many esophageal cancer patients present with recurrent dysphagia after treatment with radiotherapy and are considered at high risk for further endoscopic intervention. We assessed whether the risks were really greater than those in patients not previously irradiated. Methods: Over 6 years, 61 patients who had undergone previous radiotherapy required endoscopic dilation with or without intubation. The risk of dilating or intubating these patients was compared to that of a control group of 126 patients with similar malignancies who had not undergone previous radiotherapy. Results: The perforation rate for dilation in the radiotherapy group was not significantly different from that in controls (3% radiotherapy vs 4.7% in controls per procedure; 6.5% radiotherapy vs 8% in controls per patient) and was unrelated to previous laser therapy. Half the perforations in the control group occurred at the first therapeutic procedure. Endoprostheses were inserted in 48% of radiotherapy patients and 79% of controls at some stage of the illness. The risks of perforation related to intubation in each group were similar (3% radiotherapy vs 4% in controls) although tube migration was more frequent in the radiotherapy group, 21% vs 3% in controls ( p = 0.005). Conclusion: We conclude that there is no increased risk of perforation in endoscopic dilation or intubation for strictures occurring after radiotherapy. (Gastrointest Endosc 1996;43:584-90.)