Search

Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA) which is the precursor of the photosensitizer protoporphyrin IX (PpIX) is an available treatment for several diseases. ALA-PDT induces the apoptosis and necrosis of target lesions. We have recently reported the effects of ALA-PDT on cytokines and exosomes of human healthy peripheral blood mononuclear cells (PBMCs). This study has investigated the ALA-PDT-mediated effects on PBMC subsets from patients with active Crohn’s disease (CD). No effects on lymphocyte survival after ALA-PDT were observed, although the survival of CD3−/CD19+ B-cells seemed slightly reduced in some samples. Interestingly, ALA-PDT clearly killed monocytes. The subcellular levels of cytokines and exosomes associated with inflammation were widely downregulated, which is consistent with our previous findings in PBMCs from healthy human subjects. These results suggest that ALA-PDT may be a potential treatment candidate for CD and other immune-mediated diseases.

Photodynamic therapy (PDT) is a non-invasive therapeutic modality based on the interaction between a photosensitive molecule called photosensitizer (PS) and visible light irradiation in the presence of oxygen molecule. Protoporphyrin IX (PpIX), an efficient and widely used PS, is hampered in clinical PDT by its poor water-solubility and tendency to self-aggregate. These features are strongly related to the PS hydrophilic-lipophilic balance. In order to improve the chemical properties of PpIX, a series of amphiphilic PpIX derivatives endowed with PEG

Background Photodynamic therapy (PDT) in combination with stent have shown promising results in the treatment of biliary tract cancer (BTC) in patients not suitable for surgery. Chemotherapy has been shown to improve survival in patients with local advanced and metastatic BTC. Material and methods In the current randomized trial the combination of chemotherapy and stent with and without temoporfin (Foscan) photodynamic therapy (PDT), with a primary endpoint on feasibility and safety, has been performed. Ten patients in each group. Results No serious, acute procedure-related complication related to PDT or the treatment combination was seen. The number of patients with cholangitis was equal in both groups. In the PDT group – arm A – two patients had cutaneous erythema after sun exposition, one of them with a localized blister. No neutropenic infection was seen. Quality of Life (QoL) was similar in both treatment groups. Progression free survival was numerically longer in the PDT group. Conclusion The treatment combination was feasible. There was no serious complication related to PDT or the treatment combination. Number of cholangitis was equal in both groups, two abscesses were observed in the PDT group. Progression free survival was numerically longer in the PDT group.

SummaryBackground Genital erosive lichen planus (GELP) in women is a chronic inflammatory disease characterized by painful vulval and vaginal erosions. Topical photodynamic therapy (PDT) is increasingly used in premalignant and malignant diseases and may have an effect in inflammatory diseases. Objectives To assess the feasibility, efficacy and safety of hexyl 5-aminolevulinate-hydrocloride (HAL)-PDT in GELP. Methods Forty women, diagnosed with GELP at a specialized vulva clinic, were randomized to one session HAL-PDT in vulva and/or vagina (n = 20) or daily applications of clobetasol propionate 0·05% ointment in vulva and optional hydrocortisone acetate 1·0% foam in vagina for 6 weeks (n = 20). After 6 weeks, all patients were allowed to use topical corticosteroids as needed. Clinical examinations were performed at weeks 0, 6 and 24, using a clinical score developed for the study. All patients wrote a weekly log on pain, topical corticosteroid use and adverse events. Results Three patients, all in the corticosteroid group, withdrew from the study after 1–3 weeks. The mean reduction in clinical scores was similar in the PDT group and the corticosteroid group; 25% vs. 22% after 6 weeks (P = 0·787) and 35% vs. 38% after 24 weeks (P = 0·801). The mean reduction in pain visual analogue scale scores was 38% vs. 55% after 6 weeks (P = 0·286) and 39% vs. 12% after 24 weeks (P = 0·452). Patients in the PDT group reported significantly less topical corticosteroid use during weeks 7–24 than those in the corticosteroid group. No major adverse events were reported. Conclusions Vulvovaginal HAL-PDT seems to be an effective and safe treatment for GELP.

Patients with esophageal cancer seldom achieve long-term survival. This prospective cohort study investigated the selection of patients likely to benefit from curative treatment and whether information on patients' health-related quality of life (HRQL) would assist treatment decisions in the multidisciplinary team.Consecutive patients completed HRQL assessments and clinical data were collected before start of treatment. Logistic regression analyses identified clinical factors associated with treatment intent in patients with stage-III disease. Kaplan-Meier method was used for survival analyses and Cox proportional hazards models were used to assess the impact of clinical factors and HRQL on survival in patients planned for curative treatment.Patients with curative treatment intent (n = 90) were younger, had better WHO performance status and less fatigue than patients with palliative treatment intent (n = 89). Median survival for the total cohort (n = 179) and patients with palliative or curative treatment intent was nine, five and 19 months, respectively. In multivariate Cox regression analyses, performance status (0-1 favorable) and comorbidity (ASA I favorable) were factors of importance for survival, whereas measures of HRQL were not.Patients performance status and comorbidity must be considered in addition to stage of disease to avoid extensive curative treatment in patients with short life expectancy. This study did not provide evidence to support that information on patients HRQL adds value to the multidisciplinary team's treatment decision process.

Background Extracorporeal photopheresis that exposes isolated white blood cells to 8-methoxypsoralen (8-MOP) and ultraviolet-A (UV-A) light is used for the management of cutaneous T-cell lymphoma and graft-versus-host disease. 8-MOP binds to DNA of both tumor and normal cells, thus increasing the risk of carcinogenesis of normal cells; and also kills both tumor and normal cells with no selectivity after UV-A irradiation. Hexaminolevulinate (HAL)-induced protoporphyrin-IX is a potent photosensitizer that localizes at membranous structures outside of the nucleus of a cell. HAL-mediated photodynamic therapy selectively destroys activated/transformed lymphocytes and induces systemic anti-tumor immunity. The aim of the present study was to explore the possibility of using HAL instead of 8-MOP to kill cells after UV-A exposure. Methods Human T-cell lymphoma Jurkat and Karpas 299 cell lines were used to evaluate cell photoinactivation after 8-MOP and/or HAL plus UV-A light with cell proliferation and long term survival assays. The mode of cell death was also analyzed by fluorescence microscopy. Results Cell proliferation was decreased by HAL/UV-A, 8-MOP/UV-A or HAL/8-MOP/UV-A. At sufficient doses, the cells were killed by all the regimens; however, the mode of cell death was dependent on the treatment conditions. 8-MOP/UV-A produced apoptotic death exclusively; whereas both apoptosis and necrosis were induced by HAL/UV-A. Conclusion 8-MOP can be replaced by HAL to inactivate the Jurkat and Karpas 299 T-cell lymphoma cells after UV-A irradiation via apoptosis and necrosis. This finding may have an impact on improved efficacy of photopheresis.

Summary Genital erosive lichen planus (GELP) is a chronic inflammatory disease, in women characterized by painful vulvar and vaginal erosions. To prepare for a clinical trial on photodynamic treatment (PDT), we applied hexyl 5-aminolevulinate hydrochloride (HAL) in clinically normal and affected mucosa in 12 women with GELP using two different doses (6.25 or 50 mg/ml). Biopsies were taken after 30 min and 3 h. The biodistribution of HAL, measured as photoactive protoporphyrin IX (PpIX), was studied using non-invasive superficial fluorescence measurements and microscopic fluorescence photometry. More PpIX was detected after application of 12.5 mg HAL than after 100 mg, with large inter-individual variations. PpIX levels after 3 h were overall higher than after 30 min. PpIX fluorescence was not detected in skin distant to the genital area. In conclusion, 6.25 mg/ml HAL applied for 3 h seems adequate for HAL absorption and conversion to PpIX in submucosal inflammatory and epithelial cells and can be used in a PDT trial of GELP.

Purpose To investigate whether a combination of self-expanding metal stent (SEMS) and brachytherapy provided more rapid and prolonged effect on dysphagia without increased pain compared to brachytherapy alone in patients with incurable oesophageal cancer. Methods 41 Patients were randomised to SEMS followed by brachytherapy, 8Gy×3 (n=21) or brachytherapy alone, 8Gy×3 (n=20). Change in dysphagia and pain three and seven weeks after randomisation (FU1 and FU2) was assessed by patient-reported outcome. Dysphagia, other symptoms and health-related quality of life were assessed every four weeks thereafter. The study was closed before the estimated patient-number was reached due to slow recruitment. Results Patients receiving SEMS followed by brachytherapy had significantly improved dysphagia at FU1 compared to patients receiving brachytherapy alone (n=35). Difference in pain was not observed. At FU2, patients in both arms (n=21) had less dysphagia. Four patients in the combined treatment arm experienced manageable complications, no complications occurred after brachytherapy alone. Conclusion For the relief of dysphagia, SEMS followed by brachytherapy is preferable and safe for patients in need of immediate alleviation, while brachytherapy with or without preceding SEMS provides relief within a few weeks after treatment.

Objectives The aim of this study was to examine the clinical behavior and response to topical methyl 5-aminolevulinate (MAL) photodynamic therapy (PDT) of oral lichen planus and to describe the buildup and biodistribution of photoactive porphyrins in normal and lichen planus–affected oral mucosa after MAL application. Study Design The difference in clinical expression in 14 patients with buccal oral lichen planus was compared before and after treatment. MAL-induced photoactive porphyrins were monitored using noninvasive in situ fluorescence measurements. Microfluorometry was used to study the biodistribution. Results The absorption and conversion of protoporphyrin IX (PpIX) in epithelial and subepithelial T cells was demonstrated in histologic sections. As a result of 1 treatment session, there was a significant improvement of oral lichen planus after 6 months ( P = 0.02) and during a 4-year follow-up period. Conclusions MAL is absorbed and converted to PpIX in T cells. Oral lichen planus treated with MAL-PDT showed lasting improvement after a single treatment.

SUMMARY In a retrospective review, in order to describe the palliative care and prognosis of patients with advanced cancer of the esophagus, the clinical characteristics and the treatment modalities applied were explored in relation to survival and symptom relief for 261 patients treated without curative potential. The data were obtained from a study of all patients with cancer of the esophagus treated at the Norwegian Radium Hospital in the 10-year period from 1990 to 1999. Medical data of the patients were reviewed and missing clinical information was retrieved from local hospitals and general practitioners. The patients were divided into three groups based upon the overall survival from start of treatment to death. Survival ≤3 months is in this paper, defined as ‘short,’ while survival > 6 months is defined as ‘long.’ Median survival for the total group of patients was 4 months. The 1-, 2-, and 3-year survival was 8%, 3%, and 1%, respectively. Patients with short survival (n= 107) had more advanced disease, lower performance status, and more dysphagia, weight loss, and pain and used more analgesics than patients with long survival (n= 91). Tumor characteristics such as localization, tumor length, and histology were not significantly associated with survival. This result was confirmed in a logistic regression analysis (with backward stepwise elimination) including sex, age, clinical stage, tumor length, tumor localization, histology, performance status, dysphagia, weight loss, and pain, where clinical stage, performance status, weight loss, and pain were included in the final model. A large variety of first-line palliative treatments were applied within the studied time period; external radiotherapy ± brachytherapy (n= 149), brachytherapy alone (n= 44), endoluminal stent (n= 28), laser evaporization (n= 8), chemotherapy (n= 5), and best supportive care only (n= 27). There were no clear differences in the effect on dysphagia between the modalities. Fourteen percent of the patients had treatment related complications. In conclusion, symptoms, performance status, and use of analgesics seemed to better prognosticate survival than tumor characteristics other than stage of disease. Our study reveals that knowledge about prognostic factors is crucial for the choice of palliative treatment. Even though all of the different treatment modalities seemed to provide relief of dysphagia, several other factors should be considered when deciding which treatment modality to offer. The time to onset of relief, duration of response, level of complications, and time spent in hospital should be a part of the decision-making process when selecting the appropriate treatment.

Background and Aims: A significant change in the occurrence of oesophageal squamous cell carcinomas (SCCs) in relation to adenocarcinomas (ACs) has been observed in the Norwegian population during the last 20 years (1988–2007). The AC incidence has increased from 5–10% to more than 50% nowadays, while the incidence of SCCs has decreased. Our goal was to evaluate if the change from SCC to AC and the increased effort to control reflux could be reflected in tumour stage, patient demographics and treatment results. Material and Methods: We analysed clinical and pathological data from 347 patients with oesophageal AC (n = 189) and SCC (n = 158) treated at The Norwegian Radium Hospital during said period for patient- and tumour characteristics, treatment modalities and survival. Results: An oesophageal resection was performed in 169 of 347 patients. The median survival rate for all patients was 15 months, with a 5-year survival rate of 10%. The median survival time for operated and non-operated patients was 25 and 12 months respectively, with the corresponding 5-year survival rate of 13% and 2%. Patients with N0M0 disease operated with free resection margins presented a 5-year survival rate of 28%. Conclusions: The change from SCC to AC and the ensuing considerable efforts made in surveillance and treatment of AC did not lead to improved long time survival for our patients.

Over a 10-year period from 1990, 445 patients with carcinoma of the oesophagus were admitted to the Norwegian Radium Hospital and 184 of these patients received treatment with curative intent. Even though surgery is the treatment of choice for these patients, many of them suffer from medical conditions that increase the risk for postoperative mortality and morbidity. In a retrospective study, the effect of the curative treatment offered to patients was explored with a particular focus on patients unfit for surgery.Medical data of the 184 patients treated with curative intent were reviewed and additional clinical information was retrieved from local hospitals and general practitioners. Preoperative radiotherapy followed by surgery was the standard curative treatment for operable patients. Medically inoperable patients were offered radical split-course hyperfractionated radiotherapy followed by a brachytherapy boost.More than 50% (103/184) received non-surgical treatment only. Patients who received radical surgery (n = 81) were younger, had better performance status, less weight loss and dysphagia compared to patients treated with radical radiotherapy (n = 102). One patient received only photodynamic therapy. The 3-year survival was 29% for patients treated with radical surgery, and 8% for patients who received radical radiotherapy. The overall median crude survival for the two groups of patients were 20 months and seven months respectively.The hyperfractionated radiotherapy provided symptom relief without extensive toxicity and with a possibility for cure for patients with oesophageal cancer who are unfit for surgery and chemoradiotherapy. The literature supports the curative potential of high dose accelerated hyperfractionated radiotherapy even though the optimal radiotherapy regimen still needs to be explored.

Long-term follow-up data are needed to evaluate treatment effect after photodynamic therapy (PDT).To investigate long-term clinical, histological and cosmetic follow-up results in basal cell carcinoma (BCC) after PDT, including treatment response related to patients and lesion characteristics.A longitudinal study of 44 patients with 60 histologically verified BCC tumours, treated with one or two sessions of dimethylsulfoxide (DMSO)-supported 5-aminolaevulinic acid--PDT following curettage, was performed. Lesions in complete remission after 3 months were followed with clinical inspection, histological investigation and evaluation of cosmetic outcome at regular intervals; long-term efficacy assessed as verified recurrence within 72 months after PDT.Complete remission at 3 months was achieved in 55 lesions from 39 patients. Two patients with one lesion each died. At 72 months, 43 of 53 lesions remained disease-free (81%); 68% remained after one treatment session, and 91% remained after two treatment sessions. Recurrence of tumour occurred at 6, 12, 24 and 36 months in 2, 4, 2 and 2 lesions, respectively; clinical investigation identified 97% of them. Male sex and H-mid-face zone were significantly associated with recurrence. The cosmetic outcome at 72 months was rated as good or excellent by patients and investigators in more than 90% of evaluated cases.DMSO-PDT following curettage is an effective treatment for BCC, with favourable long-term clinical, histopathological and cosmetic results. Clinical examination of treated lesions appears to be sufficient for long term follow up.

A photosensitizer is defined as a chemical entity, which upon absorption of light induces a chemical or physical alteration of another chemical entity. Some photosensitizers are utilized therapeutically such as in photodynamic therapy (PDT) and for diagnosis of cancer (fluorescence diagnosis, FD). PDT is approved for several cancer indications and FD has recently been approved for diagnosis of bladder cancer. The photosensitizers used are in most cases based on the porphyrin structure. These photosensitizers generally accumulate in cancer tissues to a higher extent than in the surrounding tissues and their fluorescing properties may be utilized for cancer detection. The photosensitizers may be chemically synthesized or induced endogenously by an intermediate in heme synthesis, 5-aminolevulinic acid (5-ALA) or 5-ALA esters. The therapeutic effect is based on the formation of reactive oxygen species (ROS) upon activation of the photosensitizer by light. Singlet oxygen is assumed to be the most important ROS for the therapeutic outcome. The fluorescing properties of the photosensitizers can be used to evaluate their intracellular localization and treatment effects. Some photosensitizers localize intracellularly in endocytic vesicles and upon light exposure induce a release of the contents of these vesicles, including externally added macromolecules, into the cytosol. This is the basis for a novel method for macromolecule activation, named photochemical internalization (PCI). PCI has been shown to potentiate the biological activity of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane, including type I ribosome-inactivating proteins, immunotoxins, gene-encoding plasmids, adenovirus, peptide-nucleic acids and the chemotherapeutic drug bleomycin. The background and present status of PDT, FD and PCI are reviewed.

Topical photodynamic therapy (PDT) of superficial basal cell carcinoma (BCC) with 5-aminolevulinic acid (ALA) has achieved promising clinical results. However, the efficacy of this therapy for thick BCC is dramatically decreased by a limited diffusion of hydrophilic ALA into the tumor. Lipophilic esters of ALA may enhance their penetration into the lesion. In this randomized, open clinical study, microscopic fluorescence photometry incorporating a light-sensitive thermo-electrically cooled charge-coupled device (CCD) camera was employed to investigate the penetration of methyl 5-aminolevulinate-induced porphyrin fluorescence in thick BCC lesions. Both the distribution pattern and the amount of porphyrins in 32 lesions of 16 patients were studied after topical application of 16, 80 or 160 mg/g of methyl 5-aminolevulinate for 3 or 18 h. A highly selective and homogeneous distribution of methyl 5-aminolevulinate-induced porphyrin fluorescence was seen in all lesions studied, with much less fluorescence in the adjacent normal skin tissues. In lesions of up to 2 mm thickness the application of 160 mg/g methyl 5-aminolevulinate for 3 h showed the highest ratio of porphyrin fluorescence depth to tumor depth (0.98+/-0.04), thus providing a biologic rationale for a clinical PDT trial with this regimen.

Clonal chromosome abnormalities were found in 22 of 23 short-term cultured basal cell carcinomas (BCC) of the skin. The karyotypic abnormalities were nonrandom and in several cases included evidence of clonal evolution. Especially in cultures showing an epithelial growth pattern, simple numerical changes, most commonly +18, +9, +20, +7, and +5, predominated and presumably constitute pathogenetically important aberrations present in the neoplastic parenchyma. Also, several structural rearrangements of chromosome arm 9q were seen, which may be of particular interest against the background that a gene for familial BCC (Gorlin syndrome), the PTCH gene, maps to this region. Finally, most of the clonal aberrations detected in predominantly fibroblast-like cultures are likely to reflect changes acquired by cells of the tumor stroma, which raises the question whether mutations also of this tumor component may play a pathogenetic role in BCC development.

BACKGROUND Photodynamic therapy (PDT) for cancer patients has developed into an important new clinical treatment modality in the past 25 years. PDT involves administration of a tumor-localizing photosensitizer or photosensitizer prodrug (5-aminolevulinic acid [ALA], a precursor in the heme biosynthetic pathway) and the subsequent activation of the photosensitizer by light. Although several photosensitizers other than ALA-derived protoporphyrin IX (PpIX) have been used in clinical PDT, ALA-based PDT has been the most active area of clinical PDT research during the past 5 years. Studies have shown that a higher accumulation of ALA-derived PpIX in rapidly proliferating cells may provide a biologic rationale for clinical use of ALA-based PDT and diagnosis. However, no review updating the clinical data has appeared so far. METHODS A review of recently published data on clinical ALA-based PDT and diagnosis was conducted. RESULTS Several individual studies in which patients with primary nonmelanoma cutaneous tumors received topical ALA-based PDT have reported promising results, including outstanding cosmetic results. However, the modality with present protocols does not, in general, appear to be superior to conventional therapies with respect to initial complete response rates and long term recurrence rates, particularly in the treatment of nodular skin tumors. Topical ALA-PDT does have the following advantages over conventional treatments: it is noninvasive; it produces excellent cosmetic results; it is well tolerated by patients; it can be used to treat multiple superficial lesions in short treatment sessions; it can be applied to patients who refuse surgery or have pacemakers and bleeding tendency; it can be used to treat lesions in specific locations, such as the oral mucosa or the genital area; it can be used as a palliative treatment; and it can be applied repeatedly without cumulative toxicity. Topical ALA-PDT also has potential as a treatment for nonneoplastic skin diseases. Systemic administration of ALA does not seem to be severely toxic, but the advantage of using this approach for PDT of superficial lesions of internal hollow organs is still uncertain. The ALA-derived porphyrin fluorescence technique would be useful in the diagnosis of superficial lesions of internal hollow organs. CONCLUSIONS Promising results of ALA-based clinical PDT and diagnosis have been obtained. The modality has advantages over conventional treatments. However, some improvements need to be made, such as optimization of parameters of ALA-based PDT and diagnosis; increased tumor selectivity of ALA-derived PpIX; better understanding of light distribution in tissue; improvement of light dosimetry procedure; and development of simpler, cheaper, and more efficient light delivery systems. Cancer 1997; 79:2282-308. © 1997 American Cancer Society.

Fifty-eight patients with 119 nodular (2 mm or more in thickness) basal cell carcinomas successfully treated with photodynamic therapy were included in this 1-year follow-up study. The initial cure rate at 3-6 months was 92% after photodynamic therapy, which included an initial debulking procedure and topical application of dimethylsulphoxide in order to enhance penetration of 5-aminolevulinic acid (20% in cream) to which the lesions were exposed for 3 h prior to exposure to light. At examination 12-26 months (mean 17 months) after treatment 113 lesions (95%) were still in complete response. Six lesions (5%) had recurred, located on the face, scalp and ear. The cosmetic outcome was evaluated as excellent to good in 91%. Microscopic examination of biopsies taken from healed areas in 7 patients did not reveal any sign of damage in 5 and only minor alterations in 2.

Photodynamic therapy (PDT) has been investigated as an alternative treatment for cutaneous squamous cell carcinoma in situ (CIS), also known as Bowen's disease. Atypia of the squamous epithelium is graded, with the most severe atypia being equivalent to CIS. CIS on the penis is regarded as a premalignant condition and is seen either in isolation or in conjunction with carcinoma of the penis.A group of 10 patients with atypia/CIS were treated with PDT between December 2002 and April 2005. The group consisted of five patients with primary lesions and five with atypia after an organ-preserving operation for carcinoma of the penis.Eight patients were treated once, one twice and one six times. When complete remission was not achieved, a biopsy was taken for diagnosis. Three of the 10 patients had histopathological residual disease after a median follow-up period of 20 months (range 15-36 months). The first week after treatment could be painful but the cosmetic results were excellent. There was almost no loss of substance or fibrosis in the treated area, and sensitivity was restored to normal after approximately 1 month.In our experience, PDT for CIS seems to be a promising treatment modality with regard to cancer control, organ preservation, cosmetics and functional results. As with laser therapy of these lesions, careful follow-up is mandatory. Larger studies are needed and are planned.

Photodynamic treatment (PDT) was first started in the oral cavity in the mid 1980s. Hematoporphyrins were rapidly replaced by Photofrin and meta-tetrahydroxyphenylchlorin (mTHPC) as photosensitisers of choice, and over the years these two have been approved by several health authorities for PDT. 5-aminolevulinic acid (ALA) and some dyes (e.g., toluidine and methyene blue) have also been tested. Several different nonthermal lasers have been used and lately light-emitting diodes (LEDs) have been tried. Most of the clinical treatments have been carried out on oral squamous cell carcinoma (OSSC), either primary or metastatic lesions, with good results. The treatment leaves little scarring and can be used before, in conjunction with, and adjunctive to other treatment modalities. The greatest disadvantage is that the patients are photosensitive for several weeks following systemic administration of the photosensitiser. PDT is now an accepted palliative treatment. Systemic administration of ALA has been more successful than local application in the treatment of precancerous lesions such as oral leukoplakia. PDT following topical application of photosensitiser (metylene blue and methyl-ALA) has shown improvement in cutaneous diseases of the oral mucous membrane such as oral lichen planus. The bactericidal effect of PDT has also been tested on oral plaque, but little clinical work has been performed so far. Instead of mechanical cleaning or antibiotic therapy, PDT may also play a role in dental diseases.

Objectives: Urinary bladder urothelial carcinoma is diagnosed by a combination of cystoscopy and biopsy, with cytology as a valuable additional technique. The accuracy of cytological diagnosis depends on the experience of the cytologist and can inevitably vary from one cytologist to another. There is a need for an easy, reliable and objective diagnostic method. In the present study a new method was designed for the detection of bladder cancer cells in urine. Methods: Flow cytometry was utilized to detect protoporphyrin IX in an artificial model consisting of normal urinary bladder transitional epithelial cells (NBECs) from healthy volunteers’ urine and an established human urinary bladder carcinoma cell line, TCCSUP, after incubation with hexaminolevulinate (HAL). In addition, urine samples from 19 patients with histopathologically confirmed superficial bladder cancer were examined. Results: Incubation of NBECs or TCCSUP cells with HAL for 1 hour resulted in production of protoporphyrin IX only in the TCCSUP cells. Incubation of a mixture of NBECs and TCCSUP cells with HAL gave rise to a separated subpopulation of cells with protoporphyrin IX fluorescence. After cell sorting by flow cytometry the protoporphyrin IX-containing subpopulation of cells was confirmed as TCCSUP cells on cytological examination. It was possible to detect 5% TCCSUP cells in the mixture of NBECs/TCCSUP cells. To test the feasibility of the method in clinica diagnosis, urine samples from patients with bladder cancer were also measured with comparable, although preliminary and limited, results to those of cytological examination. Conclusions: The preliminary results show that the technique may be feasible for the detection of bladder cancer cells in urine with possible advantages of simplicity, reliability and objectivity.

Up to 90% of patients with localized non-Hodgkin's lymphomas (NHL) in the gastrointestinal tract (GI) are cured and decreased use of radical surgery is favoured. Although quality of life (QOL) may impact treatment choice, little is known about QOL in gastric NHL survivors. The self-reported QOL (EORTC QLQ-C30 and a gastric module) and objective findings from upper GI endoscopy were evaluated in patients in complete remission after treatment for primary gastric NHL at the Norwegian Radium Hospital (NRH). Thirty-six (90%) patients completed the questionnaires, 33 (83%) met for endoscopy. Ten patients were treated with total gastrectomy, 17 with partial gastrectomy, while nine patients did not undergo surgery. Gastroscopy was normal in 55% of the non-gastrectomised patients, oesophagoscopy in 69%. Four patients had Barrett's metaplasia. QOL was not different from population values. Patients treated with total gastrectomy reported poorer emotional function, more diarrhoea and more food-related problems (por =0.05) compared with the others. Based on the higher level of digestive and food related problems after total gastrectomy, stomach-preserving surgery should be preferred whenever possible.

Photodynamic therapy using topical methyl 5-aminolevulinate (MAL) is a new treatment modality for basal cell carcinoma (BCC) and actinic keratosis (AK). MAL induces endogenous porphyrins, which act as photosensitizers. Pharmacokinetic studies of the porphyrin-inducing effect of MAL creams (Metvix®) applied in different concentrations (16–160 mg/g) and application times are presented. Surface fluorescence measurements were used to monitor porphyrin accumulation in 18 superficial BCCs and 32 AKs. For both lesion types, the fluorescence increased during the first 13 of 28 hours of continuous MAL application. A 20-fold site-to-site variation was observed, and there were no significant MAL concentration dependencies. The selectivity between lesions and normal skin was 10-fold during the first hours and decreased throughout the application time. Fluorescence microscopy images of tissue sections from 32 nodular BCCs were analyzed to calculate the porphyrin content in tumor tissue as a function of depth. Significant correlation to MAL concentration was seen within the tumors treated for 3 hours. Increase to 18-hour MAL application enhanced the fluorescence levels in superficial tumor layers, but not in deep layers. In conclusion, application of the 160 mg/g cream for 3 hours gave advantageous porphyrin distributions for all types of lesions.

OBJECTIVE: Anyang County, China, is one of the areas with the highest incidence of esophageal cancer in the world. Esophageal cancer has a poor prognosis because most tumors are unresectable at the time of diagnosis. We launched a screening study for early esophageal carcinoma in western Anyang County in 1997. The scope was to identify patients with in situ and early invasive carcinoma, applying esophageal balloon cytology and treating with photodynamic therapy (PDT). STUDY DESIGN: The study cohort consisted of all inhabitants over 35 years of age in 10 communes. Screening was performed by balloon cytology. Grade 2 dysplasia and more advanced lesions were examined with endoscopy, including biopsy and brush cytology, followed by PDT for early cancer. RESULTS: In total, 20,049 persons participated in the screening program, and 1,018 were diagnosed with a grade 2 dysplasia or higher, including 164 invasive cancers and 169 near-cancers. Ninety-four percent of atypical lesions were of squamous cell type. Seventy-two percent of cases showing severe dysplasia and cancer were located to the middle esophageal segment. The prevalence of dysplasia and cancer increased significantly with age. The balloon cytology results were confirmed by brush cytology and histology. CONCLUSION: Balloon cytology is a reliable method for esophageal cancer screening. Positive cytology must be verified by endoscopy and biopsy.

Summary Background Methyl 5-aminolaevulinate (mALA) is an ester derivative of 5-aminolaevulinic acid (ALA) with increased lipophilicity compared with ALA. Objectives To assess long-term cure rate, cosmesis, recurrence rate and extent of fibrosis after mALA-based photodynamic therapy (PDT) of superficial and nodular basal cell carcinomas (BCCs) showing early complete response to treatment. Methods Of 350 BCCs treated, 310 responded completely. These were in 59 patients who were followed for 2‐4 years (mean 35 months) after mALA-PDT. Nodular tumours were curetted before PDT, and mALA 160 mg g 21 was applied to all tumours for 24 h or 3 h before illumination from a broad-band halogen light source with light doses from 50 to 200 J cm 22 . Fibrosis was assessed histologically in 23 biopsies. Results The overall cure rate for 350 BCCs, including non-responders and recurrences was 79%. Of 310 lesions, 277 (89%) remained in complete response, and the cosmetic outcome was excellent or good in 272 of the completely responding lesions (98%). Histological examination showed dermal fibrosis in one of 23 biopsies. Conclusions We conclude that mALA-based PDT with prior curettage of nodular lesions is a promising new method for the treatment of BCC.

This study was conducted to assess the efficacy of aminolevulinic acid-based photodynamic treatment for residual or recurrent basal cell carcinomas after radiotherapy. Photodynamic therapy with either topical 5-aminolevulinic acid 20% and dimethylsulfoxide 99% pretreatment or topical methylester aminolevulinic acid 20% w/w in cream and subsequent light illumination of 50-200 J/cm2 was performed after an initial skin shaving procedure in 20 patients with 22 residual or recurrent basal cell carcinomas. Three lesions were treated once, while twelve, three, one and two lesions received two, three, four and five treatment sessions respectively. At examination, 6-40 months (mean 22 months) after the last treatment, 18 lesions were in complete remission. All lesions were considered excellent or good with regard to cosmetic outcome. Three lesions responded only partially to photodynamic therapy and a fourth lesion recurred 21 months after photodynamic treatment. Two of these four lesions were confirmed as the morpheaform type of basal cell carcinoma.

Photodynamic therapy is a new mode of cancer treatment with promising results for basal cell carcinoma. The current study aims to investigate the accuracy of skin scrape cytology in the diagnosis of basal cell carcinoma as an integrated part of the treatment procedure. A total of 107 nodular basal cell carcinomas of the skin from 90 patients were examined and cytological and histological diagnoses were compared. Compared with histopathology, cytopathology gave 3 false benign results (2.8%) and no false malignant diagnoses. Three lesions were benign by both methods. We conclude that basal cell carcinoma is reliably diagnosed with both techniques. However, cytology is simpler and faster, allowing treatment to be instituted shortly after the first consultation.

Microscopic fluorescence photometry incorporating a light-sensitive thermo-electrically cooled charge-coupled device (CCD) camera was employed to investigate the fluorescence distribution of 5-aminolevulinic acid (ALA)-induced porphyrins in 22 patients with a total number of 52 noduloulcerative basal cell carcinomas (BCC) after topical ALA application with or without dimethylsulfoxide (DMSO)/ethylenediaminetetraacetic acid (EDTA) or after intravenous administration of ALA. Both localization patterns and amounts of ALA-induced porphyrins in the BCC were studied. The ALA-induced porphyrins were localized only in the superficial layers of the noduloulcerative BCC lesions after topical application of 20% ALA alone for 3 h. However, both the penetration of ALA into deep lesions and the production of the ALA-induced porphyrin fluorescence were increased after topical administration of 20% ALA and 20% DMSO/4% EDTA for 3 h. Prior treatment with 99% DMSO for 15 min further enhanced the ALA penetration into the BCC lesions after topical application of the ALA/DMSO/EDTA mixture and produced more ALA-induced porphyrins by a factor of about three compared with those treated with ALA alone. The penetration of ALA into the deep BCC lesions could also be increased by prolonging the time of topical application of 20% ALA/4% EDTA to 29-48 h (without DMSO). Intravenous injection of ALA led to a more homogeneous distribution of the ALA-derived porphyrins in the whole noduloulcerative BCC lesions.

Laser4nduced fluorescence was used for the monitoring of the &-amino levulinic acid (ALA)-induced protoporphyrin IX (PpIX) build-up in non-melanoma malignant tumours of the skin and some cancers in the head and neck region. An optical-fibre based point monitoring system was utilised in the recording of fluorescence spectra at different time intervals after the administration of ALA. In the cases of skin tumours ALA was normally applied topically to the area. Only in one patient with an aggressive skin tumour ALA was administered intravenously. For the PpIX induction in the head and neck tumours

Introduction Chemotherapy has been shown to improve survival in patients with locally advanced and metastatic cholangiocarcinoma (CC). Similar data have been reported with photodynamic therapy (PDT) in combination with stent drainage. A combination of these treatment modalities might improve outcomes further, but such data are still lacking. Therefore we have performed the first randomized trial on the combination of temoporfin/PDT, stent and chemotherapy versus stent and chemotherapy only. Methods Randomized phase II trial with feasibility and toxicity as endpoints. Preliminary data on progression free survival will also be reported. Inclusion criteria were unresectable, treatment naive patients with CC confirmed by histology or cytology, need for biliary stent, bilirubin level Results Twenty patients with locally advanced and metastatic disease were included, ten patients in each arm. Eight men and twelve women, age 35-75 years. Two patients in arm A did not receive chemotherapy (ECOG>2, infection) and two patients in arm B (thrombocytopenia, study withdrawal). No serious, procedure-related complication was seen. Three cases of cholangitis were observed in both group A and B during the first 30 days. Within the next two months three additional patients in each group had cholangitis, grade 3-4. No liver abscess was observed within 30 days. Within three months, liver abscess was found in two patients, group A. Neutropenia grade 3 was observed in 2 patients in both arms, no neutropenic infection. Preliminary data on progression free survival (three still without progression, one just started) were mean 212 days in group A compared to 162 days in group B. Data on QoL will be reported. Conclusion The total number of cholangitis was equal in both groups, two abscesses were seen only in group A, more than one month after PDT. No other serious complication related to PDT was seen. Preliminary, progression free survival seems to be prolonged in group A. Depending on the final data a larger study should be considered.

e14637 Background: Patients whocannot be offered curative surgical treatment for biliary tract cancer (BTC) have a poor prognosis. Photodynamic therapy (PDT) has been shown to improve survival and quality of life in patients with unresectable BTC. A combination of treatment modalities might improve survival further, but such data are still lacking. Therefore we have performed the first randomized trial on the combination of temoporfin/PDT and chemotherapy. Here we report data on the feasibility and safety. Methods: Randomized phase II trial, planned to include 20 patients with time to progression as primary endpoint, feasibility and toxicity as secondary endpoints. Inclusion criteria were unresectable BTC confirmed by histology or cytology, need for biliary stent, bilirubin level < 50 mmol/L and no previous cancer disease. The treatment arms were: A: Stent, temoporfin / PDT followed by gemcitabin / capecitabin (GemCap). B: Stent, GemCap. Only one initial PDT treatment was given. Results: Twenty patients with locally advanced and metastatic disease were included, 10 patients in each arm. Two patients in arm B did not receive any treatment (thrombocytopenia, study withdrawal) and two patients in arm A did not receive chemotherapy (ECOG>2, infection). PDT was feasible in all 10 patients without any acute procedure-related complication. During the first 30 days, two cases of cholangitis in arm A and three in arm B were observed. Cutaneous erythema (grade 1-2) was observed after PDT in two patients. Conclusions: PDT using temoporfin in combination with chemotherapy in BTC was feasible. Restrictions to light exposure were well tolerated. PDT in combination with chemotherapy did not increase the complication rate during the first 30 days follow-up. Three months follow-up data will be available at the time for presentation. Larger prospective trials are warranted to assess the efficacy of this treatment combination.

Seven hundred sixty three basal cell carcinomas (BCCs) in 122 patients were treated by photodynamic therapy by 5-aminolevulinic acid (ALA) in cream topically applied, either alone, in combination with dimethyl sulphoxide (DMSO) and ethylenediaminetetraacetic acid disodium salt (EDTA), or with DMSO as a pretreatment. After 3 hours cream exposure 40 - 200 Joules/cm2 of 630 nm laser light was given. Fluorescence imaging of biopsies showed highly improved ALA penetration depth and doubled ALA-induced porphyrin production using DMSO/EDTA. Treatment response was recorded after 3 months. After a single treatment 90% of 393 superficial lesions responded completely, independent of using DMSO/EDTA. In 363 nodulo-ulcerative lesions the complete response rate increased from 67% to above 90% with DMSO/EDTA for lesions less than 2 mm thickness and from 34% to about 50% for lesions thicker than 2 mm. Recurrence rate observed during a follow-up period longer than 12 months was 2 - 5%. PDT of superficial thin BCCs with ALA-induced porphyrins and DMSO/EDTA equals surgery and radiotherapy with respect to cure rate and recurrence. Cosmetic results of ALA-based PDT seemed to be better than those after other therapies. In patients with the nevoid BCC syndrome the complete response rate after PDT was far lower.© (1994) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

An ordinary fluorescence spectrometer equipped with a dichroic mirror and fiber optics can be used to measure sensitizer fluorescence in tumors and normal tissues. Our findings with such an instrument showed that after oral administration of 60 mg/kg 5-aminolevulinic acid (ALA) mucosas and rectal adenomas fluoresced stronger than normal skin. Also basal cell carcinomas (BCCs) showed a stronger porphyrin fluorescence than skin after topical application of ALA. The porphyrin fluorescence of BCCs decayed rapidly during standard laser irradiation at 630 nm. The degradation rate of porphyrins in the tumor was approximately constant down to at least 0.3 mm below the tumor surface, in agreement with an optical penetration depth of more than 1 mm.

Nine patients with malignant pleural mesothelioma underwent extensive surgery followed by intra-operative photodynamic therapy. Two mg/kg Photofrin was given 48 hours prior to surgery. The thoracic cavity and eventual remaining lung were exposed to 15 - 30 Joules/cm2 of 630 nm laser light. Tumor tissue was analyzed by microscopic photometrical techniques. Five patients with mixed or epithelioid tumors with fluorescence intensity > 100 gray level/pixel seemed to benefit from the given therapy. One patient was free of disease 18 months after treatment. Two patients were treated for metastasis after 12 months with no sign of intrathoracic recurrence. Both are still alive, one without further sign of disease 32 months after initial treatment. Two patients presented generalized disease after 9 and 13 months and intrathoracic recurrence several months later. Two patients with poorly differentiated tumors and 2 patients with moderate to highly differentiated tumors, but with fluorescence intensity < 100 gray level/pixel, presented recurrences after 4 months. PDT-efficiency seems to be predicted by the intensity and distribution of drug-induced fluorescence in tumor tissue. PDT may enhance the possibility to achieve complete local tumor control after excision. Multimodal therapeutic approach of local and systemic disease seems mandatory to further improve survival.© (1994) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Photodynamic therapy has been used for treatment of malignant cutaneous lesions. Photosensitizer has been topically applied, 5-aminolevulinic acid, with light delivered at 630 nm. A study of response rate to varying light doses was performed, it might seem that light doses of 40 - 50 J/cm2 is sufficient for superficial lesions. For nodular lesions higher light doses are needed. Some patients with tumors in the gastrointestinal tract have been treated with systemic administration of 5-aminolevulinic acid and re-treated with Photofrin in case of unsatisfactory results. From the preliminary material available 5-aminolevulinic acid seems less promising as a photosensitizer for internal lesions compared to dermal lesions.© (1994) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

By means of a chemical extraction procedure and confocal laser scanning microscopy, we investigated the kinetic patterns of uptake and biolocalization of 5-aminolevulinic acid (ALA)-induced porphyrins in s.c. transplanted tumors, adjacent normal skin and muscle, and liver of mice bearing mammary carcinoma, after i.p. injection of 250 mg/kg ALA or topical application of ALA (20% in an oil-in-water emulsion). Furthermore, we evaluated the tumor responses after either i.p. injection or topical application of 5-ALA followed by laser irradiation (632 nm, 150 mW/cm2, 25 min) by measuring the treated tumor regression/regrowth time and by light and electron microscopy. Strong fluorescence of ALA-induced porphyrins was detected in the tumor, skin and liver tissues, while little fluorescence was seen in the adjacent muscle tissue. Moreover, the highest amounts of ALA-induced porphyrins in the tumor and skin tissues were found 1 hr after i.p. injection, whereas the amounts of the porphyrins in both tissues increased with increasing time after topical application of ALA. The fluorescence of the porphyrins was localized in several components of the skin tissue (epidermis, hair follicles and their associated sebaceous glands). Furthermore, the fluorescence was diffusely distributed in the s.c. transplanted tumor tissue. Little could be observed under a confocal laser scan microscope (CLSM) in the muscle tissue. The uptake and biolocalization data correlate well with the results of PCT efficiency of the same tumor model with ALA-induced porphyrins. Light and electron microscopy showed that the mitochondria of the tumor cells and of the endothelial cells and the basal lamina of vascular walls beneath the endothelium in the tumor tissue were initially extensively destroyed after PCT with ALA-induced porphyrins. Thereafter, diffuse degeneration followed by local and/or diffuse severe necrosis of the tumor cells was found. This may be due mainly to the initial damage to mitochondria in the cancerous and endothelial cells and also to the destruction of the vascular wall in the tumor tissue. © 1992 Wiley-Liss, Inc.

It is hard to imagine that a narrow, one-way, coherent, moving, amplified beam of light fired by excited atoms is powerful enough to slice through steel. In 1917, Albert Einstein speculated that under certain conditions atoms could absorb light and be stimulated to shed their borrowed energy. Charles Townes coined the term laser (light amplification by stimulated emission of radiation) in 1951. Theodore Maiman investigated the glare of a flash lamp in a rod of synthetic ruby, creating the first human-made laser in 1960. The laser involves exciting atoms and passing them through a medium such as crystal, gas or liquid. As the cascade of photon energy sweeps through the medium, bouncing off mirrors, it is reflected back and forth, and gains energy to produce a high wattage beam of light. Although lasers are today used by a large variety of professions, one of the most meaningful applications of laser technology has been through its use in medicine. Being faster and less invasive with a high precision, lasers have penetrated into most medical disciplines during the last half century including dermatology, ophthalmology, dentistry, otolaryngology, gastroenterology, urology, gynaecology, cardiology, neurosurgery and orthopaedics. In many ways the laser has revolutionized the diagnosis and treatment of a disease. As a surgical tool the laser is capable of three basic functions. When focused on a point it can cauterize deeply as it cuts, reducing the surgical trauma caused by a knife. It can vaporize the surface of a tissue. Or, through optical fibres, it can permit a doctor to see inside the body. Lasers have also become an indispensable tool in biological applications from high-resolution microscopy to subcellular nanosurgery. Indeed, medical lasers are a prime example of how the movement of an idea can truly change the medical world. This review will survey various applications of lasers in medicine including four major categories: types of lasers, laser-tissue interactions, therapeutics and diagnostics.

The aim of this prospective randomized study was to compare the clinical and cosmetic outcome of superficial basal cell carcinomas (BCC), using either laser or broadband halogen light, in photodynamic therapy with topical 5-aminolevulinic acid (ALA). A total of 83 patients with 245 superficial BCC were included in the study. Standard treatment involved 15 min of local pretreatment with 99% dimethylsulfoxide (DMSO) before topical application of 20% ALA with DMSO (2%) and ethylendiaminetetraacetic acid (2%) as cofactors for 3 h before light exposure with either laser or a broadband lamp (BL). A complete response was achieved in 95 lesions (86%) in the laser group and 110 lesions (82%) in the BL group 6 months after treatment. Of these, 80 lesions (84%) in the laser group and 101 lesions (92%) in the lamp group were independently evaluated to have an excellent or good cosmetic post-treatment score. No serious adverse events were reported. This study shows that there is no statistical significant difference in cure the rate (P = 0.49) and the cosmetic outcome (P = 0.075) with topical application of a modified ALA-cream between light exposure from a simple BL with continuous spectrum (570-740 nm) or from a red-light laser (monochromatic 630 nm). Cost and safety are further elements in favor of the BL in this setting.