Photodynamic Effects with 5-Aminolevulinic Acid on Cytokines and Exosomes in Human Peripheral Blood Mononuclear Cells from Patients with Crohn's Disease.

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 Effects with 5-Aminolevulinic Acid on Cytokines and Exosomes in Human Peripheral Blood Mononuclear Cells.

Photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA), a precursor to the potent photosensitizer, protoporphyrin IX (PpIX), is an established modality for several malignant and premalignant diseases. This treatment is based on the light-activated PpIX in targeted lesions. Although numerous studies have confirmed the necrosis and apoptosis involved in the mechanism of action of this modality, little information is available for the change of exosome levels after treatment. We report from the first study on the effects of ALA-PDT on cytokines and exosomes of human healthy peripheral blood mononuclear cells (PBMCs). The treatment reduced the cytokines and exosomes studied, although there was variation among individual PBMC samples. This reduction is consistent with PDT-mediated survivals of subsets of PBMCs. More specifically, the ALA-PDT treatment apparently decreased all pro-inflammatory cytokines included, suggesting that this treatment may provide a strong anti-inflammatory effect. In addition, the treatment has decreased the levels of different types of exosomes, the HLA-DRDPDQ exosome in particular, which plays an important role in the rejection of organ transplantation as well as autoimmune diseases. These results may suggest future therapeutic strategies of ALA-PDT.

Amphiphilic Protoporphyrin IX Derivatives as New Photosensitizing Agents for the Improvement of Photodynamic Therapy.

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 PEG550 headgroups and hydrogenated or fluorinated tails was synthetized. Hydrophilic-lipophilic balance (HLB) and log p-values were computed for all of the prepared compounds. Their photochemical properties (spectroscopic characterization, photobleaching, and singlet oxygen quantum yield) were also evaluated followed by the in vitro studies of their cellular uptake, subcellular localization, and photocytotoxicity on three tumor cell lines (4T1, scc-U8, and WiDr cell lines). The results confirm the therapeutic potency of these new PpIX derivatives. Indeed, while all of the derivatives were perfectly water soluble, some of them exhibited an improved photodynamic effect compared to the parent PpIX.

Improved treatment decisions in patients with esophageal cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Biodistribution of protoporphyrin IX in female genital erosive lichen planus after topical application of hexaminolevulinate.

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 50mg/ml). Biopsies were taken after 30 min and 3h. 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 12.5mg HAL than after 100mg, with large inter-individual variations. PpIX levels after 3h were overall higher than after 30 min. PpIX fluorescence was not detected in skin distant to the genital area. In conclusion, 6.25mg/ml HAL applied for 3h 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.

Palliative brachytherapy with or without primary stent placement in patients with oesophageal cancer, a randomised phase III trial.

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, 8 Gy×3 (n=21) or brachytherapy alone, 8 Gy×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.

Photodynamic treatment of oral lichen planus.

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.

Radical treatment for oesophageal cancer patients unfit for surgery and chemotherapy. A 10-year experience from the Norwegian Radium Hospital.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Photodynamic therapy with methyl aminolevulinate for atypial carcinoma in situ of the penis.

OBJECTIVE: 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. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 of oral lesions.

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.

[Retraction of: Diagnostics and treatment of early stages of oral cancer]. / Tilbaketrekking av: Diagnostikk og behandling av forstadier til munnhulekreft.

The undersigned, who are co-authors of the article Diagnostics and treatment of early stages of oral cancer, wish to retract it. The reason is that the basis for the review article has been shown to be false. A review committee, that has assessed the research activity of the main author, has concluded that the data in this article are fabricated. We can no longer stand behind the article and hereby retract it.

Quality of life after total or partial gastrectomy for primary gastric lymphoma.

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 (p< or =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.

Porphyrin formation in actinic keratosis and basal cell carcinoma after topical application of methyl 5-aminolevulinate.

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.

Cytologic screening for esophageal cancer in a high-risk population in Anyang County, China.

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.