Background/Objectives: With the increasing prevalence of Crohn’s disease (CD), treatment options for patients who fail conventional and advanced therapy are highly needed. Therefore, we explored the safety and efficacy of extracorporeal photopheresis (ECP) using 5-aminolevulinic acid (ALA) and blue light (405 nm). Methods: Patients with active CD who failed or were intolerant to biological therapy were eligible. Mononuclear cells (90 mL) were collected from each patient using a Spectra Optia® apheresis system and diluted with 100 mL of 0.9% sodium chloride in a collection bag. The cells were incubated with ALA at a concentration of 3 millimolar (mM) for 60 min ex vivo and illumination with an LED blue light (405 nm) source (BLUE-PIT®) before reinfusion to the patient. Recording of vital signs and adverse events were regularly performed. At week 13, we assessed the patients with colonoscopy, the Harvey Bradshaw Index (HBI), the Inflammatory Bowel disease Health Related Quality of Life Questionnaire, and the measurement of serum C-reactive protein and fecal calprotectin (FC) levels. Biopsies of the intestines were taken for immunohistochemistry. Results: Seven patients were included. Four patients completed the treatments, with a total of 24 treatments. Three of the four patients achieved a favorable response, including a lower HBI, lower FC levels, and/or endoscopic improvement. No significant adverse events were observed. The remaining three patients received only one, three, or five treatments due to technical difficulties, medical reasons, or the withdrawal of informed consent. Conclusions: ALA-based ECP appears safe and seems to give some clinical improvement for the patients with active CD who failed to respond to conventional and advanced therapies.

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.

The two families of dyes that have been most extensively studied in relation to photodynamic therapy are the phthalocyanines and the porphyrins. Series of such dyes are available in a relatively pure form and are well suited for studies attempting to evaluate how the hydrophobicity of a dye influences its cellular uptake, its retention, and its photosensitizing efficiency. Derivatives of phthalocyanines and porphyrins decrease in lipophilicity as the number of sulfonate groups increases. The chapter demonstrates that the cellular uptake of the components of he-matoporphyrin derivative and PII increases with increasing lipophilicity of the components. Photoexcitation of cells containing PII results in a destruction of the binding sites of PII on proteins and a displacement of the dye molecules to other sites. A general finding for all sensitizers studied in our laboratory is that cells tend to accumulate in mitosis after being exposed to light in their presence.

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.

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.

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. (C) 2015 Elsevier B.V. All rights reserved.

Thank you for the interest in our article titled “Photodynamic treatment of oral lichen planus.” We will try to answer the questions raised by Drs Farzaneh Agha-Hosseini and Nada Mohammad Pour. The numbers correspond to the numbering in their letter.1.The methyl 5-aminolevulinate cream was applied to normal mucosa to compare the absorption and distribution with that observed in mucosa that was clinically affected by oral lichen planus. The results are shown in Figure 2.2.The question of clinical scoring of oral lichen planus is an interesting topic to discuss. Scoring is difficult because frequently more than one score may apply to each area. We agree that papular or bullous lesions could have been divided, but in this study it had no practical implication, because there were no patients with this score.3.The criteria for this study were reductions in clinical signs. In further investigation, symptom scores, control groups, and a VAS scale as mentioned in the letter's last sentence could be included.4.The flare-up periods were based on patients' reported symptoms. Further studies should also include self-reported registration of the flare-up periods.The two patients with oral lichen planus of the lip and tongue (one affected with each) were excluded for statistical reasons. Both had excellent results (i.e., total remission) after treatment.5.In the clinical setting that was available for this study, the natural flow from the salivary glands was not a problem, but it tended to pool in the lower buccal sulcus. We did not want to use drugs to reduce the flow, and even with good suction it is difficult to avoid this pooling.The normal mucosa that was “treated” was in an area distant from the clinically affected mucosa. The lower lip was most commonly used, because both buccal mucosae were typically affected. Thank you for the interest in our article titled “Photodynamic treatment of oral lichen planus.” We will try to answer the questions raised by Drs Farzaneh Agha-Hosseini and Nada Mohammad Pour. The numbers correspond to the numbering in their letter.1.The methyl 5-aminolevulinate cream was applied to normal mucosa to compare the absorption and distribution with that observed in mucosa that was clinically affected by oral lichen planus. The results are shown in Figure 2.2.The question of clinical scoring of oral lichen planus is an interesting topic to discuss. Scoring is difficult because frequently more than one score may apply to each area. We agree that papular or bullous lesions could have been divided, but in this study it had no practical implication, because there were no patients with this score.3.The criteria for this study were reductions in clinical signs. In further investigation, symptom scores, control groups, and a VAS scale as mentioned in the letter's last sentence could be included.4.The flare-up periods were based on patients' reported symptoms. Further studies should also include self-reported registration of the flare-up periods.The two patients with oral lichen planus of the lip and tongue (one affected with each) were excluded for statistical reasons. Both had excellent results (i.e., total remission) after treatment.5.In the clinical setting that was available for this study, the natural flow from the salivary glands was not a problem, but it tended to pool in the lower buccal sulcus. We did not want to use drugs to reduce the flow, and even with good suction it is difficult to avoid this pooling.The normal mucosa that was “treated” was in an area distant from the clinically affected mucosa. The lower lip was most commonly used, because both buccal mucosae were typically affected. Photodynamic treatment of oral lichen planusOral Surgery, Oral Medicine, Oral Pathology and Oral RadiologyVol. 117Issue 2PreviewWe would like to congratulate Kvaal et al. for their article entitled “Photodynamic treatment of oral lichen planus.”1 However, we have a few questions about it. Full-Text PDF

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.

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. (C) 2014 Elsevier B.V. All rights reserved.

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.

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.

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.

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.