A scoping review on Chronic Venous Disease and the development of a Venous Leg Ulcer: The role of obesity and mobility.

OBJECTIVE: The risk factors obesity and reduced mobility are not well known in the development of a Venous Leg Ulcer (VLU). The aim of this scoping review is to explore the mechanisms by which obesity and reduced mobility contribute the development of a VLU in patients with Chronic Venous Disease (CVD). METHODS: For this scoping review a search was performed in May 2019 in the Cochrane Library and Pubmed to identify studies on the working mechanisms of obesity and mobility in developing a VLU. Hand searches were performed to find additional studies explaining the working mechanisms (indirectly related to the VLU). Two reviewers independently reviewed the abstracts and full-text articles. RESULTS: Twenty-eight studies met our eligibility criteria. Disturbed range of ankle motion and gait can lead to a reduced Calf Muscle Pump (CMP) function which leading to a venous outflow disorder. Increased abdominal pressure due to obesity can lead to a venous outflow obstruction and increased adipose tissue mass results in an increase in adipokine secretion. The venous outflow disorder, outflow obstruction and increased adipokine secretion can all lead to chronic systemic inflammation, increased endothelial permeability and hence microcirculatory dysfunction. This alone can result in a VLU. CONCLUSION: Obesity and reduced mobility can lead to a reduction of the CMP function, an increase in abdominal pressure and an increase in adipose tissue mass. This can simultaneously lead to haemodynamic changes in the macro- and microcirculation of the lower extremities and eventually in a VLU. In patients with obesity and reduced mobility the microcirculation alone can lead to skin changes and eventually a VLU. Therefore, early recognition of CVD symptoms in patients with obesity and reduced mobility is crucial to diagnose and treat CVD to prevent a VLU.

A qualitative study on the patient's narrative in the progression of chronic venous disease into a first venous leg ulcer: a series of events.

BACKGROUND: A venous leg ulcer (VLU) has a significant negative impact on quality of life. Prevention of a VLU is not yet imbedded in clinical practice because risk factors for developing a first VLU are not well known. OBJECTIVES: To explore further the progression of chronic venous disease (CVD) into a first VLU from the patient's perspective. METHODS: A qualitative study using semistructured interviews was conducted among male and female patients with a VLU. Patients from primary and secondary care, under and over 50 years of age, and with first and recurrent VLUs were included. The interviews were transcribed and analysed using a narrative approach to a thematic analysis. Transcripts were organized in chronological order and an iterative process was used to code the transcripts. RESULTS: Four key themes and the connections made between them emerged from the 11 narratives on the progression of CVD towards a first VLU: 'comorbidity', 'mobility', 'work and lifestyle' and 'acknowledgment of CVD'. Comorbidity was linked to reduced mobility and late acknowledgment of CVD. Comorbidity also affected work and lifestyle and vice versa. Work and lifestyle affected mobility and was linked to the acknowledgment of CVD. CONCLUSIONS: A reduction in mobility as a result of comorbidity and work and lifestyle occurred before the VLU developed. Patients did not recognize symptoms of CVD and did not acknowledge the chronicity of CVD. Healthcare professionals should be aware of reductions in mobility and the knowledge deficit in patients with CVD. What's already known about this topic? Not all patients with chronic venous disease (CVD) develop a venous leg ulcer (VLU). A patient's quality of life decreases significantly when a VLU develops. Risk factors for the development of a first VLU in patients with CVD are not well known, unlike risk factors for other chronic wounds like diabetic foot ulcer and pressure ulcers. What does this study add? The patient's narrative towards the development of a first VLU, a series of events. Insight into the events (comorbidity, mobility, work and lifestyle) that patients themselves link to the development of a VLU. Insight into the patients' acknowledgment of CVD in the progression of CVD towards a first VLU. What are the clinical implications of this work? More awareness is needed of CVD symptoms among patients and healthcare providers, as well as more awareness for prevention of a VLU in clinical practice. New insights (for further studies) are needed into the concept of mobility and the development of a VLU. Improved patient education and follow-up are needed for patients with CVD.

A systematic review on risk factors in developing a first-time Venous Leg Ulcer.

Venous Leg Ulcers (VLU) occur in about 1% of the Western population. A VLU takes 3-12 months to heal, it recurs often, and it has a negative impact on the quality of life. The risk factors for the development of a first VLU are not well-understood and prevention of a first VLU therefore remains underappreciated. The aim of this study was to identify risk factors for developing a first VLU in adults (aged > 18 years) by searching the literature. We searched the Cochrane Library, Pubmed, Cinalh and Narcisto identify studies that investigated risk factors in developing a VLU. The last search was performed in January 2018. Two reviewers independently reviewed the abstracts and full-text articles, and assessed the methodological quality of the included studies. Results of studies using duplex scanning, and comparing participants with and without VLUs were included in the qualitative analysis. Where possible a quantitative meta-analysis was conducted. We found five studies that investigated the relation of several risk factors with VLU development. The methodological differences of the studies made it impossible to perform a quantitative analysis. The risk factors higher age (four studies), higher body mass index (four studies), low physical activity (four studies), arterial hypertension (four studies), deep vein reflux (three studies), deep venous thrombosis (three studies) and family history of VLU (three studies) were significantly associated with a VLU in the majority of the studies. To what extent they influence the development of a VLU remains unclear because of the limited number of studies that investigated the association of these risk factors with VLU development, and the heterogeneity of these studies. Further studies are needed to confirm the association of these risk factors with the development of a VLU and to explore overweight and low physical activity in more detail.

Progressive multifocal leukoencephalopathy associated with fumaric acid esters treatment in psoriasis patients.

BACKGROUND: Fumaric acid esters (FAEs) are a systemic treatment for psoriasis considered to have a favourable long-term safety profile without an increased risk for immunosuppression. However, progressive multifocal leukoencephalopathy (PML), a rare, opportunistic viral infection of the central nervous system, has been linked anecdotally to FAE treatment. OBJECTIVE: To assess clinical features and outcomes of FAE-associated PML cases. METHODS: Systematic literature search in multiple databases up to 25th February 2016 for reports of PML in psoriasis patients treated with FAEs. RESULTS: Eight cases (four male, four female) of FAE-associated PML were identified. Median age was 64 years (range 42-74 years); median FAE treatment duration was 3 years (range 1.5-5 years). Six patients were treated with a formulation containing dimethyl fumarate (DMF) and monoethyl fumarates, and two patients with a DMF formulation. Patients exhibited neurological symptoms, such as aphasia, hemiparesis and dysarthria. PML diagnosis was based on MRI findings and presence of JC virus in cerebrospinal fluid and/or brain tissue. All cases were linked to moderate-to-severe reductions in absolute lymphocyte counts, with nadirs ranging from 200 to 792 cells per mm3 . Median exposure to lymphocytopenia was 2 years (range 1-5 years). In all cases, FAE treatment was discontinued; PML was treated with mefloquine plus mirtazapine. Three patients improved, two had stable disease, two had residual symptoms, and one patient died to an immune reconstitution inflammatory syndrome. CONCLUSION: Progressive multifocal leukoencephalopathy is infrequently linked to FAE treatment, but underreporting cannot be excluded. Physicians treating patients with FAEs should be vigilant for the occurrence of PML, and both clinicians and patients should be alert for onset of new neurological symptoms. Periodic monitoring of lymphocyte counts and FAE discontinuation in case of moderate-to-severe lymphocytopenia is recommended to minimize the risk for PML.

Reliability of diagnosis from Mohs slides: interpersonal and intrapersonal agreement on basal cell carcinoma presence and histological subtype.

BACKGROUND: The success of Mohs micrographic surgery (MMS) depends partly on the correct diagnosis of slides. OBJECTIVES: To determine reliability of diagnosis from Mohs slides. METHODS: This was a prospective study evaluating the reliability of diagnosis from Mohs slides of basal cell carcinoma (BCC) presence, BCC location on the slide and BCC subtype among six raters who independently assessed 50 Mohs slides twice with a 2-month interval. Slides were randomly selected whereby difficult-to-diagnose slides were oversampled. For each slide, a reference diagnosis was established by an expert panel. Cohen's kappa (κ) was calculated to determine levels of agreement interpersonally (rater vs. reference diagnosis) and intrapersonally (rater at T1 vs. T2). Multivariable logistic regression was used to determine independent risk factors for slides with interpersonal discordant diagnosis. The variables studied were BCC presence, whether a slide was scored as easy or difficult to diagnose, review duration of the 50 slides, profession and years of experience in diagnosis from Mohs slides. RESULTS: Interpersonal and intrapersonal agreement were substantial on BCC presence (κ = 0·66 and 0·68) and moderate on BCC subtype (κ = 0·45 and 0·55). Slides that were scored as difficult to diagnose were an independent risk factor for interpersonal discordant diagnosis on BCC presence (odds ratio 3·54, 95% confidence interval 1·81-6·84). CONCLUSIONS: Reliability of diagnosis from Mohs slides was substantial on BCC presence and moderate on BCC subtype. For slides that are scored difficult to diagnose, a second opinion is recommended to prevent misinterpretation and thereby recurrence of skin cancer.

Efficacy, effectiveness and safety of fumaric acid esters in the treatment of psoriasis: a systematic review of randomized and observational studies.

Fumaric acid esters (FAEs) are increasingly used as a systemic treatment for psoriasis, but there are still uncertainties regarding their suitability. The objective of this systematic review was to assess the evidence for the efficacy and safety of FAEs in psoriasis treatment. A systematic literature search was performed in seven databases up to 17 August 2015. Inclusion criteria were studies that reported clinical effects of FAEs in patients with psoriasis without restrictions in study design, language or publication date. Methodological quality of randomized controlled trials (RCTs) and overall level of quality were assessed using the Cochrane risk of bias tool and the Grading of Recommendation, Assessment, Development and Evaluation approach, respectively. A total of 68 articles were included. There were seven RCTs (total 449 patients) that had an unclear risk of bias and were too clinically heterogeneous to allow a meta-analysis. Overall, mean Psoriasis Area and Severity Index decreased by 42-65% following 12-16 weeks of treatment. There were 37 observational studies (a total of 3457 patients) that supported the RCT findings, but most were uncontrolled with a high risk of bias. Commonly reported adverse events included gastrointestinal complaints and flushing, leading to treatment withdrawal in 6-40% of patients. Several case-reports described rare adverse events, such as renal Fanconi syndrome and progressive multifocal leukoencephalopathy. There was a lack of studies focusing on long-term use and comparisons with other treatments. This review concluded that there is low-quality evidence to recommend the use of oral FAEs to treat plaque psoriasis in adult patients. Studies focusing on long-term safety and comparison with systemic psoriasis treatments could lead to a better understanding of the role of FAEs as a treatment for psoriasis.

Induction therapy with a combination of fumarates and cyclosporine: A benefit for the patient?

Fumarates or fumaric acid esters derivates (FAED) have appeared to be effective and less toxic than other systemic treatments for psoriasis. Due to its safe adverse event profile, FAED can be used as a long-term maintenance therapy. One of the greatest reasons why FAED are not preferred as a first-line treatment is that according to the recommended dosing schedule, clinically meaningful improvement is seen just after 6 to 8 weeks of therapy. In this manuscript, we suppose an alternative induction scheme with a combination therapy of fumarates and cyclosporine for a more rapid improvement and better compliance.

Validation of the Lymphoedema Quality-of-Life Questionnaire (LYMQOL) in Dutch Patients Diagnosed with Lymphoedema of the Lower Limbs.

BACKGROUND: The Lymphoedema Quality-of-Life Questionnaire is a validated disease-specific instrument to measure the impact of lymphoedema on patients' lives. In this study, we tested its psychometric properties and validated the use of the questionnaire in its Dutch translation. METHODS: We obtained the answers to a standardised questionnaire, including Lymphoedema Quality-of-Life Questionnaire and Short-Form (36) Health Survey, twice at an interval of 2 weeks in 60 patients with lower limb lymphoedema. Feasibility was tested on the basis of missing responses and response distribution. Structure was studied using factor analysis. The reliability of the Lymphoedema Quality-of-Life Questionnaire was assessed using Crohnbach's α and test-retest reliability. Construct validity was tested by correlating Lymphoedema Quality-of-Life Questionnaire scores with the Short-Form (36) Health Survey scores. RESULTS: The response rate was 88.2%. One of the 22 items missed >10% of responses; another showed a borderline ceiling effect. Internal consistency was good and test-retest reliability was excellent. The Lymphoedema Quality-of-Life Questionnaire correlated well with the physical component of the Short-Form (36) Health Survey and moderately with the mental component, suggesting that its construct validity was good. CONCLUSION: The Dutch Lymphoedema Quality-of-Life Questionnaire can be used for health-related quality-of-life research in lower limb lymphoedema patients.

Development of consensus International Classification of Functioning, Disability and Health (ICF) core sets for lymphedema.

To understand the challenges of patients with lymphedema it is important to describe functioning and to measure the effectiveness of treatment in changing functioning. The International Classification of Functioning, Disability and Health (ICF) offers an international framework to classify functioning of persons in their personal environment. ICF Core Sets are lists of selected ICF categories concerning those important aspects of functioning that are most likely to be affected by a specific health problem or disease. These Core Sets make it easier and faster to describe and communicate the patient's problems and to define treatment goals. Furthermore, they are available to health care providers of all professions, researchers, health insurance companies and policy-makers. The objective of this document is to present the outcomes of a consensus conference held to determine the first versions of the ICF Core Sets for lymphedema. Frequency rankings were made of the ICF categories derived from four preparatory studies, being: a) a systematic review; b) a qualitative study; c) an expert survey; and d) a cross-sectional study. By means of working group discussions and plenary sessions, a final consensus on ICF categories was achieved and Comprehensive and Brief Core Sets for lymphedema for the upper limb, lower limb, and midline lymphedema were defined. These ICF Core Sets contain different items in each region. Future validation of these Core Sets for health professions and for countries is needed.

Five-year results of a randomized clinical trial of conventional surgery, endovenous laser ablation and ultrasound-guided foam sclerotherapy in patients with great saphenous varicose veins.

BACKGROUND: A variety of techniques exist for the treatment of patients with great saphenous vein (GSV) varicosities. Few data exist on the long-term outcomes of these interventions. METHODS: Patients undergoing conventional surgery, endovenous laser ablation (EVLA) and ultrasound-guided foam sclerotherapy (UGFS) for GSV varicose veins were followed up for 5 years. Primary outcome was obliteration or absence of the treated GSV segment; secondary outcomes were absence of GSV reflux, and change in Chronic Venous Insufficiency quality-of-life Questionnaire (CIVIQ) and EuroQol - 5D (EQ-5D™) scores. RESULTS: A total of 224 legs were included (69 conventional surgery, 78 EVLA, 77 UGFS), 193 (86.2 per cent) of which were evaluated at final follow-up. At 5 years, Kaplan-Meier estimates of obliteration or absence of the GSV were 85 (95 per cent c.i. 75 to 92), 77 (66 to 86) and 23 (14 to 33) per cent in the conventional surgery, EVLA and UGFS groups respectively. Absence of above-knee GSV reflux was found in 85 (73 to 92), 82 (72 to 90) and 41 (30 to 53) per cent respectively. CIVIQ scores deteriorated over time in patients in the UGFS group (0.98 increase per year, 95 per cent c.i. 0.16 to 1.79), and were significantly worse than those in the EVLA group (-0.44 decrease per year, 95 per cent c.i. -1.22 to 0.35) (P = 0.013). CIVIQ scores for the conventional surgery group did not differ from those in the EVLA and UGFS groups (0.44 increase per year, 95 per cent c.i. -0.41 to 1.29). EQ-5D™ scores improved equally in all groups. CONCLUSION: EVLA and conventional surgery were more effective than UGFS in obliterating the GSV 5 years after intervention. UGFS was associated with substantial rates of GSV reflux and inferior CIVIQ scores compared with EVLA and conventional surgery. REGISTRATION NUMBER: NCT00529672 (http://www.clinicaltrials.gov).

Correction for tissue optical properties enables quantitative skin fluorescence measurements using multi-diameter single fiber reflectance spectroscopy.

BACKGROUND AND OBJECTIVE: Fluorescence measurements in the skin are very much affected by absorption and scattering but existing methods to correct for this are not applicable to superficial skin measurements. STUDY DESIGN/MATERIALS AND METHODS: The first use of multiple-diameter single fiber reflectance (MDSFR) and single fiber fluorescence (SFF) spectroscopy in human skin was investigated. MDSFR spectroscopy allows a quantification of the full optical properties in superficial skin (µa, µs' and γ), which can next be used to retrieve the corrected - intrinsic - fluorescence of a fluorophore Qµa,x(f). Our goal was to investigate the importance of such correction for individual patients. We studied this in 22 patients undergoing photodynamic therapy (PDT) for actinic keratosis. RESULTS: The magnitude of correction of fluorescence was around 4 (for both autofluorescence and protoporphyrin IX). Moreover, it was variable between patients, but also within patients over the course of fractionated aminolevulinic acid PDT (range 2.7-7.5). Patients also varied in the amount of protoporphyrin IX synthesis, photobleaching percentages and resynthesis (>100× difference between the lowest and highest PpIX synthesis). The autofluorescence was lower in actinic keratosis than contralateral normal skin (0.0032 versus 0.0052; P<0.0005). CONCLUSIONS: Our results clearly demonstrate the importance of correcting the measured fluorescence for optical properties, because these vary considerably between individual patients and also during PDT. Protoporphyrin IX synthesis and photobleaching kinetics allow monitoring clinical PDT which facilitates individual-based PDT dosing and improvement of clinical treatment protocols. Furthermore, the skin autofluorescence can be relevant for diagnostic use in the skin, but it may also be interesting because of its association with several internal diseases.

Additional review of Mohs slides to optimize Mohs micrographic surgery.

BACKGROUND: One significant risk factor for recurrence after Mohs surgery is misinterpretation of slides. OBJECTIVES: To determine how often pathologists detected incompletely excised basal cell carcinoma (BCC) on Mohs slides and to determine risk factors for incompletely excised BCCs. METHODS: This retrospective study included 1653 BCCs treated with Mohs surgery in a university hospital between 2007 and 2011. For routine quality assurance, all slides were additionally reviewed by a pathologist within 1 week of the procedure. For this study, all cases that had divergent interpretations were re-evaluated by a Mohs surgeon and a pathologist. Mixed-effects logistic regression models with Mohs surgeon effects as random effects were used to determine risk factors for incompletely excised BCC. RESULTS: Incompletely excised BCCs were detected in 31 cases (2%), in which defects > 20 mm in diameter were an independent risk factor (odds ratio 3.58, 95% confidence interval 1.55-8.28). Other studied variables (i.e. aggressive subtype, previously treated BCC, location on nose and > 2 Mohs stages) did not affect the risk of incompletely excised BCCs. CONCLUSIONS: The additional review of Mohs slides might increase accurate interpretation, especially in large BCCs.

Identification of relevant ICF (International Classification of Functioning, Disability and Health) categories in lymphedema patients: A cross-sectional study.

BACKGROUND: To describe functioning and health of lymphedema patients and to identify their most common problems using the International Classification of Functioning, Disability and Health (ICF) as part of the preparatory studies for the development of ICF Core Sets for lymphedema. METHODS: Cross-sectional study in a population of lymphedema patients (n = 200), undergoing treatment in a Dutch lymphedema-specialized hospital. The second-level categories of the ICF were used to collect information on patients' problems in daily functioning. RESULTS: The mean age of the study group was 56 years (22-84). In total 78.5% of the patients were female. The most frequent mentioned items were: In the Body Functions component: muscle power and mobility of joints, in the Activities and Participation component: doing housework, and changing and maintaining a body position, in the Environmental Factors: Health professionals, who can act as both facilitators and barriers. Interestingly, patients assessed their health more positively than health professionals do. CONCLUSION: By using the ICF, a considerable part of the broad spectrum of problems in functioning of lymphedema patients was reported.

Addition of an oral histamine antagonist to reduce adverse events associated with fumaric acid esters in the treatment of psoriasis: a randomized double-blind placebo-controlled trial.

BACKGROUND: Fumaric acid esters (FAEs) are considered an effective and safe long-term treatment for psoriasis. However, 30-40% of patients need to discontinue FAE treatment due to intolerable adverse events. OBJECTIVES: To assess whether the addition of cetirizine, an oral histamine-1 receptor antagonist, to FAEs would reduce the incidence of adverse events. METHODS: In a randomized, double-blind, placebo-controlled trial, patients with psoriasis with a Psoriasis Area and Severity Index ≥ 10 starting an FAE up to a dose of dimethylfumarate 720 mg per day were randomized 1 : 1 to receive either additional cetirizine 10 mg once daily (n = 25) or placebo (n = 25) for 12 weeks. Randomization and treatment allocation were done at our hospital trial pharmacy. Primary outcomes were the incidence of adverse events and the proportion of patients discontinuing treatment. RESULTS: Fifty patients (33 male, 17 female; median age 44 years) were enrolled. Addition of cetirizine did not reduce the incidence of adverse events compared with placebo (84% vs. 84%, P = 1·00). The types of adverse events were not different between the cetirizine and placebo groups, the most common being gastrointestinal complaints (68% vs. 64%) and flushes (60% vs. 48%). The proportion of patients discontinuing treatment was not statistically different between the cetirizine and placebo groups (24% vs. 32%, P = 0·53). CONCLUSIONS: Addition of oral cetirizine 10 mg once daily to FAE treatment did not reduce adverse events in patients with psoriasis during the first 12 weeks of treatment. The mechanisms underlying FAE-induced gastrointestinal and flushing symptoms likely involve mediators other than histamine.

Randomized clinical trial of endovenous laser ablation versus steam ablation (LAST trial) for great saphenous varicose veins.

BACKGROUND: The aim was to compare endovenous laser ablation (EVLA) and endovenous steam ablation (EVSA) for great saphenous varicose veins in a non-inferiority study. METHODS: Patients with primary great saphenous vein reflux were randomized to EVLA (940 nm) or EVSA (SVS™). Primary outcomes were treatment success (vein obliteration or abolition of reflux) [corrected] at 52 weeks, and Venous Clinical Severity Score (VCSS) at 12 weeks. Secondary outcomes were pain, satisfaction with treatment, duration of analgesia use and days lost from daily activities, changes in Aberdeen Varicose Vein Questionnaire (AVVQ) and EQ-5D™ scores after 12 weeks, and complications at 2 and 12 weeks. RESULTS: A total of 227 legs were treated (EVSA, 117; EVLA, 110); 36 legs treated with EVSA received a low dose and the remaining 81 a higher dose. At 1 year, the treatment success rate after high-dose EVSA was not inferior to that of EVLA: 92 (95 per cent confidence interval (c.i.) 86 to 98) versus 96 (92 to 100) per cent respectively. Changes in VCSS after 12 weeks were similar: -2·69 (95 per cent c.i. -2·34 to -3·04) and -2·51 (-2·10 to -2·93). AVVQ, EQ-5D™ and EQ VAS scores improved equally 12 weeks after both treatments. Patients treated with EVSA reported less postprocedural pain, fewer days of analgesia use, were more satisfied with therapy, and had a shorter convalescence. Complication rates were comparable. CONCLUSION: The 1-year treatment success of high-dose EVSA was not inferior to that of EVLA. Several secondary outcomes were in favour of EVSA. Registration number NCT02046967 (http://www.clinicaltrials.gov).

Treatment of psoriasis with non-registered fumaric acid esters in The Netherlands: a nationwide survey among Dutch dermatologists.

BACKGROUND: Psoriasis vulgaris is a T-cell mediated disease that affects 2-3% of the worldwide white-skinned population. Fumaric acid esters are mentioned as an effective therapy for moderate-to-severe psoriasis vulgaris in adult patients in the new guidelines for psoriasis treatment. OBJECTIVES: To obtain an insight into the use of fumaric acid esters by Dutch dermatologists in the Netherlands. METHODS: This was a cross-sectional postal survey. An anonymous survey was posted to all Dutch dermatologists. In this survey, data were collected on the extent of fumaric acid esters use, the reasons for use, the reasons for non- or limited use of fumaric acid esters, the perception of fumaric acid esters as a mono-therapy with regards to the effectiveness, the safety, the adverse events and the overall satisfaction of fumaric acid esters as a mono-therapy. RESULTS: Sixty-three per cent of the 300 responders indicated to prescribe fumaric acid esters for the treatment of psoriasis. About 37% of the dermatologists indicated (almost) never to prescribe it. Biologicals were considered as the most effective therapy. Fumaric acid esters were regarded as the safest therapy. They were generally well-tolerated by the patients similar to that for methotrexate according to the respondents. CONCLUSION: A large proportion of the dermatologists in our survey indicated to prescribe fumaric acid esters. It is considered to be effective, safe and without adverse events profile that is favourable in the practice, also as compared with other systemic therapies such as methotrexate and biologicals.

The effect of light fractionation with a 2-h dark interval on the efficacy of topical hexyl-aminolevulinate photodynamic therapy in normal mouse skin.

BACKGROUND: Light fractionation with a 2-h dark interval increases the efficacy of topical aminolevulinic acid (ALA) photodynamic therapy (PDT). Hexyl-aminolevulinate (HAL) is the hexyl ester of ALA. Both HAL and ALA lead to protoporphyrin IX (PpIX) accumulation in endothelial cells and to vascular effects, which are important for light fractionation. We investigated light fractionation for HAL-PDT in a mouse skin model and compared this with ALA. METHODS: Three illumination schemes were studied: (a) 100 J cm(-2) in a single illumination; (b) 50+50 J cm(-2) in a twofold illumination; (c) a small first light fraction until 50% of PpIX was photobleached (ca. 3 J cm(-2)), followed by 97 J cm(-2) 2h later. PpIX fluorescence was measured continuously during illumination. Efficacy was evaluated by daily visual skin damage scoring up to 7 days after PDT. RESULTS: Light fractionation showed a trend towards increased efficacy for HAL-PDT. Both the initial PpIX synthesis and the PpIX resynthesis during the dark interval were higher for ALA, but these were not correlated with efficacy. Single HAL-PDT was more effective than single ALA-PDT. Photobleaching rates of HAL and ALA were similar indicating similar biodistributions at depth. CONCLUSION: Our results provide evidence to support that light fractionation may be beneficial for HAL-PDT. We are cautious because we found only a non-significant increase in response. However, combining our results with literature data suggest that the illumination scheme may be further optimized for HAL-PDT to potentially enhance the effect of light fractionation.