[Potassium hydroxide 5 % solution in actinic keratosis : A novel therapeutic approach in the lesion-directed treatment]. / Kaliumhydroxid-5 %-Lösung bei aktinischer Keratose : Ein neuer Therapieansatz zur läsionsgerichteten Behandlung.

BACKGROUND: Actinic keratosis (AK) is an epithelial carcinoma in situ of the skin. There is a need for early treatment due to the risk of malignant transformation. In addition to being effective, the initial therapy in particular should be well tolerated and user-friendly. Potassium hydroxide (KOH) solution is already established as keratolytic treatment option for hyperkeratotic skin diseases such as mollusca contagiosa. MATERIALS AND METHODS: A prospective single-arm, multicentre medical device study (Treatment of AK with KOH, TAKKOH) was conducted to investigate the efficacy and safety of KOH 5% solution for the treatment of mild to moderate AK. Patients applied KOH solution twice daily for 14 days with a subsequent off-treatment phase of 14 days (≙ one treatment cycle) for a maximum of three treatment cycles or at least until treatment success was achieved. Treatment success, defined as complete remission (CR) of all AK lesions of a patient, was the primary objective. Secondary objectives included the evaluation of partial remission (PR), the number of AK lesions in remission, efficacy assessment by investigators and patients with a 6­point grading system and several safety parameters. RESULT: In all, 73 patients were enrolled in the study. CR was achieved in 54.9% of patients, whereas PR was observed in 64.8% with a 69.9% reduction in lesion numbers. With respect to safety, 46.6% of the patients experienced adverse events. Most of these events (82.6%) were adverse reactions comprising exclusively short-lived and mild local skin reactions. CONCLUSIONS: The study provides an indication of the efficacy and safety of KOH 5% solution for the lesion-directed topical therapy of AK.

Topical resiquimod dosing regimens in patients with multiple actinic keratoses: a multicentre, partly placebo-controlled, double-blind clinical trial.

BACKGROUND: Topical immune response modifiers are established for actinic keratosis (AK) treatment and efforts are underway to make further improvements to their efficacy and safety. OBJECTIVES: To investigate the optimal dosing regimens of the Toll-like receptor 7/8 agonist resiquimod in terms of efficacy, safety and tolerability. METHODS: In a multicentre, partly placebo-controlled, double-blind clinical trial, we randomized 217 patients with AK lesions to 0·03% resiquimod gel once-daily application three times per week for 4 weeks or seven times within 2 weeks or five times for 1 week (arms 1/2/3) followed by a treatment-free interval of 8 weeks and one repetition of the cycle. In two additional arms (arms 4/5), patients applied either resiquimod gel 0·01% or 0·03% three times per week up to a biological end point defined by skin erosion or for a maximum duration of 8 weeks. Clearance was assessed clinically and histologically. RESULTS: Complete clinical clearance ranged from 56% to 85% with the highest rate observed in arm 2. Resiquimod 0·03% gel was more effective than 0·01% gel. Clearance rates in arms 1/2/3 were comparable and higher than with placebo and were reached with 24, 14 and 10 gel applications, respectively. Overall, 128 patients (59%) experienced treatment-related adverse reactions. CONCLUSIONS: Resiquimod 0·03% gel is more effective than 0·01% gel. From the perspectives of safety and tolerability, the lower concentration and shorter duration are preferable. The clinical response in arms 2/3 was reached with fewer gel applications. The dosing regimens that used the biological end point (arms 4/5) proved equally efficacious as predefined treatment durations and may therefore be suitable for personalized AK treatment.

Optical coherence tomography of basal cell carcinoma: influence of location, subtype, observer variability and image quality on diagnostic performance.

BACKGROUND: We previously described the principal results from an observational, prospective, multicentre, clinical trial of the diagnostic value of optical coherence tomography (OCT) for basal cell carcinoma (BCC) in a clinical setting. In this trial, much additional useful information was gathered that warranted further analysis, presented here. OBJECTIVES: To investigate the influence of candidate diagnostic criteria, OCT image quality, lesion location, and observer confidence and interobserver variability on the diagnostic performance of OCT, and to assess its potential use for diagnosis of BCC subtypes. METHODS: A total of 234 clinically unclear 'pink lesions' were evaluated in three steps: after clinical examination, after adding dermoscopy and after adding OCT. In addition to the diagnoses (including lesion subtype), observers recorded which of 15 diagnostic criteria the OCT image contained, their confidence in the diagnoses, the OCT image quality and the anatomical location of the lesion. RESULTS: Diagnostic performance of OCT did not depend on the lesion's anatomical location. Good OCT image quality was correlated with improved diagnostic performance, but diagnostic performance for lesions with mediocre image quality was still better than by clinical and dermoscopic examination. The main reason for reduced image quality was superficial scales and crusting. Observer confidence in diagnosis was correlated with diagnostic performance. Interobserver diagnostic performance was consistently higher than clinical examination and dermoscopy across all sites. BCC subtype could be determined with moderate accuracy, but further independent image markers are required. CONCLUSION: OCT is useful in the diagnosis of BCC.

A randomized, multinational, noninferiority, phase III trial to evaluate the safety and efficacy of BF-200 aminolaevulinic acid gel vs. methyl aminolaevulinate cream in the treatment of nonaggressive basal cell carcinoma with photodynamic therapy.

BACKGROUND: Basal cell carcinoma (BCC) represents the most common nonmelanoma skin cancer worldwide, affecting mainly adult, fair-skinned individuals. The World Health Organization distinguishes aggressive and nonaggressive forms, of which prototypical variants of the latter are primary nodular and superficial BCC. OBJECTIVES: To demonstrate noninferiority of BF-200 ALA (a nanoemulsion gel containing 5-aminolaevulinic acid) compared with MAL (a cream containing methyl aminolaevulinate) in the treatment of nonaggressive BCC with photodynamic therapy (PDT). Noninferiority of the primary efficacy variable (overall patient complete response 12 weeks after last PDT) would be declared if the mean response for BF-200 ALA was no worse than that for MAL, within a statistical margin of Δ = -15%. METHODS: The study was a randomized, phase III trial performed in Germany and the U.K. with ongoing 5-year follow-up. Of 281 randomized patients, 138 were treated with BF-200 ALA and 143 with MAL. Patients received two PDT sessions 1 week apart. Remaining lesions 12 weeks after the second PDT were retreated. Illumination was performed with a red light source (635 nm, 37 J cm-2 ). The results shown include clinical end points and patients' reassessment 12 months after the last PDT. The study was registered with EudraCT (number 2013-003241-42). RESULTS: Of the BF-200 ALA-treated patients, 93·4% were complete responders compared with 91·8% in the MAL group. The difference of means was 1·6, with a one-sided 97·5% confidence interval of -6·5, establishing noninferiority (P < 0·0001). The results for secondary efficacy parameters were in line with the primary outcome. Recurrence rates 12 months after the last treatment were ≤ 10%. CONCLUSIONS: Treatment of nonaggressive BCC with BF-200 ALA-PDT is highly effective and well tolerated with proven noninferiority to MAL-PDT. It demonstrates low recurrence rates after 1 year of follow-up.

Use of reflectance confocal microscopy to evaluate 5-fluorouracil 0.5%/salicylic acid 10% in the field-directed treatment of subclinical lesions of actinic keratosis: subanalysis of a Phase III, randomized, double-blind, vehicle-controlled trial.

BACKGROUND: Actinic keratosis (AK) is a common skin disorder that can progress to invasive squamous-cell carcinoma. AK can present as clinical (visible) or subclinical (invisible) lesions within areas of chronic sun damage. The importance of treating subclinical AK is gaining support. We present a subanalysis of a previously published Phase III, double-blind, vehicle-controlled study (NCT02289768), to assess 5-fluorouracil (5-FU) 0.5%/salicylic acid 10% treatment of subclinical AK lesions, based on reflectance confocal microscopy (RCM). OBJECTIVE: To determine the efficacy of 5-FU 0.5%/salicylic acid 10% as field-directed treatment for subclinical AK lesions using RCM. METHODS: For inclusion in this subanalysis, patients had to have at least three subclinical AK lesions within a 25 cm2 area of skin. Subclinical AK lesions were diagnosed according to the presence of three key RCM criteria: architectural disarray; keratinocyte atypia and pleomorphism at the basal, spinous and granular layer. Subclinical AK lesions were evaluated by RCM at baseline, after 4, 6 and 12 weeks of 5-FU 0.5%/salicylic acid 10% treatment or vehicle, and 8 weeks following the end of treatment. RESULTS: Twenty-seven patients were included: 17 [mean age = 72.2 years, standard deviation (SD) = 6.3] received 5-FU 0.5%/salicylic acid 10% treatment and 10 (mean age = 76.4 years, SD = 3.9) received vehicle. Eight weeks following the end of treatment, the mean number of subclinical lesions declined (from 3.0 at baseline) to 0.3 (95% confidence interval [CI] 0.06-0.57) for the 5-FU 0.5%/salicylic acid 10% group and 1.6 (95% CI 0.52-2.68) in the vehicle group (reductions of 90% [95% CI 72.1-107.1] vs. 47% [95% CI 24.8-69.5], respectively; P = 0.005). The proportion of patients receiving 5-FU 0.5%/salicylic acid 10% showing complete clearance of three preselected subclinical AK lesions was numerically greater than in the vehicle group (69% vs. 40%, respectively; P = 0.183). CONCLUSION: To the best of our knowledge, this is the first randomized, vehicle-controlled study investigating 5-FU 0.5%/salicylic acid 10% treatment for subclinical AK lesions. The present data suggest some treatment efficacy for subclinical AK lesions detected using RCM. However, this subanalysis was not sufficiently powered and should be reproduced in a larger, subsequent cohort.

Histological examination confirms clinical clearance of actinic keratoses following treatment with ingenol mebutate 0·05% gel.

BACKGROUND: To date, studies with ingenol mebutate gel have used clinical clearance, not histological clearance, as a primary efficacy endpoint. OBJECTIVES: This phase I, multicentre, single-arm, open-label study sought to confirm histologically the clinical clearance of actinic keratoses (AKs) to support a treatment effect deep in the epidermis. METHODS: Patients (n = 108) aged ≥ 18 years with histologically confirmed AK within a 25-cm2 contiguous treatment area on the trunk and extremities received ingenol mebutate 0·05% gel for two consecutive days and were followed up on day 3 and week 8. One AK was randomly preselected at day 1 for clinical and histological evaluation at week 8 and for reflectance confocal microscopy (RCM) in a subset of patients. The primary endpoint was clinical and histological clearance of AKs at week 8. RESULTS: The observed agreement rate between clinical and histological assessments of clearance of a single AK was 81·9% and the positive predictive value of a clinical assessment of clearance was 87%. Agreement between the two pathologists was 88%. The common composite 8-week complete clearance rate was 41% (95% confidence interval 32-50). Observed agreement rates between RCM and pathologist I and II assessments of clearance were 72·9% and 81·4%, respectively. Overall, 30 patients (27·8%) experienced 38 adverse events (AEs). Application-site pain (four patients, 3·7%) was the most common treatment-related AE inside the treatment area. CONCLUSIONS: Ingenol mebutate achieves histopathological clearance of AKs that correlates with observed clinical clearance. Clinical clearance is a good predictor for histological clearance.

Low-dose 5-fluorouracil in combination with salicylic acid for the treatment of actinic keratoses on the hands and/or forearms - results of a non-interventional study.

BACKGROUND: As an in situ carcinoma, actinic keratoses should be treated early. Previous studies on the efficacy of a low-dose 0.5% 5-fluorouracil solution in combination with 10% salicylic acid (low-dose 5-FU/SA) are mostly related to lesions appearing on the head and face. In contrast, actinic keratoses (AK) lesions of the upper extremities are considered to be difficult to treat. OBJECTIVE: The efficacy of low-dose 5-FU/SA in the treatment of actinic keratoses on the hands and/or forearms was studied for the first time in this non-interventional study (NIS) under practical conditions in a large patient population. In addition to the clinical course during therapy and a follow-up period, the length of application and adherence were documented. METHODS: As part of this NIS, 649 patients with AK were treated at 207 centres with low-dose 5-FU/SA. The data of the study were recorded at baseline, optionally during an intermediate examination, at the end of therapy and during a final assessment. RESULTS: The average number of AK lesions decreased during the entire observation period by 92%. Side-effects were documented only rarely in the form of local skin reactions (2%). The attending physicians assessed the efficacy, tolerability and safety of the therapy as being predominantly very good or good (in each case ≥90%). CONCLUSION: AK lesions on the hands and/or forearms were effectively treated with low-dose 5-FU/SA under routine conditions in dermatological practice and the treatment was well tolerated.

A randomized, double-blind, phase III, multicentre study to evaluate the safety and efficacy of BF-200 ALA (Ameluz(®) ) vs. placebo in the field-directed treatment of mild-to-moderate actinic keratosis with photodynamic therapy (PDT) when using the BF-RhodoLED(®) lamp.

BACKGROUND: Multiple actinic keratosis (AK) lesions may arise from the cancerization of large, sun-damaged skin areas. Although photodynamic therapy (PDT) is considered the most effective therapeutic option, the efficacy and safety of field treatment of multiple AK lesions with PDT has never before been tested in a pivotal trial. OBJECTIVES: To evaluate the efficacy, safety and cosmetic outcome of BF-200 ALA (a nanoemulsion formulation containing 10% aminolaevulinic acid hydrochloride) combined with the BF-RhodoLED(®) lamp for the field-directed treatment of mild-to-moderate AK with PDT. METHODS: The study was performed as a randomized, multicentre, double-blind, placebo-controlled, parallel-group, phase III trial with BF-200 ALA and placebo in seven centres in Germany. A total of 94 patients were enrolled in this study; 87 were randomized (55 patients received BF-200 ALA, 32 received placebo). Patients received one PDT. If residual lesions remained at 3 months after treatment, PDT was repeated. Illumination was performed with the PDT lamp BF-RhodoLED (635 nm ± 9 nm) until a total light dose of 37 J cm(-2) was achieved. RESULTS: BF-200 ALA was superior to placebo with respect to patient complete clearance rate (91% vs. 22%, P < 0·0001) and lesion complete clearance rate (94·3% vs. 32·9%, P < 0·0001) after a maximum of two PDTs. The confirmatory analysis of all key secondary variables supported this superiority" should not be skipped since this is an important result. Treatment-emergent adverse events (TEAEs) were experienced by 100% of the BF-200 ALA group and 69% of the placebo group. The most commonly reported TEAEs were TEAEs of the application site. The cosmetic outcome was improved in the BF-200 ALA group compared with placebo. CONCLUSIONS: Field-directed therapy with BF-200 ALA and BF-RhodoLED lamp is highly effective and well tolerated for multiple mild-to-moderate AK lesions, providing greatly improved skin quality.

The sensitivity and specificity of optical coherence tomography for the assisted diagnosis of nonpigmented basal cell carcinoma: an observational study.

BACKGROUND: The diagnostic criteria for basal cell carcinoma (BCC) using optical coherence tomography (OCT) have been described previously, but the clinical value of these findings remains unknown. OBJECTIVES: To investigate the diagnostic value of OCT for BCC in a typical clinical setting. The primary efficacy end point was a diagnosis of BCC for each lesion. Secondary end points were the diagnosis of other possible conditions. METHODS: This was an observational, prospective, multicentre study in which consecutive patients with nonpigmented pink lesions suspicious for BCC underwent clinical assessment, dermoscopy and OCT, with the diagnosis recorded at each stage. Once all diagnoses had been recorded, the histological results were disclosed. In total 164 patients with 256 lesions were recruited. Histology was missing for 21 lesions, leaving 235 lesions in 155 patients for analysis. RESULTS: Sixty per cent of lesions (141 of 235) were identified as BCC by histology. A slight increase of sensitivity was noted following OCT, which did not reach statistical significance. The specificity increased significantly from 28·6% by clinical assessment to 54·3% using dermoscopy and to 75·3% with the addition of OCT (P < 0·001). The positive predictive value for the diagnosis of BCC using OCT was 85·2% [95% confidence interval (CI) 78·6-90·4], and the negative predictive value was 92·1% (95% CI 83·6-97·0). The accuracy of diagnosis for all lesions increased from 65·8% with clinical evaluation to 76·2% following additional dermoscopy and to 87·4% with the addition of OCT. CONCLUSIONS: OCT significantly improved the diagnostic specificity for BCC compared with clinical assessment and dermoscopy alone.

[Modern diagnostic procedures in dermatological oncology]. / Moderne Diagnoseverfahren in der Dermatoonkologie.

BACKGROUND: New technologies, such as confocal laser scanning microscopy (CLSM), optical coherence tomography (OCT), electrical impedance spectroscopy (EIS) and multispectral analysis have greatly enriched the possibilities of diagnostics in dermatological oncology. They can be supplementary tools to dermatoscopy and histopathology to make a more precise diagnosis of skin lesions. OBJECTIVES: Increasing relevance of new systems for diagnosis and monitoring of dermatological therapy. Presentation of the technology and the diagnostic range of application for various skin lesions. MATERIAL AND METHODS: Presentation of scientifically relevant studies and statistical data, discussion of basic research and expert recommendations. RESULTS: The diagnostic spectrum of dermatological oncology has been significantly enriched in recent years. New technologies, such as CLSM, OCT, EIS and multispectral analysis are non-invasive and therefore painless for the patient. In only a few minutes these techniques deliver valid data and findings and provide dermatologists with more accurate diagnostic information about benign or malignant melanocytic skin lesions or the various forms of white skin cancer. CONCLUSION: In recent years, non-invasive diagnostic and analytical imaging procedures have been progressively established in dermatological oncology and supplement classical dermatoscopy and histopathology. With respect to the follow-up of different therapeutic modalities unnecessary tissue biopsies and scars can be reduced for patients.

Clinical performance of the Nevisense system in cutaneous melanoma detection: an international, multicentre, prospective and blinded clinical trial on efficacy and safety.

BACKGROUND: Even though progress has been made, the detection of melanoma still poses a challenge. In light of this situation, the Nevisense electrical impedance spectroscopy (EIS) system (SciBase AB, Stockholm, Sweden) was designed and shown to have the potential to be used as an adjunct diagnostic tool for melanoma detection. OBJECTIVES: To assess the effectiveness and safety of the Nevisense system in the distinction of benign lesions of the skin from melanoma with electrical impedance spectroscopy. METHODS: This multicentre, prospective, and blinded clinical study was conducted at five American and 17 European investigational sites. All eligible skin lesions in the study were examined with the EIS-based Nevisense system, photographed, removed by excisional biopsy and subjected to histopathological evaluation. A postprocedure clinical follow-up was conducted at 7 ± 3 days from the initial measurement. A total of 1951 patients with 2416 lesions were enrolled into the study; 1943 lesions were eligible and evaluable for the primary efficacy end point, including 265 melanomas - 112 in situ and 153 invasive melanomas with a median Breslow thickness of 0·57 mm [48 basal cell carcinomas (BCCs) and seven squamous cell carcinomas (SCCs)]. RESULTS: The observed sensitivity of Nevisense was 96·6% (256 of 265 melanomas) with an exact one-sided 95% lower confidence bound estimated at 94·2% and an observed specificity of 34·4%, and an exact two-sided 95% confidence bound estimated at 32·0-36·9%. The positive and negative predictive values of Nevisense were 21·1% and 98·2%, respectively. The observed sensitivity for nonmelanoma skin cancer was 100% (55 of 48 BCCs and seven SCCs) with an exact two-sided 95% confidence bound estimated at 93·5-100·0%. CONCLUSIONS: Nevisense is an accurate and safe device to support clinicians in the detection of cutaneous melanoma.

Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis.

BACKGROUND: Two phase III trials of photodynamic therapy (PDT) with BF-200 ALA, a recently approved nanoemulsion formulation of 5-aminolaevulinic acid (ALA) demonstrated high clearance rates in mild-to-moderate actinic keratosis (AK). The comparison to a registered methyl aminolaevulinate (MAL) cream demonstrated significantly superior total patient clearance rates. OBJECTIVES: To evaluate long-term efficacy and safety of PDT for AK 6 and 12 months after the last PDT with BF-200 ALA, MAL or placebo. METHODS: The follow-up phase (FUP) was performed with patients of two phase III studies. Both studies compared BF-200 ALA with placebo, one of the studies additionally with MAL. Overall recurrence rates and various subgroups (light source, lesion severity, lesion location, complete responders after first PDT) were assessed 6 and 12 months after the last PDT. RESULTS: Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. The proportion of patients who were fully cleared during PDT and remained completely clear for at least 12 months after PDT were 47% for BF-200 ALA (both studies) and 36% for MAL treatment. The subgroup that was illuminated with narrow wavelength LED lamps reached 69% and 53% for BF-200 ALA (both studies, respectively) and 41% for MAL. No safety concerns were reported. CONCLUSIONS: The FUP data confirmed the high efficacy and safety of PDT with BF-200 ALA. The slightly lower recurrence rates after BF-200 ALA treatment compared with MAL treatment enhanced the better treatment outcome due to the significantly superior efficacy.

Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5-aminolaevulinate cream and placebo.

BACKGROUND: Photodynamic therapy (PDT) with 5-aminolaevulinic acid (ALA) or its methylester [methyl-5-aminolaevulinate (MAL) or 5-amino-4-oxopentanoate] was recently ranked as first-line therapy for the treatment of actinic keratosis (AK) and is an accepted therapeutic option for the treatment of neoplastic skin diseases. BF-200 ALA (Biofrontera Bioscience GmbH, Leverkusen, Germany) is a gel formulation of ALA with nanoemulsion for the treatment of AK which overcomes previous problems of ALA instability and improves skin penetration. OBJECTIVES: To evaluate the efficacy and safety of PDT of AKs with BF-200 ALA in comparison with a registered MAL cream and with placebo. METHODS: The study was performed as a randomized, multicentre, observer-blind, placebo-controlled, interindividual trial with BF-200 ALA, a registered MAL cream and placebo in a ratio of 3:3:1. Six hundred patients, each with four to eight mild to moderate AK lesions on the face and/or the bald scalp, were enrolled in 26 study centres in Germany, Austria and Switzerland. Patients received one PDT. If residual lesions remained at 3months after treatment, PDT was repeated. RESULTS: PDT with BF-200 ALA was superior to placebo PDT with respect to patient complete clearance rate (78·2% vs. 17·1%; P<0·0001) and lesion complete clearance rate (90·4% vs. 37·1%) at 3months after the last PDT. Moreover, superiority was demonstrated over the MAL cream regarding the primary endpoint patient complete clearance (78·2% vs. 64·2%; P<0·05). Significant differences in the patient and lesion complete clearance rates and severity of treatment-related adverse events were observed for the narrow- and broad-spectrum light sources. CONCLUSIONS: BF-200 ALA is a very effective, well-tolerated new formulation for AK treatment with PDT and is superior to a registered MAL medication. Efficacies and adverse events vary greatly with the different light sources used.

[Electrochemotherapy of skin tumors]. / Elektrochemotherapie von Hauttumoren.

Electrochemotherapy represents a new innovative technology using a combination of electroporation and application of very low dose cytotoxic drugs for the treatment of cutaneous and subcutaneous skin tumors and metastases. Based on a high number of preclinical and clinical studies this procedure has been established as a simple, safe and very effective tumor treatment whose costs are acceptable. The procedure can be performed as a single treatment of localized disease as well as a repeated palliative treatment of cutaneous metastases regardless of the tumor type. Because of the lack of significant side effects and of short duration the procedure can be performed on an out-patient basis. Several studies led to the validation of standard operating procedures for its use in daily clinical practice. This treatment has become established in many different European countries.

Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a prospective, randomized, double-blind, placebo-controlled phase III study.

BACKGROUND: Photodynamic therapy (PDT) with 5-aminolaevulinic acid (ALA) provides a therapeutic option for the treatment of actinic keratosis (AK). Different strategies are applied to overcome the chemical instability of ALA in solution and to improve skin penetration. A new stable nanoemulsion-based ALA formulation, BF-200 ALA, is currently in clinical development for PDT of AK. OBJECTIVES: To evaluate the efficacy and safety of PDT of AK with BF-200 ALA. METHODS: The study was performed as a randomized, multicentre, double-blind, placebo-controlled, interindividual, two-armed trial with BF-200 ALA and placebo. A total of 122 patients with four to eight mild to moderate AK lesions on the face and/or the bald scalp were included in eight German study centres. The efficacy of BF-200 ALA after one and two PDT treatments was evaluated. BF-200 ALA was used in combination with two different light sources under illumination conditions defined by European competent authorities. RESULTS: PDT with BF-200 ALA was superior to placebo PDT with respect to patient complete clearance rate (per-protocol group: 64% vs. 11%; P < 0.0001) and lesion complete clearance rate (per-protocol group: 81% vs. 22%) after the last PDT treatment. Statistically significant differences in the patient and lesion complete clearance rates and adverse effect profiles were observed for the two light sources, Aktilite CL128 and PhotoDyn 750, at both time points of assessment. The patient and lesion complete clearance rates after illumination with the Aktilite CL128 were 96% and 99%, respectively. CONCLUSIONS: BF-200 ALA is a very effective new formulation for the treatment of AK with PDT. Marked differences between the efficacies and adverse effects were observed for the different light sources used. Thus, PDT efficacy is dependent both on the drug and on the characteristics of the light source and the illumination conditions used.

Long-term follow-up of photodynamic therapy with a self-adhesive 5-aminolaevulinic acid patch: 12 months data.

BACKGROUND: Photodynamic therapy with a self-adhesive 5-aminolaevulinic acid (5-ALA) patch shows high efficacy rates in the treatment of mild to moderate actinic keratosis (AK) in short term trials. OBJECTIVES: The purpose of the trial was to follow up patients after successful 5-ALA patch-PDT at 3 month intervals over a total period of 12 months. Patients who had received placebo-PDT or cryosurgery served for comparison. PATIENTS/METHODS: Three months after therapy, 360 patients from two separate randomized parallel group phase III studies (one superiority trial vs. placebo-PDT, one noninferiority trial vs. cryosurgery) were suitable for the follow-up study. Patients had to show at least one successfully treated AK lesion after initial therapy. A total of 316 patients completed the follow-up. RESULTS: Twelve months after a single treatment, 5-ALA patch-PDT still proved superior to placebo-PDT and cryosurgery (P < 0.001 for all tests). On a lesion basis, efficacy rates were 63% and 79% for PDT, 63% for cryosurgery and 9% and 25% for placebo-PDT. Recurrence rates of patch-PDT proved superior to those of cryosurgery (per protocol set: P = 0.011, full analysis set: P = 0.049). While 31% of cryosurgery lesions were still hypopigmented after 1 year, the 5-ALA patch-PDT groups showed hypopigmentation in 0% (superiority trial) and 3% (noninferiority trial) of the treated lesions. CONCLUSION: Twelve months after a single 5-ALA patch-PDT the majority of lesions were still cleared with an excellent cosmetic outcome. 5-ALA patch-PDT proved to be superior to cryosurgery in the noninferiority study setting.

Optimization of photodynamic therapy with a novel self-adhesive 5-aminolaevulinic acid patch: results of two randomized controlled phase III studies.

BACKGROUND: Photodynamic therapy (PDT) is increasingly used for treatment of actinic keratoses (AKs) but is a cumbersome procedure. A thin self-adhesive patch (PD P 506 A) containing 5-aminolaevulinic acid (5-ALA) was developed to facilitate PDT. OBJECTIVES: To investigate efficacy and safety of the patch in comparison with placebo-PDT (superiority design, observer-blinded; study AK 03) and standard therapy, cryosurgery (noninferiority design, open; study AK 04). METHODS: Two separate confirmatory randomized parallel-group phase III studies were set up. In total, 449 patients with up to eight mild to moderate AK study lesions located on the head were treated in 29 German study centres (study AK 03: 103 patients; study AK 04: 346 patients). RESULTS: Twelve weeks after treatment, 5-ALA patch-PDT proved to be superior to placebo-PDT (P < 0.001) and cryosurgery (P = 0.007). Efficacy rates on a lesion basis were 82% (AK 03) and 89% (AK 04) for PDT, 77% for cryosurgery and 19% (AK 03) and 29% (AK 04) for placebo-PDT. Local reactions at the treatment site occurred in almost all patients treated with 5-ALA patch-PDT or cryosurgery. Headache was the only side-effect not related to the treatment site which occurred in more than one patient. CONCLUSIONS: PD P 506 A is an innovative, easy-to-handle 5-ALA patch for PDT of mild to moderate AK lesions. Compared with current PDT procedures, pretreatment (e.g. curettage) is not needed and handling is considerably facilitated. A single PDT treatment results in efficacy rates being statistically significantly superior to placebo and cryosurgery.

The CD7(-) subset of CD4(+) memory T cells is prone to accelerated apoptosis that is prevented by interleukin-15 (IL-15).

The CD7(-) subset of CD4(+) T cells reflects a stable differentiation state of post-thymic helper T cells with CD45R0(+)CD45RA(-) 'memory' phenotype. Here we report that CD4(+)CD7(-) T cells are prone to increased spontaneous apoptosis in vitro compared to CD4(+)CD7(+) T cells. Spontaneous apoptosis is prevented by IL-15, but not by IL-2. Moreover, IL-15 increases Bcl-2 and decreases CD95/Fas expression of CD7(-), but not of CD7(+) T cells. Because IL-15 is physiologically not secreted but expressed in a membrane-bound form, we cocultured T cells with TNF-alpha stimulated fibroblasts that expose membrane IL-15. TNF-alpha stimulated fibroblasts rescue CD4(+)CD7(-) T cells from apoptosis whereas unstimulated fibroblasts do not. Rescue from apoptosis requires cell-cell contact and is abolished by addition of neutralizing antibodies to IL-15. We conclude that membrane IL-15 prevents accelerated apoptosis of CD4(+)CD7(-) T cells. This mechanism may contribute to accumulation of CD7(-) T cells in chronic inflammatory skin lesions.

Increased serum concentration of angiogenic factors in malignant melanoma patients correlates with tumor progression and survival.

PURPOSE: To determine the predictive value of the angiogenic serum factors angiogenin, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and interleukin-8 (IL-8) for the prognosis of patients with malignant melanoma. PATIENTS AND METHODS: Angiogenin, VEGF, bFGF, and IL-8 were measured in sera of 125 melanoma patients with different stages of disease and with or without current therapy including interferon alfa and different cytostatics in comparison with 30 healthy controls using enzyme-linked immunosorbent assay. RESULTS: Serum levels of angiogenin, VEGF, bFGF, and IL-8 were significantly increased in melanoma patients compared with healthy controls. Elevated serum concentrations of VEGF, bFGF, and IL-8 were associated with advanced disease stages and tumor burden. Cytostatic therapy of patients was accompanied by increased serum levels of angiogenin, bFGF, and IL-8. As shown by univariate analysis, elevated serum levels of VEGF (P = .0001 and .0036), bFGF (P < .00005 and < .00005), and IL-8 (P < .00005 and < .00005) were strongly correlated with a poor overall and progression-free survival, respectively. Multivariate analysis revealed stage of disease (P = .0238), tumor burden (P = .0347), VEGF (P = .0036), bFGF (P = .0252), and IL-8 (P = .0447) as independent predictive factors of overall survival. Tumor burden (P = .0081), VEGF (P = .0245), and IL-8 (P = .0089) were found as independent predictive factors of progression-free survival. CONCLUSION: Our data suggest that the angiogenic serum factors VEGF, bFGF, and IL-8 are useful predictive markers for overall and progression-free survival in melanoma patients.