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Background: Transcription factor retinoic acid-related orphan receptor 2 (RORC2/RORγT) mediates interleukin (IL)-17A and IL-17F expression. IL-17A plays a central role in the pathogenesis of several inflammatory disorders, including psoriasis. The RORC2 inhibitor PF-06763809 has been hypothesized to inhibit IL-17A production in T-helper 17 (Th17) cells, thereby reducing psoriasis symptoms., Aim: To assess the safety, tolerability and effect on skin infiltrate thickness of PF-06763809 in participants with mild/moderate chronic plaque psoriasis., Methods: This was a randomized, double-blind, first-in-human study (trial registration: ClinicalTrials.gov NCT03469336). Participants received each of the following six treatments once daily for 18 days: three topical doses (2.3%, 0.8%, 0.23%) of PF-06763809, a vehicle and two active comparators (betamethasone and calcipotriol). Primary endpoints included change from baseline in psoriatic skin infiltrate thickness [echo-poor band (EPB) on ultrasonography] at Day 19, and safety. Change in psoriasis-associated gene expression (Day 19), evaluated by real-time reverse transcription PCR of skin biopsies, was an exploratory endpoint., Results: In total, 17 participants completed the study. Change from baseline in the EPB on Day 19 for all three doses of PF-06763809 was not significantly different from that of vehicle (P > 0.05). A significant reduction in EPB from baseline was observed with betamethasone on Day 19 relative to all other treatments (P < 0.0001). Treatment-related adverse events were mild/moderate. There were no significant differences in gene expression on Day 19 between vehicle and PF-06763809-treated skin lesions., Conclusion: Using a psoriasis plaque test design, PF-06763809 was found to be well tolerated with an acceptable safety profile in participants with psoriasis, but without reduction in skin infiltrate thickness or disease biomarkers., (© 2020 The Authors. Clinical and Experimental Dermatology published by John Wiley & Sons Ltd on behalf of British.)

Introduction: Over the last few years, it has been demonstrated that a moist environment enhances the healing process and reduces scar formation of wounds. Such moist conditions can be created and maintained using hydrogels. The aim of this study was to evaluate wound healing, cooling efficacy, local tolerability, and cosmetic appearance of abrasive wounds treated with BepanGel wound care hydrogel., Methods: This study was designed as a within-person, single-center, randomized, investigator-blind clinical investigation comparing a hydrogel-treated test field with an untreated test field in an abrasive wound model. In 33 subjects, two small superficial wounds were induced on the non-dominant forearms. Wounds were treated with BepanGel and covered with a standard semi-occlusive wound plaster or covered with a plaster alone for 11 consecutive days. Wound healing efficacy, cooling effect, and tolerability of the treatment were assessed over 12 investigational days. During follow-up at day 31, the cosmetic appearance of the wounds was evaluated., Results: On day 12, the test field treated with BepanGel was completely healed in nearly all subjects (97.0%) in contrast with the test field treated with a plaster alone (18.2%, AUC days 2-12 p < 0.0001) as assessed by a blinded investigator. Two-thirds of the unblinded subjects indicated an immediate cooling effect of the hydrogel (p = 0.0555). At the end of the investigation, the cosmetic appearance of the BepanGel-treated test fields scored superior to the fields treated with a plaster alone as evaluated by a blinded investigator (p = 0.0005) and the unblinded subjects (p = 0.0078). The hydrogel was generally well tolerated and no signs of infection or adverse events (AEs) related to the treatment were observed., Conclusion: This evaluation shows that treatment of superficial cutaneous wounds with BepanGel results in improved wound healing as demonstrated by faster wound closure and a considerably better cosmetic appearance, while providing immediate cooling., Trial Registration Number: EUDAMED-No.: CIV-19-09-029744.

Objective: During the development of cosmetic formulations, in vitro and in vivo methods are essential tools used to reliably assess the skin irritation potential of a product or ingredient. Epicutaneous patch testing (single and/or multiple application protocols) has long been used as an initial in vivo method to screen for possible skin irritation properties of a substance or formulation. To confirm the mildness and dermatological and/or consumer acceptance of a product, use tests are often subsequently conducted. A study was therefore initiated to see how well patch test results correlate with use tests with respect to irritation elicited by skincare (leave-on) products., Methods/results: A number of different cosmetic formulations were assessed in both tests. Although the patch test results did not indicate substantial irritation potentials, immediate-type reactions (stinging and redness) were observed in some volunteers which disappeared within approx. 1 h. Although transient, these reactions suggested that consumer acceptance would probably be low and the studies were discontinued. Immediate-type reactions are rare but have been described for some substances used in cosmetics. These unexpected results were nevertheless intriguing and prompted the start of a journey to see if patch test protocols could be modified to assess these reactions. An occlusive short-term patch test protocol with an application period of 20 min was developed. Successful identification of the spontaneous reactions became possible. Furthermore, there was a correlation between the intensity of reactions observed in the short-term patch test and those observed in the controlled in-use studies. Short-term patch testing using the developed protocol can therefore reliably be used as a screening method, for example in the development and optimization of cosmetic formulations containing ingredients that could cause spontaneous reactions, for instance of non-immunological contact urticaria type., Conclusion: The lessons learned from this studies indicate that simple modifications of existing test protocols can lead to important insights into skin reactions. These modifications can then be used to create further building blocks in the development and optimization of test strategies for cosmetic formulations which offer reliable study designs for possible reactions product developers may encounter., (© 2020 The Authors. International Journal of Cosmetic Science published by John Wiley & Sons Ltd on behalf of Society of Cosmetic Scientists and Société Française de Cosmétologie.)

Background: Androgenetic alopecia (AGA) is the most common cause of hair loss in men. Topical minoxidil solutions can help to treat AGA but have to be applied continuously to be effective., Objectives: A new minoxidil formulation with improved cosmetic characteristics (DC0120, Pierre-Fabre Dermatologie) was tested for noninferiority vs a comparator minoxidil product (ALOSTIL ® , Johnson & Johnson) in stimulating hair growth in men with AGA., Methods: Two 10 cm 2 areas on the scalp of each subject were randomized to receive DC0120, the comparator, or one of their corresponding vehicles, applied twice per day for 16 weeks. Nonvellus target area hair count (TAHC) was measured within treatment areas at baseline (day 1) and after 8 and 16 weeks by digital phototrichogram., Results: Two hundred and twenty subjects were included and randomized, of which 210 completed the study. The mean change in nonvellus TAHC between baseline and week 16 was +22.0 hairs/cm 2 (95% CI: 18.1; 25.9) in the DC0120 group and +20.5 hairs/cm 2 (95% CI: 16.6; 24.4) in the comparator group. The adjusted mean difference in TAHC changes between the two treatments was +1.5 hairs/cm 2 (95% CI -2.3; 5.2), with the lower 95% confidence interval above the noninferiority threshold of -7 hairs/cm 2 . This indicated that DC0120 was noninferior to the comparator. Both minoxidil treatments also increased nonvellus TAHC compared to vehicle groups at 8 and 16 weeks. No new safety signals were observed., Conclusions: DC0120 was as safe and effective as a similar marketed minoxidil product for stimulating hair growth in men with AGA., (© 2018 Wiley Periodicals, Inc.)

Background: Little is known about the impact of nutrition on the development of skin structure and function in infants., Methods: We investigated epidermal, dermal, and subcutis parameters of aged-matched well-nourished and moderately undernourished infants in this single-center, cross-sectional, noninterventional study using noninvasive methods (skin caliper, 20-MHz sonography, transepidermal water loss, skin pH, and corneometry). Plasma fatty acids were determined as an indicator of nutritional differences. 310 infants from different age groups, i.e., 1 week, 4 weeks, and 6, 9, 12, 24, and 36 months were included. Approximately half of each age group was well-nourished (WHO reference values weight-for-height/length Zscore: -0.75 ≤ Z ≤ 0.75) and the other half was moderately undernourished (-3 ≤ Z < -2)., Results: Structural maturational differences in the deeper dermis and subcutis regions of the skin and subtle functional changes in the epidermis were observed in moderately undernourished infants without notable clinical symptoms. Reduced skin barrier function or skin hydration were not observed in the undernourished infants, and skin pH shifted to more acidic values in this group., Conclusion: These findings reveal a greater impact of moderate undernutrition on the development of the dermis and subcutis and suggest that critical epidermal functions such as skin barrier and pH are mostly maintained., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Rosacea is a widespread inflammatory skin disease that is chronically recurrent and affects predominately the central parts of the face. Affected individuals typically react to numerous cosmetics with redness, burning, and/or worsening of the complexion. Consequently, there is a high demand for dermocosmetics that do not provoke such reactions and are suitable for use in rosacea. The present guideline of the Society for Dermopharmacy describes the requirements that dermocosmetics for use in rosacea should meet. They include, inter alia, methods to prove the efficacy of and tolerance to these cosmetics, as well as the product documentation that the manufacturer or the distributing company should make available to professionals, like dermatologists and pharmacists, counseling patients with rosacea., (© 2018 S. Karger AG, Basel.)

Vaginal dryness and associated symptoms may occur in women of any age and are a frequent burden after menopause. The North American Menopause Society recommends long-acting non-hormonal vaginal creams as first-line therapy. A new type of such creams was developed (Remifemin® FeuchtCreme in Austria and Germany). This hormone-free cream contains hamamelis virginiana distillate and well-established vaginal cream ingredients. We explored its physical function and tolerability in an open interventional clinical trial. 20 postmenopausal women (54 to 76 years, median 60) treated their vaginal dryness using this cream once daily for 7 days and reported about their symptoms before, 4 to 8 h after first and 14 to 22 h after last application. A physician assessed tolerability and local physical function. All patients completed the study. Local physical function significantly improved from dryness at baseline (mean 4.0 ± SD 1.8) to a normal moisture level, on average (6.3 ± 2.1 after first, 6.7 ± 2.1 after last application, p = 0.0001). Subjective assessment of a feeling vaginal dryness showed a significant improvement at both times (p = 0.0001). Onset and duration of feeling moisturized were reported to be 0 to 2 min and 11.3 ± 6.9 h after application. All women reported vaginal dryness at baseline. 55 and 80% of patients reported no dryness after first application and at the end of the investigation. The cream was seen at the application site for up to 21 h. Tolerability assessments did not reveal any relevant change over time. There were four adverse events in 4 patients, all not serious and of mild intensity: urinary urgency (2), diarrhoea (1) and mild spotting after first application (1). The latter was caused by the dry surface of the applicator and was avoided by moisturizing the surface of the applicator at subsequent applications. In conclusion, these study results indicate a well-tolerated and long-acting function of this new vaginal moisturizing cream. Further clinical research in more patients will follow.

Background/aims: Psoriasis plaque tests (PPTs) are important tools in the early phases of antipsoriatic drug development. Two distinct PPT design variants (open vs. occluded drug application) are commonly used, but no previous work has aimed to directly compare and contrast their performance., Methods: We compared the antipsoriatic efficacy of mapracorat 0.1% ointment and reference drugs reported in 2 separate studies, representing open and occluded PPT designs. The drug effect size was measured by sonography (mean change in echo-poor band thickness), chromametry, and standardized clinical assessment., Results: Antipsoriatic effects were detectable for the study drugs in both occluded and open PPTs. Differences between the potency of antipsoriatic drugs and vehicle were observable. The total antipsoriatic effect size appeared to be higher in the occluded PPT than the open PPT, despite the shorter treatment duration (2 vs. 4 weeks). Effect dynamics over time revealed greater differences between some study drugs in the open PPT compared to the occluded PPT., Conclusion: Taking the higher technical challenges for the open PPT into account, we recommend the occluded PPT as a standard screening setting in early drug development. In special cases, considering certain drug aspects or study objectives that would require procedural adaptations, an open PPT could be the better-suited design. Finally, both PPT models show clear advantages: classification as phase I studies, small number of psoriatic subjects, relatively short study duration, excellent discrimination between compounds and concentrations, parallel measurement of treatment response, and go/no go decisions very early in clinical development., (© 2017 S. Karger AG, Basel.)

Background: Oral phosphodiesterase (PDE)4 inhibitors have shown efficacy in chronic obstructive pulmonary disease and psoriasis., Objectives: To assess the effectiveness, local safety and tolerability, and systemic pharmacokinetics of two topical PDE4 inhibitors, roflumilast and TAK-084, in plaque psoriasis., Methods: An intraindividual comparison of six topical products was made in 15 patients aged 18-65 years with stable chronic plaque psoriasis in an investigator-blinded, within-subject randomized study. The products evaluated were calcipotriol 0·005% cream; betamethasone valerate 0·1% (both in their marketed formulations); investigational cream formulations of roflumilast 0·5% and TAK-084 0·5% and 5%; and a vehicle cream formulation as a control. Each treatment was applied daily to different test sites located on psoriasis plaques for 3 weeks., Results: The primary end point of (mean) change from baseline in skin infiltrate thickness after 3 weeks of treatment showed statistically significant improvements for all treatments: betamethasone valerate cream (-286·9 μm), the selective PDE4 inhibitors roflumilast 0·5% (-237·1 μm) and TAK-084 (0·5% cream, -153·6 μm; 5% cream, -216·7 μm) and calcipotriol 0·005% (-187·7 μm) when compared with vehicle cream control (all P < 0·001). Both the TAK-084 5% and roflumilast 0·5% formulations performed well overall compared with the potent corticosteroid, betamethasone, and were ranked better than the vitamin D analogue calcipotriol. All adverse events were mild or moderate and none was serious., Conclusions: Topical treatment with cream formulations of the PDE4 inhibitors roflumilast and TAK-084 reduced inflammation, measured as a change in skin infiltrate thickness, and reduced psoriasis severity. Corticosteroid treatments have known systemic and cutaneous side-effects; PDE4 inhibitors could offer an alternative to these and deserve further study., (© 2016 British Association of Dermatologists.)

Propylene glycol is one of the known substances added in cosmetic formulations as a penetration enhancer. Recently, nanocrystals have been employed also to increase the skin penetration of active components. Caffeine is a component with many applications and its penetration into the epidermis is controversially discussed in the literature. In the present study, the penetration ability of two components - caffeine nanocrystals and propylene glycol, applied topically on porcine ear skin in the form of a gel, was investigated ex vivo using two confocal Raman microscopes operated at different excitation wavelengths (785nm and 633nm). Several depth profiles were acquired in the fingerprint region and different spectral ranges, i.e., 526-600cm(-1) and 810-880cm(-1) were chosen for independent analysis of caffeine and propylene glycol penetration into the skin, respectively. Multivariate statistical methods such as principal component analysis (PCA) and linear discriminant analysis (LDA) combined with Student's t-test were employed to calculate the maximum penetration depths of each substance (caffeine and propylene glycol). The results show that propylene glycol penetrates significantly deeper than caffeine (20.7-22.0μm versus 12.3-13.0μm) without any penetration enhancement effect on caffeine. The results confirm that different substances, even if applied onto the skin as a mixture, can penetrate differently. The penetration depths of caffeine and propylene glycol obtained using two different confocal Raman microscopes are comparable showing that both types of microscopes are well suited for such investigations and that multivariate statistical PCA-LDA methods combined with Student's t-test are very useful for analyzing the penetration of different substances into the skin., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In this series of Phase I, randomized, placebo-controlled studies in healthy volunteers, the potential for ozenoxacin 1 and 2% cream formulations to cause irritation, sensitization, phototoxicity and photoallergy under occlusive patch conditions was evaluated. Both ozenoxacin formulations showed excellent dermal tolerability; in the vast majority of cases, only minimal signs of erythema were observed, with no evidence of edema or a papular response. No subject met the criteria for a phototoxic reaction with the ozenoxacin 1 or 2% cream formulations. Only a few adverse events were reported across repeated-dose studies, and virtually all events were considered to be unrelated or unlikely to be related to ozenoxacin application. Ozenoxacin was safe, well tolerated and showed little or no tendency to cause irritation, sensitization, phototoxicity or photoallergy.

Background: Topical preparations are a common treatment for superficial acute wounds, which at the least do not interfere with healing and ideally result in enhanced wound healing irrespective of microbial colonization., Objective: To examine the effects of a topical antimicrobial gel and its vehicle on the wound healing of standardized, superficial abrasions., Methods: Thirty-three healthy volunteers were enrolled in a double-blinded, randomized, intraindividual comparison study. Three standardized, superficial abrasions were induced on their forearms. A tyrothricin 0.1% gel (Tyrosur® gel; Engelhard Arzneimittel GmbH & Co. KG, Niederdorfelden, Germany) and its vehicle were randomly applied to two of the test areas, and one lesion remained untreated., Results: A significant improvement of wound healing was seen with both tyrothricin 0.1% gel and its corresponding vehicle in the clinical assessment. The mean area under the curve (AUC) of wound healing scores was the same for both preparations and the mean reepithelization scores were comparable at all test points over the entire 12 days. A lower mean AUC representing less reepithelization was found for the untreated test fields., Conclusion: The use of tyrothricin 0.1% gel and its corresponding vehicle resulted in statistically significant improved wound healing with an earlier onset of healing in particular. Based on these results obtained using an abrasive wound model, it can be concluded that the addition of tyrothricin 0.1% to the gel vehicle did not interfere with the improved wound healing seen with the vehicle alone., (Copyright © 2012 S. Karger AG, Basel.)

Background: The aim of the present study was to analyze in detail the time course of the incidence of radiation-induced late effects. For this purpose, unpublished data of patients treated by radiation therapy in Hamburg in the late 1980s were analyzed. Relatively large volumes were exposed to comparatively high doses, thus leading to a high rate of treatment-related side effects., Patients and Methods: A total of 180 consecutive patients received radiotherapy for prostate cancer. The median age was 66 years (range 41-88 years). The median of the maximum dose was 77.5 Gy (range 56.3-95 Gy) and overall treatment time was 51 days (range 28-128 days). Endpoints analyzed were late complications of grade 3 or higher, overall and disease-free survival, local tumor control, and distant metastases. Data analysis was actuarial and the log-rank test was used to compare the various subgroups., Results: After 2 years, 80.5 ± 3.2% of the patients were without any complications of grade 3 or higher, and after 5 years a constant level of 70.3 ± 4.0% was approached. When multiple lesions occurred per patient, the later events were disregarded. A total of 66 complications occurred in 42 patients. The percentage of patients being free from late complications, plotted as a function of time after start of radiation therapy, was adequately described by an exponential function and a constant fraction. Complications approached a constant level of 70.3% at a rate of 5.3% per month. This means that patients who will develop a complication do so at exponential kinetics and at a relatively high rate, whereas about 70% of the patients will never experience a late effect even over long observation periods. After subdividing the maximum dose into three equal dose groups of 55 patients each (< 73.3 Gy, 73.3-80 Gy, > 80 Gy), the constant fraction decreased from 85.7 to 72.8% and 52.2%, whereas the incidence rate was 4.3%, 7.7%, and 5.6% per month and, thus, almost independent of radiation dose., Conclusion: For a given group of patients, the rate of the incidence of late complications appears to be independent of radiation dose and (from analyzing data in the literature) independent of the grade of lesions, whereas the fraction of patients without late effects depends on both parameters.

Background: The barrier perturbation pattern and molecular markers of inflammation upon tandem repeated irritation in chronologically aged skin have not been previously studied., Objectives: We aimed to investigate the barrier impairment kinetic and in vivo cytokine profile following sequential irritation with sodium lauryl sulfate (SLS) and undiluted toluene (Tol) in aged compared with young skin., Methods: Four fields on the volar forearm of healthy aged and young volunteers (median age, respectively, 63.9 and 32.6 years) were sequentially exposed to 0.5% SLS and undiluted toluene in a controlled tandem repeated irritation test; an adjacent nontreated field served as control. The permeability barrier function was monitored by repeated measurements of transepidermal water loss (TEWL), capacitance and erythema every 24 h up to 96 h. The stratum corneum cytokines were harvested by sequential tape stripping and quantified by multiplex bead array and enzyme-linked immunosorbent assay., Results: Compared with young skin, aged skin was characterized by delayed and/or less pronounced alterations in the visual irritation score, TEWL, chromametry a*-value and capacitance, assessed by the respective Δ-values for each parameter and monitoring time point. In both groups, exposure to SLS/SLS, SLS/Tol and Tol/SLS resulted in decreased interleukin (IL)-1α levels, whereas the application of Tol/Tol induced an increase in IL-1α. Furthermore, decreased IL-1 receptor antagonist (IL-1RA) levels and a lower IL-1RA/IL-1α ratio were found following repeated exposure to the irritants., Conclusions: Our results provide evidence for selective alterations in the cytokine profile and distinct barrier impairment kinetic following tandem repeated irritation with SLS and Tol in aged compared with young skin in vivo., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists.)

Botulinum toxins are frequently used in esthetics to improve the appearance of facial wrinkles. In this setting, precise localization of the neurotoxin is required to produce the desired clinical effects. Unwanted effects can occur if the neurotoxin diffuses into untargeted muscle. Therefore, a neurotoxin with low and predictable spread would be preferable for esthetic applications. The aim of this study was to investigate the spread of three approved botulinum toxin type A preparations, with and without complexing proteins, by measuring and comparing the size of the anhidrotic halos they produced following injection of equivalent doses in an identical volume into the forehead of patients. The results showed that incobotulinumtoxinA and onabotulinumtoxinA displayed comparable spread at 6 weeks (maximal area of anhidrosis within 6 weeks) and area under the effect curve (AUEC) over 6 months. However, abobotulinumtoxinA, when assuming a 1:2.5 injection volume ratio, produced a statistically significantly greater maximal area of anhidrosis within 6 weeks and AUEC over 6 months compared with incobotulinumtoxinA. All preparations were well tolerated. The results of this study demonstrate that incobotulinumtoxinA and onabotulinumtoxinA have comparable spread, while abobotulinumtoxinA has significantly greater spread than incobotulinumtoxinA.

Mometasone furoate, a potent glucocorticoid (class III) with a favorable benefit/risk ratio, has emerged as a standard medication for the treatment of inflammatory skin disorders. The purpose of the investigation presented here was to determine the noninferiority of a topical mometasone formulation, a light cream (O/W 60/40 emulsion) with mometasone furoate 0.1% (water content of 33%) versus marketed comparators. Using the vasoconstrictor assay, a strong blanching effect of the new cream (called Mometasone cream) comparable to that of a mometasone comparator, a fatty cream with mometasone furoate 0.1%, could be demonstrated. Thus, the topical bioavailability of the active ingredient mometasone furoate (0.1%) was regarded to be similar for Mometasone cream and the mometasone comparator. Using the psoriasis plaque test, a strong antipsoriatic effect comparable to that of the mometasone comparator was found for Mometasone cream after 12 days of occlusive treatment. A nearly identical reduction in the mean infiltrate thickness and similar mean AUC values were noted with both formulations confirmed by clinical assessment data. The noninferiority of Mometasone cream to its active comparator with respect to the AUC of change to baseline in infiltrate thickness was demonstrated. Both medications were well tolerated. Overall, Mometasone cream and the mometasone comparator showed similar efficacy and tolerability. Mometasone cream, in addition to its high potency and good tolerability, provides the properties of a light cream, which might make this new medication particularly suitable for application on acutely inflamed and sensitive skin., (Copyright © 2012 S. Karger AG, Basel.)

This double-blind controlled phase II study was conducted to compare a newly developed formulation of mometasone furoate with a water content of 33% (Monovo® Cream) and with a smooth consistency versus the commercially available fatty cream of mometasone furoate (Ecural® Fettcreme) in terms of efficacy, cosmetic properties, and patients' acceptance. In 20 patients with mild to moderate atopic eczema, the preparations were tested intraindividually in a randomized mode and in two comparable lesion areas. Both preparations were equally effective and well tolerated. Due to improved cosmetic properties, the new formulation was preferred by the patients when asked for preferential use. Quality of life could be improved by treating with both preparations., (Copyright © 2012 S. Karger AG, Basel.)

The present study was conducted to assess the efficacy of a new mouthrinse formulation in reducing oral malodour compared to that of commercially available products containing chlorhexidine (CHX) and a negative control. 174 healthy volunteers, each with an organoleptic score of at least 2 and an H(2)S level as part of the volatile sulfur compounds (VSC) higher than 50 ppb, were divided into four groups. Participants were stratified according to their organoleptic ratings (OR). Group I: mouthrinse I (250 ppm F(-) from amine fluoride/stannous fluoride (ASF), 0.2% zinc lactate, oral malodour counteractives); group II: mouthrinse II (0.05% CHX, 0.05% cetylpyridinium chloride, 0.14% zinc lactate); group III: mouthrinse III (0.12% CHX); group IV: tap water. All groups were instructed to perform standardized oral hygiene measures and to apply the respective test rinse twice daily after tooth brushing. Malodour was assessed by organoleptic measurement and by VSC levels at baseline, day 1, day 7, day 14 and day 21 into the study. To evaluate discolouration of the teeth, the colour was assessed at baseline and final visit. The ASF mouthrinse showed superior efficacy as compared to the negative control. A significant reduction in OR and VSC readings was achieved after single application as well as after 7 and 21 days of continuous use. Between test groups I-III no statistically significant differences were found at any time point. There was also a trend towards fewer side effects caused by the ASF product compared to the products containing CHX. The newly developed mouthrinse product significantly reduces oral malodour in patients with increased values both in OR and in VSC.

Background: Development of cosmetic products and household detergents necessitates comparative study designs to assess the skin tolerance of products. In initial tests, the epicutaneous patch test for irritation is widely used., Objectives: This study was conducted to develop a protocol that would facilitate a comparison of results obtained when tests are conducted by different laboratories., Methods: 'In-house' and standardized patch test protocols were used to assess irritation potentials of surfactant-based products in intra- and interlaboratory studies using defined surfactant samples., Results: The various in-house protocols tested did not consistently produce equivalent results. In order to develop a study design that yields comparable results, various factors were identified and adjusted. The standardized study protocol includes occlusive application of 70 microl of the test substance to the back of 30 subjects, defined reading times and schemes, assessments based mainly on erythema, and inclusion of sodium laureth sulfate and sodium dodecyl sulfate as positive controls as well as water as a negative control., Conclusions: Use of the standardized protocol and training of assessors improved the reliability and consistency of results whereby the irritation potentials of the references and test samples were ranked similarly by the laboratories.

Objective: To establish a new wound model that can induce uniform abrasions and use it to assess the healing properties of a range of products commonly applied to these wounds., Method: Ten healthy volunteers were enrolled into an open-label, randomised, intra-individual comparison pilot study. Five standardised, superficial abrasions were induced on their forearms by repeatedly scrubbing the skin with a surgical brush until the first signs of uniform glistening and punctuate bleeding were observed. Three products that promote a moist wound environment (polyurethane, hydrocolloid, hydrogel) and two standard plasters were randomly allocated to the test areas., Results: Evaluation of wound healing on days 2, 5, 8 and 14 +/- 1 showed best results for the polyurethane and hydrocolloid plasters. Visible re-epithelialisation was recorded on days 5 and 8. More than 50% of the wound area had closed. Video microscope images support these findings. The investigator and volunteers assessed cosmetic outcomes on day 31 +/- 2. Best results were obtained for the polyurethane and hydrocolloid products, which had high mean scores close to the maximum of 10. Histological examination of biopsies taken from the abrasions of two volunteers showed the dermis remained intact, making the model highly suitable for the study of superficial wounds., Conclusion: Uniform and identical standardised wounds created using an abrasive brush technique can be used to reliably detect differences in the performance of plasters intended for superficial wounds. In general, products that promote a moist wound environment produced better results than those that promote a dry wound environment, with an earlier onset of healing and better healing outcomes. Superficial cutaneous wounds treated with polyurethane or hydrocolloid products demonstrated superior rates of re-epithelialisation and overall cosmetic outcomes., Declaration of Interest: This study was funded by Beiersdorf AG. Neither author has any interest in the sponsor's commercial activities.

Purpose: We tested whether the chromosomal radiosensitivity of in vitro irradiated lymphocytes could be used to predict the risk of acute reactions after radiotherapy., Methods and Materials: Two prospective studies were performed: study A with 51 patients included different tumor sites and study B included 87 breast cancer patients. Acute reaction was assessed using the Radiation Therapy Oncology Group score. In both studies, patients were treated with curative radiotherapy, and the mean tumor dose applied was 55 Gy (40-65) +/- boost with 11 Gy (6-31) in study A and 50.4 Gy +/- boost with 10 Gy in study B. Individual radiosensitivity was determined with lymphocytes irradiated in vitro with X-ray doses of either 3 or 6 Gy and scoring the number of chromosomal deletions., Results: Acute reactions displayed a typical spectrum with 57% in study A and 53% in study B showing an acute reaction of Grade 2-3. Individual radiosensitivity in both studies was characterized by a substantial variation and the fraction of patients with Grade 2-3 reaction was found to increase with increasing individual radiosensitivity measured at 6 Gy (study A, p = 0.238; study B, p = 0.023). For study B, this fraction increased with breast volume, and the impact of individual radiosensitivity on acute reaction was especially pronounced (p = 0.00025) for lower breast volume. No such clear association with acute reaction was observed when individual radiosensitivity was assessed at 3 Gy., Conclusion: Individual radiosensitivity determined at 6 Gy seems to be a good predictor for risk of acute effects after curative radiotherapy.

Background and Purpose: Conventional radiotherapy (RT) still is the standard technique for head-and-neck cancer in many centers worldwide, whereas other centers replaced this technique by 3-D conformal RT, which is associated with more appropriate dose distributions. Comparative studies regarding outcome and toxicity are lacking. This study compared both techniques for overall survival (OS), metastases-free survival (MFS), loco-regional control (LC), and toxicity in stage III/IV head-and-neck cancer., Patients and Methods: Data of 345 patients irradiated for stage III/IV squamous cell head-and-neck cancer were retrospectively analyzed. Patients received conventional RT (group A, n = 166) or 3-D conformal RT (group B, n = 179). Both techniques were compared for outcomes and toxicity. Eleven further potential prognostic factors were investigated: age, gender, performance status, tumor site, grading, T-stage, N-stage, AJCC-stage, chemotherapy, surgery, pre-RT hemoglobin., Results: 3-year-OS was 62% in group A and 57% in group B (p = 0.15). 3-year-MFS was 67% and 76% (p = 0.46), 3-year-LC was 65% and 68%, respectively (p = 0.71). On multivariate analysis, gender (p = 0.005), performance status (p < 0.001), T-stage (p = 0.002), and N-stage (p < 0.001) were associated with OS. MFS was influenced by performance status (p < 0.001) and N-stage (p < 0.001), LC by gender (p = 0.021), T-stage (p < 0.001), and pre-RT hemoglobin level (>or= 12 better than < 12 g/dl, p = 0.004). Grade 2-3 xerostomia was less frequent with 3-D conformal RT (43% vs. 58%, p = 0.06). Otherwise, toxicities were similar., Conclusion: Both RT techniques resulted in similar treatment outcomes. Because xerostomia was less with 3-D conformal RT, this technique appeared beneficial for patients, in whom one parotid gland can be spared. Outcome was associated with gender, performance status, tumor stage, and pre-RT hemoglobin.

Background: Melasma is a common pigmentation disorder having considerable effect on patients' emotional and psychological well-being., Objective: Assessment of efficacy and tolerability of a new face care product for the targeted spot treatment of darker pigmented areas in subjects with melasma and evaluation of effects on patients' quality of life., Methods: Twenty subjects with melasma were enrolled in this study. Data of 19 participants were available for analysis. Melasma severity was evaluated at baseline, after 4 weeks, and after 8 weeks by using the Melasma Area and Severity Index (MASI). Furthermore, chromametry and digital image analysis of videomicroscopic photographs were performed, and quality of life was measured using the Melasma Quality of Life Scale., Results: The application of the product resulted in a significant lightening of melasma in comparison with baseline and to untreated control areas. The MASI score dropped by more than 40% after 8 weeks. Measurement of skin color by chromametry revealed lightening of pigmented areas and a significant decrease in contrast between melasma and normal-pigmented surrounding skin. These results were confirmed by digital image analysis. Tolerability of the product was rated to be excellent, and patients experienced a significant gain in quality of life., Conclusion: The data demonstrate that the new face care product is effective and highly skin tolerable and clearly improves quality of life of patients with melasma.

Purpose: Experiences with a new high-dose-rate brachytherapy (HDR-BT) boost technique in 41 patients with stage T3b prostate cancer are presented., Patients and Methods: The patients received 18 Gy of HDR-BT (9 Gy on days 1 + 8) plus 50.4 Gy of EBRT. 20 patients (group A) had BT applicators placed into the prostate alone resulting in 18 Gy to prostate and 0 Gy (tip) to 12 Gy (base) to seminal vesicles (SV). The cumulative EQD2 (equivalent dose in 2-Gy fractions, alpha/beta 1.5 Gy) to the SV was 47.5-73.3 Gy. 21 patients (group B) had BT applicators placed into both prostate and SV resulting in 18 Gy to prostate and to > 80% (but not 100%) of the SV (cumulative EQD2 81.5-101.5 Gy). Both groups were compared for acute and late toxicity and for biochemical relapse-free survival (bRFS)., Results: The 3-year bRFS was 57% for group A and 79% for group B patients (p = 0.29). A grade 3 acute toxicity (CTC 2.0) was not observed. Grade 2 acute toxicity (proctitis, cystitis, skin toxicity) was comparable in both groups. A grade 3 late toxicity did not occur. Impotence rates were 35% in group A and 24% in group B, respectively (p = 0.73)., Conclusion: The new HDR-BT technique (group B) was associated only with minor acute and late toxicity and appears to result in better bRFS than the conventional HDR-BT technique (group A). The results must be confirmed in a prospective trial.

Purpose: To evaluate the accuracy of virtual simulation, which is less time-consuming than physical simulation, with the new laser system Dorado CT4 in 96 prostate cancer patients., Patients and Methods: Virtual simulation was based on a spiral scan with 8 mm reconstruction index and 8 mm slice thickness in 64 patients (group A), and 3 mm reconstruction index and 3 mm slice thickness in 32 patients (group B). Both groups were evaluated for impact on maximum difference (Deltamax) regarding the isocenters obtained from virtual simulation versus those obtained from physical simulation., Results: In the entire cohort, mean differences were as follows: Deltamax 5.7 +/- 3.5 mm, Deltax (left/right) 2.8 +/- 2.9 mm, Deltay (anterior/posterior) 4.5 +/- 3.8 mm, and Deltaz (cranial/caudal) 2.1 +/- 2.2 mm. In group A, mean values were Deltamax 6.2 +/- 3.8 mm, Deltax 2.9 +/- 3.1 mm, Deltay 4.9 +/- 4.2 mm, and Deltaz 2.3 +/- 2.3 mm. In group B, mean values were Deltamax 4.8 +/- 2.8 mm, Deltax 2.7 +/- 2.7 mm, Deltay 3.7 +/- 2.7 mm, and Deltaz 1.7 +/- 2.0 mm. Time of radiotherapy (primary vs. salvage RT) and radiation regimen (external-beam radiotherapy [EBRT] vs. high-dose-rate brachytherapy [HDR-BT] plus EBRT) had no significant impact on Deltamax., Conclusion: Virtual simulation with the new laser system Dorado CT4 was very precise for both primary and salvage RT in the treatment of prostate cancer patients. High precision was achieved for both EBRT and HDR-BT plus EBRT. Virtual simulation should be performed with a planning CT with 3 mm reconstruction index and 3 mm slice thickness for high accuracy.

Objective and Design: The aim of the study was to evaluate the vasoconstrictive activity of four new galenic preparations of hydrocortisone and to compare it with concentration-equivalent reference preparations. The study comprised two study phases: the pilot study phase and the main study phase. During open, nonrandomized pilot study, the optimal administration period was tested. The main study was performed in a randomized, double-blind intraindividual comparative design., Subjects: Twenty male and female volunteers with healthy skin who responded to topically applied clobetasol-17-propionate before entering the trial participated in this study., Treatment: All subjects received the same treatments. The test preparations new galenic formulation (NGF) hydrocortisone 0.25% cream, NGF hydrocortisone acetate 0.25% cream, NGF hydrocortisone 0.5% cream, and NGF hydrocortisone 1.0% cream were compared with the respective reference preparations Soventol hydrocortisone (hydrocortisone acetate 0.25%), Hydroderm HC 0.5% cream (hydrocortisone 0.5%), Hydrogalen cream (hydrocortisone 1.0%) and placebo (vehicle of test preparations)., Method: The topical preparations were applied occlusively for 2 h (pilot study) or 24 h (main study) on outlined areas (5 x 5 cm with a distance of 3 cm) of both forearms (4 areas for each). Assessment of vasoconstriction was performed before treatment, and 0.5, 4, 6 and 24 h after treatment (observation period) using a subjective rating scale (OLSEN vasoconstriction score) and measuring the colorimetric parameter a* (redness) by use of the Chroma-Meter (Minolta company, Ahrensburg, Germany)., Results: A significant vasoconstriction (positive blanching effect) was measured by use of chromametry for test preparations hydrocortisone 0.25% cream, hydrocortisone 0.5% cream, hydrocortisone 1.0% cream and for the reference preparation Hydrogalen cream compared to placebo 30 min after the end of treatment. In contrast, the reference preparations Soventol hydrocortisone and Hydroderm HC 0.5% did not differ significantly from placebo 30 min after treatment. No statistically significant effect of all formulations was observed 4-24 h after treatment in comparison with placebo., Conclusions: The vasoconstrictive efficacy of test preparations was mostly stronger than the concentration-equivalent reference preparations. This effect was achieved by use of new galenics of test preparations resulting in enhanced skin penetration and improved efficiency. No unwanted side effects were observed during the course of the study despite increased efficacy of the topically applied test preparations., (Copyright (c) 2007 S. Karger AG, Basel.)

Purpose: To evaluate potential prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression (MSCC)., Patients and Methods: The following potential prognostic factors were investigated retrospectively in 1,852 patients irradiated for MSCC: age, sex, performance status, primary tumor, interval between tumor diagnosis and MSCC (< or = 15 v > 15 months), number of involved vertebrae (one to two v > or = three), other bone metastases, visceral metastases, pretreatment ambulatory status, time of developing motor deficits before radiotherapy (faster, 1 to 14 v slower, > 14 days), and radiation schedule (short-course v long-course radiotherapy)., Results: On univariate analysis, improved local control of MSCC was associated significantly with favorable histology (breast cancer, prostate cancer, lymphoma/myeloma), no visceral metastases, and long-course radiotherapy. On multivariate analysis, absence of visceral metastases and radiation schedule maintained significance. On univariate analysis, improved survival was associated significantly with female sex, favorable histology, no visceral or other bone metastases, good performance status, being ambulatory before radiotherapy, longer interval between tumor diagnosis and MSCC, and slower development of motor deficits before radiotherapy. Long-course radiotherapy showed a trend. On multivariate analysis, histology, visceral metastases, other bone metastases, ambulatory status before radiotherapy, interval between tumor diagnosis and MSCC, and time of developing motor deficits maintained significance., Conclusion: Poorer local control after radiotherapy for MSCC is associated with visceral metastases and short-course radiotherapy. Long-course radiotherapy seems preferable for patients with more favorable prognoses, given that these patients may live long enough to develop MSCC recurrences. Long-term survival after radiotherapy for MSCC may be predicted if several prognostic factors are considered.

Purpose: This prospective, nonrandomized study evaluates the effectiveness of epoetin alfa to maintain the hemoglobin levels at 12 to 14 g/dL (optimal range for tumor oxygenation) during chemoradiation for Stage III esophageal cancer and its impact on overall survival (OS), metastatic-free survival (MFS), and locoregional control (LC)., Methods and Materials: Ninety-six patients were included. Forty-two patients received epoetin alfa (150 IU/kg, 3 times a week) during radiotherapy, which was started at hemoglobin less than 13 g/dL and stopped at 14 g/dL or higher. Hemoglobin levels were measured weekly during RT., Results: Both groups were balanced for age, sex, performance status, tumor length/location, histology, grading, T-stage/N-stage, chemotherapy, treatment schedule, and hemoglobin before RT. Median change of hemoglobin was +0.3 g/dL/wk with epoetin alfa and -0.5 g/dL/wk without epoetin alfa. At least 60% of hemoglobin levels were 12 to 14 g/dL in 64% and 17% of the patients, respectively (p < 0.001). Patients who received epoetin alfa had better OS (32% vs. 8% at 2 years, p = 0.009) and LC (67% vs. 15% at 2 years, p = 0.001). MFS was not significantly different (42% vs. 18% at 2 years, p = 0.09)., Conclusions: The findings suggest that epoetin alfa when used to maintain the hemoglobin levels at 12 to 14 g/dL can improve OS and LC of Stage III esophageal cancer patients.

Purpose: To evaluate the outcome of hyperfractionated-accelerated radiotherapy and subsequent planned primary tumor resection and radical neck dissection in locally advanced tumors of the oral cavity., Patients and Methods: This retrospective analysis evaluates 126 subsequent patients who were treated between 1988 and 1997 for locally advanced tumors of the oral cavity (with extension into the oropharynx in 17 patients), 34 (27%) AJCC stage III and 92 (73%) stage IV. Primary tumor and nodal metastases were irradiated with 1.4 Gy bid to a median total dose of 72.8 Gy (range 58.8-75.6 Gy). Then, planned radical surgery of the primary site according to the initial tumor extent and cervical nodes was performed. Median follow-up of living patients was 6 years (range 1-11 years)., Results: 4 weeks after radiotherapy, 14 patients (11%) had complete tumor remission, 92 (73%) partial remission, 15 (12%) no change, and five (4%) progressive disease. Complete resection was achieved in 117 (93%) patients (nine incomplete resections). 5-year locoregional control rate was 62 +/- 9%, overall survival 36 +/- 9%. Surgery-related morbidity occurred in 42 patients (33%; mainly delayed wound healing and fistulae), overall severe treatment-related morbidity in 46 patients (36%). 24/84 relapse-free patients (29%) required a percutaneous gastrostomy or nasal tube > or = 1 year after therapy., Conclusion: In this study, the outcome of combined curative radiotherapy and planned surgery of the primary tumor and neck nodes was comparable to reported results of hyperfractionated radiotherapy with or without salvage surgery of the neck nodes with respect to locoregional control and overall survival. Planned surgery carries a substantial risk of morbidity and seems to offer no benefit in comparison to salvage surgery of the neck nodes only. Therefore, salvage surgery is preferred.

Aims: To evaluate the prognostic value of haemoglobin levels during radio-chemotherapy for overall survival, metastases-free survival (MFS) and locoregional control in patients with locally advanced oesophageal cancer., Materials and Methods: Age, gender, performance status, tumour location, tumour length, histology, histologic grading, T-stage, N-stage, UICC-stage and weekly haemoglobin levels during concurrent radio-chemotherapy were retrospectively investigated and related to outcome in 108 patients, who received radio-chemotherapy for stage II/III oesophageal cancer. Radio-chemotherapy consisted of 59.4-60 Gy irradiation, two to four courses of cisplatin (75 mg/m2 on day 1) and 5-fluorouracil (1000 mg/m2 on days 1-5). Haemoglobin levels during radio-chemotherapy were compared among the following three groups: patients with over 60% of haemoglobin levels less than 12 g/dl; patients with over 60% of haemoglobin levels at 12-14 g/dl; and patients with over 60% of haemoglobin levels greater than 14 g/dl., Results: On univariate analysis, haemoglobin levels of 12-14 g/dl and greater than 14 g/dl during concurrent radio-chemotherapy provided better outcomes than haemoglobin levels less than 12 g/dl. The 2-year overall survival rates were 34%, 35% and 16%, respectively (P = 0.002). The 2-year MFS survival rates were 23%, 46% and 21%, respectively (P = 0.06). The 2-year locoregional control rates were 44%, 58% and 19%, respectively (P < 0.001). ECOG performance status (1 better than 2-3) was significantly associated with overall survival (P = 0.013), tumour length (<7 cm better than > or = 7 cm) with overall survival (P = 0.002) and MFS (P = 0.002), N-stage (N0 better than N1) with overall survival (P = 0.004) and MFS (P < 0.001), and UICC-stage (stage II better than III) with overall survival (P = 0.025) and MFS (P = 0.010). On multivariate analysis, haemoglobin levels during radio-chemotherapy maintained significance for overall survival (P = 0.002) and locoregional control (P < 0.001), tumour length for overall survival (P = 0.002) and MFS (P = 0.008), and N-stage for MFS (P = 0.003)., Conclusions: Haemoglobin during radiotherapy and concurrent radio-chemotherapy is an independent prognostic factor in oesophageal cancer treatment. To improve outcome, it seems important to maintain the haemoglobin at 12-14 g/dl.

Alcohol-based hand rubs are used frequently in healthcare settings, but their tolerance among atopic subjects is unknown. The dermal tolerance to five alcohol-based hand rubs was assessed among atopic and non-atopic subjects in a repetitive occlusive patch test. In total, 54 subjects were analysed. One half of the subjects were atopic (modified Erlanger atopy score > or = 8), the other half were non-atopic. Treatments were controlled with water and 2% sodium dodecyl sulphate (SDS). Treatment sites were assessed by visual inspection (tolerability score 0-4). Skin redness was determined with a chromameter. The overall mean tolerability to all five hand rubs was lower than or identical to the negative control (0.02+/-0.07) and significantly different from the SDS control (0.19+/-0.39). Skin redness was in the same range as for the negative control (0.15+/-0.8) which was significantly lower than the SDS control (1.35+/-1.6). A comparison of the atopic and non-atopic subjects revealed no significant difference. In conclusion, we found that tolerance to the five alcohol-based hand rubs was good among atopic and non-atopic subjects.

The objective of this study is to determine the effect of emollients in a propanol-based hand rub on skin dryness and erythema. In this prospective, randomized, controlled, double-blind trial, 35 subjects participated; of them approximately half were atopic (modified Erlanger atopy score > or =8). 2 propanol-based formulations were tested in a repeated open application test, 1 contained a mixture of emollients (0.81%, w/w). 2 aliquots of 0.7 ml of each formulation were applied twice per day over 2 weeks to the cubital fossa of each subject after random assignment of the preparations. Treatment areas were assessed before each application and 3 days postfinal application by visual inspection for erythema and dryness according to a standard scale. The sum score over all assessment time-points served as primary parameter. The mean sum score for erythema and dryness was significantly lower for the hand rub with emollients (0.8 +/- 2.4) in comparison with that for the hand rub without emollients (1.5 +/- 3.5; P = 0.022; Wilcoxon signed rank test). A comparison of the atopic and non-atopic subjects revealed no significant difference for any of the products (P > 0.05; Mann-Whitney U-test). It is concluded that the addition of emollients to a propanol-based hand rub can significantly decrease irritant contact dermatitis under frequent-use conditions.

Purpose: In a nonrandomized, prospective study the efficacy of radiotherapy with 16 and 20 Gray (Gy) for subfoveal neovascularization in age-related macular degeneration (ARMD) was analysed., Material and Methods: From 1996 to 1998, 63 eyes were irradiated with 16 Gy and 38 eyes with 20 Gy for exudative ARMD. A total of 12 eyes had classic ARMD, 89 eyes occult ARMD, median baseline visual acuity (VA) was 6/30 (range: 3/60-6/9.5), median age was 78 years. Risk factors (type of ARMD, baseline VA) were evenly distributed in both groups. Median follow-up was 1.3 years (range: 4 months-4.7 years). VA of +/-1 line or better and unchanged size and activity of the membrane in fluorescein angiography were defined as stable. Actuarial methods were used., Results: Median loss of VA was -3 lines (range: -14 to +5), neovascularization remained unchanged or decreased in size and activity in 35 eyes. At 18 months, the probability of stabilized VA was 0.4 (95% confidence interval (CI): 0.3-0.5), at 24 months 0.3 (95% CI: 0.2-0.4). Radiation dose, type of ARMD or baseline VA had no significant impact on outcome of VA and membrane size and activity (P>0.05). Side effects were mild and transient increased tearing., Conclusion: In this study, the results after radiotherapy were comparable to the natural course of the disease. An impact of radiation dose (16 vs 20 Gy) on stabilizing visual acuity and subfoveal neovascularization could not be shown. The results of studies on dose escalation using very small fields and high radiation doses should be awaited.

Background and Purpose: Breast irradiation after lumpectomy is an integral component of breast-conserving therapy (BCT). As the prognosis is general good following BCT, late morbidity and cosmesis are important. The present study compares two different radiation schedules with respect to these two endpoints., Patients and Methods: 129 breast cancer patients (pT1-2 pN0-1 cM0) were irradiated between 09/1992 and 08/1994 with either a 22-day fractionation schedule (2.5 Gy to 55 Gy, 4x/week, n = 65) or with a conventional fractionation schedule (28 days, 2.0 Gy to 55 Gy, 5x/week, n = 64), both without additional boost. The equivalent dose of 2-Gy fractions (EQD2) was 55 Gy and 62 Gy, respectively. Late toxicity, assessed according to the LENT-SOMA criteria, and cosmetic outcome, graded on a 5-point scale, were evaluated after a median of 86 months (range 72-94 months) in tumor-free breast cancer patients., Results: LENT-SOMA grade 2/3 toxicity (2.5 Gy vs. 2.0 Gy): breast pain (18% vs. 11%; p = 0.3), fibrosis (57% vs. 16%; p < 0.001), telangiectasia (22% vs. 3%; p = 0.002), atrophy (31% vs. 3%; p < 0.001). Medication to breast pain was taken by 8% versus 9% of patients. Cosmesis was very good/good/acceptable in 75% versus 93% (2.5 Gy vs. 2.0 Gy; p = 0.006)., Conclusion: Late morbidity was significantly frequent and cosmesis was significantly worse after hypofractionated radiotherapy (2.5 Gy to 55 Gy). However, morbidity was not associated with major implications on daily life.

Background and Purpose: Radiation myelopathy is a serious late toxicity after radiotherapy (RT) of metastatic spinal cord compression (MSCC). The risk of myelopathy depends on the equivalent dose in 2-Gy fractions (EQD2). Many radiation oncologists are concerned about spinal Re-RT, because it may result in a high cumulative EQD2. This study investigates effectiveness and feasibility of Re-RT for in-field recurrence of MSCC., Patients and Methods: 74 patients, irradiated between 01/1995 and 12/2003 for MSCC, were reirradiated for in-field recurrence of MSCC (Table 1). Primary RT was performed with 1 x 8 Gy (n = 34), 5 x 4 Gy (n = 28), 10 x 3 Gy (n = 4), 15 x 2.5 Gy (n = 4), or 20 x 2 Gy (n = 4). Recurrence occurred after median 6 months (2-40 months). Re-RT was performed with 1 x 8 Gy (n = 35), 5 x 3 Gy (n = 16), 5 x 4 Gy (n = 13), 10 x 2 Gy (n = 4), 12 x 2 Gy (n = 3), or 17 x 1.8 Gy (n = 3). Cumulative EQD2 (alpha/beta = 2 Gy) was 39-40 Gy (n = 21), 49-50 Gy (n = 41), 56-60 Gy (n = 6), or > 60 Gy (n = 6). Follow-up after Re-RT was median 9 months (2-52 months)., Results: Re-RT led to an improvement of motor function in 29/74 patients (39%; Figures 1 to 3). On multivariate analysis, outcome was significantly influenced by type of primary tumor (p = 0.013) and by the time of developing motor deficits before Re-RT (p = 0.037), but not by radiation schedule (p = 0.560), by ambulatory status before Re-RT (p = 0.471), by cumulative EQD2 (p = 0.795), nor by the interval between primary RT and Re-RT (p = 0.420; Table 2). Radiation myelopathy was not observed in the whole series., Conclusion: Re-RT is an effective treatment for an in-field recurrence of MSCC. After a cumulative EQD2 < or = 50 Gy, radiation myelopathy appears unlikely.

Background and Purpose: Analysis of treatment results of combined three-dimensional conformal radiotherapy (3DCRT) and hormonal therapy in patients with locally recurrent prostate cancer after radical prostatectomy., Patients and Methods: Between 1992 and 1998, 24 patients presented with a rising prostate-specific antigen (PSA) between 4 and 152 months following radical prostatectomy and a local recurrence demonstrated by imaging. Recurrence was biopsy-proven in 13 cases. All patients were treated with 3DCRT to a total dose of 60-70 Gy. 21 patients (88%) received adjuvant hormone therapy up to a maximum of 6 months., Results: All patients showed a response in PSA values after therapy. Median follow-up is 43 months. Overall survival is 80% and 67% at 3 and 5 years, respectively. Biochemical control rates are 53% and 38% at 3 and 5 years, respectively. 14 patients developed a second PSA relapse. Acute and late toxicities, classified with the RTOG score, were moderate., Conclusion: Radiotherapy and short-term adjuvant hormone therapy represent an effective and well-tolerated treatment for locally recurrent prostate cancer after radical prostatectomy resulting in good local control. Long-term prognosis in terms of biochemical control and disease-specific survival remains poor.

Purpose: Since life expectancy is markedly reduced in patients with metastatic spinal cord compression (MSCC), a short and effective radiation schedule is desired. This study investigates a reduction of the overall treatment time to only one day by comparing 1 x 8 Gy to the multi-fractionated 10 x 3 Gy for functional outcome., Methods and Materials: Data of 204 patients, treated for MSCC with either 1 x 8 Gy (n = 96) or 10 x 3 Gy (n = 108), were analyzed retrospectively. Motor function and ambulatory status were evaluated before and up to 24 weeks after RT. A multivariate analysis (nominal regression) was performed including radiation schedule, performance status, age, irradiated vertebra, and relevant prognostic factors (histology, ambulatory status, time of developing motor deficits). Improvement of motor deficits was selected as basic category and compared with no change and deterioration., Results: Univariate analysis showed no significant difference between the schedules for post-treatment motor function and ambulatory rates. Multivariate analysis demonstrated a significant effect on functional outcome for the prognostic factors, but not for the radiation schedule (p = 0.853 for no change, p = 0.237 for deterioration)., Conclusions: Our data suggest the two fractionation schedules to be comparably effective for functional outcome. Thus, 1 x 8 Gy should be considered for patients with a poor survival prognosis.

Refinement in procedures to assess skin surface water loss (SSWL) dynamics of the vulvar skin on a large sample of subjects (60) is described and compared to another semi-occluded skin site, the inner thigh. Vulvar SSWL significantly decreased over a 30-min period from 46.2 +/- 2.6 (SE) to 24.7 +/- 1.6 g m(-2) h (p < 0.001). The inner thigh, another semi-occluded region, showed no similar pattern for SSWL (6.2 +/- 0.3 to 6.6 +/- 0.5 g m(-2) h), and the values were significantly less than those for vulvar skin. There was no significant effect of age, body mass index or atopic status on vulvar SSWL., (Copyright 2005 S. Karger AG, Basel.)

Purpose: To establish a grading system for mammographic fibrosis and correlate it with clinical fibrosis., Patients and Methods: Analogous to the LENT/SOMA scale a four-tiered scoring scale of breast fibrosis in mammography (G0 = absent, G1 = barely increased density, G2 = definitely increased density to G3 = very marked density) was established by two observers in a group of 16 patients. Reference mammograms were selected. Independently and blinded to clinical results, three observers scored the fibrosis in mammograms of further 31 patients examined by one radiation oncologist in a cross-sectional follow-up study. Pretreatment parenchyma density was judged according to the American College of Radiology (ACR). Interobserver correlation of mammography scoring as well as correlation of mammography and clinical findings were calculated with Cohen's weighted kappa. All patients had breast-conserving surgery and axillary resection for breast carcinoma T1-2N0-1. The breast was irradiated to a median reference dose of 55 Gy (range 50-60 Gy) with 2 Gy five times weekly or 2.5 Gy four times weekly. Two patients received chemotherapy, 14 patients tamoxifen. Median age was 55 years, median follow-up 8 years (4-15 years)., Results: 14 of 31 patients had clinical fibrosis, twelve G1 and two G2. In mammography, mild fibrosis (G1) was seen in 12/12/18 patients (observer 1/2/3) and moderate fibrosis (G2) in 9/10/2 patients. Interobserver correlation for observers 1 and 2 who had developed the score was fair (Cohen's weighted kappa 0.64, 95% confidence interval 0.4-0.88). However, it was weak for observer 3 (0.36 and 0.42, respectively) who relied on reference mammograms only. Independent interobserver correlation of pretreatment breast density was good for all observers (Cohen's weighted kappa 0.73-0.8). The correlation of fibrosis by mammography and palpation was weak (Cohen's weighted kappa 0.32-0.42)., Conclusion: Grading fibrosis as depicted by mammography is possible, especially if observers prepare by jointly analyzing a training group. It may be useful to study treatment effects, e. g., of fractionation or drugs, because retrospective and repeated analysis is possible. The correlation of mammography with clinical grading should be further evaluated with more objective clinical reference tools.

Toxicity and functional outcome were evaluated in 199 MSCC-patients irradiated with 1 x 8 Gy. Motor function improved in 54/199 patients (27%). Patients who regained walking ability were 20/78 (26%). Long-term-survivors (> or =12 months) who needed re-irradiation for in-field-recurrence were 19/65 (29%). Acute toxicity was mild, late toxicity not observed. A randomised trial comparing single-fraction RT to multi-fraction RT is mandatory.

Purpose: Analysis of the efficacy of fast neutron radiotherapy in the treatment of adenoid cystic carcinomas (ACC) of the salivary glands, identification of prognostic variables and dedifferentiation after radiotherapy., Patients and Methods: Histological slides of primary and recurrent lesions of 71 patients were reviewed to confirm the diagnosis and to analyse subtypes. Median follow-up was 52 months. Local control rate and overall survival were analysed in multivariate analysis. Complications are also described., Results: Primary vs. recurrent therapy (p=0.001), margin-status (p=0.01) and subtype (p=0.019) influenced overall survival. Primary vs. recurrent therapy (p=0.001), margin-status (p=0.018) and T-stage (p=0.043) influenced local control rate. Dedifferentiation was seen in only 1/17 cases., Conclusion: The calculated prognostic factors illustrate the importance of a radical primary therapy. Histological subtype is a significant additional factor for overall survival and, in case of dedifferentiation, it is a strong predictor of a detrimental outcome.

Most neurocytomas are well differentiated, being associated with better long-term survival than the more aggressive atypical lesions. Atypical neurocytomas are characterized by an MIB-1 labeling index >3% or atypical histologic features. This analysis focuses on well differentiated neurocytomas in order to define the optimal treatment. A case with a follow-up of 132 months is presented. The patient developed two recurrences two and four years after first surgery, each showing an increasing proliferation activity. Furthermore, all published well-differentiated neurocytoma cases were reviewed for surgery, radiotherapy, and prognosis. Additional relevant data were obtained from the authors. Complete resection (CTR), complete resection plus radiotherapy (CTR + RT), incomplete resection (ITR), and incomplete resection plus radiotherapy (ITR + RT) were compared for outcome by using the Kaplan-Meier method and the log-rank test. Data were complete in 301 patients (CTR, 108; CTR + RT, 27; ITR, 81; ITR + RT, 85). Local control and survival were better after CTR than after ITR (P < 0.0001 and P = 0.0085, respectively). Radiotherapy improved local control after ITR (P < 0.0001) and after CTR (P = 0.0474), but not survival (P = 0.17 and P = 1.0, respectively). In the ITR + RT group, doses < or =54 Gy (n = 33) and >54 Gy (n = 32) were not significantly different for local control (P = 0.88) and survival (P = 0.95). The data demonstrated CTR to be superior to ITR for local control and survival. After CTR and ITR, radiotherapy improved local control, but not survival. A radiation dose of 54 Gy appeared sufficient. Application of postoperative radiotherapy should be decided individually, taking into account the risk of local failure, the need for another craniotomy, and potential radiation toxicity.

Adaptation of the skin to repeated influence of exogenous irritants is called the hardening phenomenon. We investigated the stratum corneum lipid composition before and after induction of a hardening phenomenon. Irritant contact dermatitis was induced in 23 non-atopic volunteers by repeated occlusive application of 0.5% sodium lauryl sulfate (SLS) over 3 weeks. At 3, 6 and 9 weeks after irritation, the SLS responses of pre-irritated skin and normal skin were compared. The horny layer lipid composition (ceramides 1-7, cholesterol and free fatty acids) was assessed before irritation and 3, 6 and 9 weeks after irritation. During the first 2 weeks of irritation the transepidermal water loss increased continuously and seemed to decrease during the third week (effect of adaptation). The barrier function of pre-irritated sites was more stable to SLS challenge. Three weeks after irritation, there was a significant increase of ceramide 1 (p<0.001). The only volunteer without hardening phenomenon showed no increase of ceramide 1. Ceramide 1 seems to play a key role as a protection mechanism against repeated irritation.

Background: The optimal treatment of patients with metastatic spinal cord compression (MSCC) is still being debated. The current observational multicenter study, performed prospectively by the authors, evaluated two radiotherapy (RT) schedules and prognostic factors with respect to functional outcome, Methods: In the current study, 214 patients with MSCC were irradiated between April 2000 and September 2003 with 30 gray (Gy) per 10 fractions per 2 weeks (n = 110) or with 40 Gy per 20 fractions per 4 weeks (n = 104). Motor function and ambulatory status were evaluated before RT and until 6 months after RT. The following potential prognostic factors were investigated: RT schedule, performance status, age, number of irradiated vertebrae, type of primary tumor, pretreatment ambulatory status, and length of time developing motor deficits before RT., Results: Both groups were balanced for patient characteristics and potential prognostic factors. Motor function improved in 43% of patients after 30 Gy and in 41% of patients after 40 Gy (P = 0.799). Posttreatment ambulatory rates were 60% and 64% (P = 0.708), respectively. A multivariate analysis demonstrated that a slower progression of motor deficits before RT (P < 0.001), a favorable histology of the primary tumor (P < 0.001), and being ambulatory before RT (P = 0.035) were associated with a better functional outcome. RT schedule (P = 0.269) and other variables had no significant impact. Acute toxicity was mild, and late toxicity was not observed during the period of follow-up. Follow-up was 12 (6-28) months in patients surviving >/= 6 months., Conclusions: Thirty gray per 10 fractions was preferable to 40 Gy per 20 fractions, because it was associated with similar outcome, less treatment time, and lower costs. The type of tumor, pretreatment ambulatory status, and length of time developing motor deficits before RT were relevant prognostic factors and should be considered in future studies., ((c) 2004 American Cancer Society)

Purpose: To investigate magnetic resonance imaging (MRI) features of radiation-induced plexopathy (RIP) and radiation-induced fibrosis frequently associated with RIP., Patients and Methods: Seven patients with late radiation sequelae in the supraclavicular region were examined with MRI after a median interval of 7 years (range, 5-18 years) following radiotherapy and 4-7 years after the onset of RIP. Four patients had RIP plus severe soft-tissue fibrosis, two RIP without soft-tissue fibrosis (n = 2/6), and one patient fibrosis without RIP. Patients underwent surgery of breast cancer (n = 6) or chest wall relapse (n = 1) and radiotherapy to the supraclavicular fossa with cobalt with an anterior portal in fractions of 1.7-2.6 Gy to 43-51.6 Gy in 3 cm depth. All patients were relapse-free at the time of MRI. Fibrosis and RIP were scored clinically (RTOG classification). Fibrosis of the supraclavicular and/or axillary region was marked in three and mild in two patients. RIP was mild, marked and severe in two patients each. MRI was performed with a 1.5-T unit including coronal STIR, coronal and transversal T2-weighted, transversal T1-weighted and fat-saturated post-contrast (gadolinium-DTPA) spin echo sequences., Results: The brachial plexus appeared normal in all patients, but subtle changes of adjoining tissue (slight, linear signal intensity in T2-weighted images or contrast enhancement surrounding the plexus) were detected in patients with RIP (n = 4/6) and the patient without RIP (n = 1). However, alterations of the soft tissue (marked signal intensity in T2-weighted sequences) correlated well with the clinical degree of fibrosis and were restricted to areas of marked to severe fibrosis (n = 3/3)., Conclusion: Reliable MRI signs of RIP could not be identified. The severity of fibrosis closely corresponded to MRI features. The role of MRI in the diagnostic work-up of RIP is, therefore, the exclusion of tumor relapse.

Background: This prospective multi-center study investigates a reduction of the overall treatment time for radiotherapy of MSCC, which is important for these mostly disabled patients., Patients and Methods: Two standard fractionation schedules, 30 Gy/10 fractions/2 weeks (n = 71) and 40 Gy/20 fractions/4 weeks (n = 65) were compared for functional outcome and ambulatory status. Motor function was graded using an 8-point-scale before RT, at the end and at 6, 12 and 24 weeks after RT. A multi-variate analysis was performed for functional outcome. Included variables were the fractionation schedule and the three relevant prognostic factors. These factors are the type of primary tumor, the time of developing motor deficits before RT and the pre-treatment ambulatory status., Results: The ambulatory rates were 49% in the 30 Gy group and 52% in the 40 Gy group before RT (P = 0.888), and 56% and 60% after RT (P = 0.888). Improvement of motor function occurred in 45% of the 30 Gy group and 40% of the 40 Gy group (P = 0.752). The relevant prognostic factors were comparably distributed in both groups. According to the multivariate analysis, a slower development of motor deficits (P < 0.001), a favorable histology (P = 0.040) and being ambulatory (P = 0.045) were associated with better functional outcome, whereas the fractionation schedule had no significant impact (P = 0.311)., Conclusions: The data suggest both schedules to be comparably effective for functional outcome. Thus, 30 Gy/10 fractions/2 weeks should be applied instead of 40 Gy/20 fractions/4 weeks. The reduction of the overall treatment time from 4 to 2 weeks means less discomfort for the paraparetic or paraplegic patient.

Recently, it has been reported that brachytherapy catheters ruptured in vivo. Localization of lost beta-radiation-emitting seeds is a problem because no appropriate technique is available that is rapid and precise. We developed a technique to localize beta-emitting seeds utilizing the effect that beta-radiation induces bremsstrahlung. The loss of a single radioactive source was simulated in an Alderson Phantom representing a human body. The beta-induced bremsstrahlung could be detected selectively by a gamma-camera. The position of the radioactive seed could be located within 5 min with an accuracy of +/- 0.5 cm. The result of this study suggests that in an emergency case of loss of a brachytherapy source, a commercially available gamma-camera can be a valuable tool to detect lost beta-radiation-emitting seeds rapidly and precisely. In addition, the technique minimizes the patient's as well as the surgeon's exposure to radiation and reduces the extent of surgical trauma., (Copyright 2004 Wiley-Liss, Inc.)

In a clinical study, the skin penetration properties of melatonin 0.01% in a cream and 0.01 and 0.03% in a solution were investigated by evaluation of the serum melatonin levels over a 24-hour time course in 15 healthy volunteers. Blood samples for melatonin measurements were taken at 9.00 a.m. before applying the test preparations and 1, 4, 8 and 24 h after application. The measurements were carried out by radioimmunoassay for melatonin. In 15 volunteers, the serum levels of melatonin before application of the topical preparations were between 0.6 and 15.9 pg/ml. After application of the 0.01% melatonin cream, there was a steady increase starting from 9.00 a.m. up to a mean serum value of 9.0 pg/ml at 9.00 a.m. the next day. The solution of 0.01% melatonin also showed an increase, starting from 5.00 p.m., up to a mean melatonin level of 12.7 pg/ml 24 h after application. The solution containing 0.03% melatonin resulted in elevated melatonin levels 1 and 8 h after application. The values were 18.1 and 19.0 pg/ml. The cumulative melatonin values for each preparation were 7.1, 8.6 and 15.7 pg/ml, respectively. This study shows that the strongly lipophilic substance melatonin is able to penetrate through the skin and leads to dose- and galenic-dependent melatonin levels in the blood. No increase of melatonin above the physiological range was observed.

Purpose: To determine the sensitivity and specificity of 18F-fluorodeoxyglucose-positron-emission tomography (FDG-PET) in the diagnosis of R1H tumours after fractionated radiotherapy, and the dependency of sensitivity and specificity on time after therapy. In addition, the time benefit of FDG-PET concerning early recognition of recurrences after fractionated radiotherapy was assessed., Material and Methods: Subcutaneously growing rat rhabdomyosarcoma R1H tumours were irradiated by applying total doses of 80 or 85 Gy after reaching a start volume of 0.8 cm3. Twenty animals were treated. Tumour volume was determined twice a week. FDG-PET was performed weekly before, during and for 6 months after therapy using a conventional full-ring whole-body PET scanner. In total, 600 PET results were evaluated qualitatively using a six-scale score. PET results and actual tumour volumes were compared. The sensitivity and specificity of tumour detection by PET was calculated for different times after the onset of therapy. The optimal score for tumour detection and the influence of time after therapy on the quality of PET (time benefit) was evaluated using receiver-operating characteristics., Results: After irradiation, 8/20 tumours (40%) were locally controlled, while 12/20 recurred. In this tumour model, evidence of relapse is assured when a volume of 0.1 cm3 is reached. Sensitivity of tumour diagnosis by PET increases with time, i.e. with the volume of recurrent tumours after the onset of therapy, mounting to > 0.95 after 100 days. Specificities of 0.95-1.0 were determined after therapy, showing no increase with time. Tumour diagnosis by PET is highly accurate when performed 80 days after the start of treatment. On average, tumours were recognized by PET on 31, 62, 74 and 81 days (median) before approaching volumes of 0.2, 0.5, 0.8 or 1.0 cm3, respectively., Conclusion: An experimental system was implemented that allows reproducible detection of recurrent R1H tumours after radiotherapy using FDG-PET. The usefulness of PET as a diagnostic test for R1H tumours is very good and a reliable resolution for PET is demonstrated for volumes < 1 cm3. The results indicate that FDG-PET enables early recognition of recurrences after fractionated radiotherapy.