Radiological assessment of response and adverse events associated with novel systemic oncological therapies.

The last decade has seen a paradigm shift in medical oncology treatment with the rise of novel systemic agents, principally molecular targeted therapy and immunotherapy. These new groups of anti-cancer treatment have revolutionised the prognostic landscape for certain patient cohorts with advanced disease, and it is hoped that through ongoing extensive clinical research, significant survival benefits may be demonstrated in the majority of tumour types. However, radiological response assessment of these new agents has become more nuanced for radiologists, as the behaviour of both responding and progressing tumour burden can be more diverse than with conventional chemotherapy. Additionally, radiologists need to be aware of adverse events associated with these treatments as some side effects carry a high morbidity/mortality and may manifest radiologically before they become clinically apparent. This review discusses radiological response assessment and adverse events associated with these novel agents, which have become fundamental aspects of systemic oncological therapy.

[Practical guidelines to ensure the quality of compounded preparations in community pharmacies]. / Directives pratiques pour garantir la qualité des preparations magistrales à l'officine.

Compounded preparations are an additional therapeutic option besides registered medicines. Because of their <> they have a great value and thus an undeniable place in the therapeutic arsenal available to the physician. To maintain this position, however, they must be of unquestionable quality. Structuring and documenting the compounding operations, incorporating the necessary controls and respect for evident basic rules and precautions can reduce potential errors to a minimum. Pharmacists can rely for this on existing recommendations listed in the different reference books such as the Therapeutic Magistral Form and the Guidelines for Good Officinal Practices, but which aren't always commonly used by pharmacists.

Overview of skin whitening agents with an insight into the illegal cosmetic market in Europe.

Lightening skin tone is an ancient and well-documented practice, and remains common practice among many cultures. Whitening agents such as corticosteroids, tretinoin and hydroquinone are medically applied to effectively lighten the skin tone of hyperpigmented lesions. However, when these agents are used cosmetically, they are associated with a variety of side-effect. Alternative agents, such as arbutin and its derivatives kojic acid and nicotinamide have been subsequently developed for cosmetic purposes. Unfortunately, some cosmetics contain whitening agents that are banned for use in cosmetic products. This article provides an overview of the mode of action and potential side-effects of cosmetic legal and illegal whitening agents, and the pattern of use of these types of products. Finally, an EU analysis of the health problems due to the presence of illegal products on the market is summarized.

Practical problems encountered during the cultivation of an open-source reconstructed human epidermis model on a polycarbonate membrane and protein quantification.

During recent years, the importance of in vitro technology in skin research has increased significantly. A variety of skin culture models have been developed and commercialized. In this respect, the availability of reconstructed human epidermis (RHE) equivalents represents a significant improvement compared to the use of monolayer cultures. However, when an in-house RHE model is being developed, researchers might encounter some difficulties during cultivation. The scope of this paper is to report our experiences and practical problems with the development of a three-dimensional RHE model cultured on a polycarbonate membrane. Some important issues including cell density, the use of lysing enzymes, culture media, cell storage and viability, cell confluency and protein extraction are reported and optional solutions are given.

Current status of healthy human skin models: can histone deacetylase inhibitors potentially improve the present replacement models?

Histone deacetylase inhibitors (HDACi), a relatively new group of epigenetic agents, are being investigated as powerful chemotherapeutics because of their antiproliferative and prodifferentiation effects both in vitro and in vivo, in various tumor cell lines. Only little is known with respect to their effects on normal cells. Yet, to understand tissue pathology and evaluate potential effects of new chemical entities in tissue homeostasis, insight into the physiology of healthy tissue is necessary. Therefore, this review addresses the effects of HDACi on healthy human primary skin cell cultures and three-dimensional epidermal models. In general, HDACi exert an effect on both the epidermal morphology and differentiation process of human skin. The latter is manifested through cell cycle arrest, disorganization of the basal layer, thinning of the stratum spinosum and thickening of the stratum corneum, reorganization of the cytoskeleton and increased formation of cornified envelopes. This overview shows that, although only a limited number of reports exist, these molecules might be an interesting tool for the development and study of new human skin models.

Silicones as nonocclusive topical agents.

BACKGROUND/AIMS: Silicone excipients are commonly used ingredients because of their emollient and skin-conditioning effects, and their ability to form uniform, water-resistant, yet permeable films. Based on comparisons with organic materials and conflicting knowledge from silicones used in scar treatment, the misconception still exists that silicone topical excipients are occlusive substances that may block the passive loss of water through the upper skin layers. Therefore, 3 types of common silicone excipients and 3 water-in-(oil-plus-silicone) or W/(O + Si) creams, containing 10% (w/w) of the respective silicones, were investigated as a function of time and compared to petrolatum. METHODS: Transepidermal water loss (TEWL) and skin hydration measurements were carried out after a single topical application on forearm skin of 26 healthy young female volunteers. RESULTS: Both petrolatum and silicones significantly decreased TEWL 15 min after application, but the measurements for the silicones were not significantly different from the untreated control values. The tested silicones did not moisturize the skin. Petrolatum formed an occlusive layer, creating an increase in skin hydration for more than 4 h. The results measured for the W/(O + Si) creams indicated that they moisturized the skin, without any effect on TEWL. CONCLUSION: A clear difference was shown between the skin occlusive properties of petrolatum and the water vapor permeability of the common silicone excipient materials.

An Inter-observer Study to Determine Radiotherapy Planning Target Volumes for Recurrent Gynaecological Cancer Comparing Magnetic Resonance Imaging Only With Computed Tomography-Magnetic Resonance Imaging.

AIMS: Target delineation uncertainty is arguably the largest source of geometric uncertainty in radiotherapy. Several factors can affect it, including the imaging modality used for delineation. It is accounted for by applying safety margins to the target to produce a planning target volume (PTV), to which treatments are designed. To determine the margin, the delineation uncertainty is measured as the delineation error, and then a margin recipe used. However, there is no published evidence of such analysis for recurrent gynaecological cancers (RGC). The aims of this study were first to quantify the delineation uncertainty for RGC gross tumour volumes (GTVs) and to calculate the associated PTV margins and then to quantify the difference in GTV, delineation uncertainty and PTV margin, between a computed tomography-magnetic resonance imaging (CT-MRI) and MRI workflow. MATERIALS AND METHODS: Seven clinicians delineated the GTV for 20 RGC tumours on co-registered CT and MRI datasets (CT-MRI) and on MRI alone. The delineation error, the standard deviation of distances from each clinician's outline to a reference, was measured and the required PTV margin determined. Differences between using CT-MRI and MRI alone were assessed. RESULTS: The overall delineation error and the resulting margin were 3.1 mm and 8.5 mm, respectively, for CT-MRI, reducing to 2.5 mm and 7.1 mm, respectively, for MRI alone. Delineation errors and therefore the theoretical margins, varied widely between patients. MRI tumour volumes were on average 15% smaller than CT-MRI tumour volumes. DISCUSSION: This study is the first to quantify delineation error for RGC tumours and to calculate the corresponding PTV margin. The determined margins were larger than those reported in the literature for similar patients, bringing into question both current margins and margin calculation methods. The wide variation in delineation error between these patients suggests that applying a single population-based margin may result in PTVs that are suboptimal for many. Finally, the reduced tumour volumes and safety margins suggest that patients with RGC may benefit from an MRI-only treatment workflow.

Skin efficacy and biophysical assessment of glycerol-containing hydrocolloid patches.

Hydrocolloid patches are developed with 10, 20 and 30% (w/w) glycerol as the main active ingredient. By making use of two experimental forearm models, skin efficacy and its dependency on the glycerol concentration applied were compared with a blank reference patch, a commercialized protective patch and a cosmetic barrier cream. Skin hydration and transepidermal water loss measurements were combined with skin erythema assessments. After a single application to healthy skin, a clear concentration-dependent effect of glycerol-containing patches was observed with - for the highest glycerol content - a 31% increase in skin hydration and an improvement in skin barrier properties of 15%. This glycerol-containing patch also accelerated barrier recovery of mechanically irritated skin after stripping with cyanoacrylate tape. After 7 days of repetitive application, a significantly hydrating effect of the 30% glycerol-containing patch was observed, which was of the same order of magnitude as observed for the cosmetic barrier cream, the latter being applied twice daily. The effects seen were maximal after 3 days of patch application.

Seasonal effects on the nasolabial skin condition.

In the present work, nasolabial skin condition and the influence of seasonal changes during autumn and winter were studied in 16 healthy female volunteers. Apart from visual scoring of erythema and skin scaliness, transepidermal water loss (TEWL), skin hydration, apparent skin pH, skin colour and skin desquamation were biophysically measured. The study results showed that nasolabial TEWL was significantly higher during wintertime than in autumn. Also skin colour measurements and squamometry scorings revealed higher values, indicating a more reddish and scaly nasolabial skin during winter compared to autumn. Results from tape stripping and skin surface lipid analysis by high-performance thin-layer chromatography demonstrated significant differences for triglycerides and cholesterol esters, indicating a functionally inferior hydrolipidic layer during the winter season.

LEKTI-1 in sickness and in health.

The stratum corneum (SC) is a biosensor that mediates responses to a variety of exogenous insults through various signalling mechanisms, including the activation of SC serine proteases (SP) kallikrein cascade. The SPINK5 gene encodes an SP inhibitor, the lympho-epithelial-Kazal-type-1 inhibitor (LEKTI-1), which in turn will buffer the excess of SP cascade initiation, key in the maintenance of permeability barrier homeostasis. We demonstrate that LEKTI processing can occur within the SC after secretion from stratum granulosum keratinocytes at least partially by klk7, an SC-specific chymotryptic SP. Unlike the recently described LEKTI-2, neither recombinant full-length LEKTI-1 nor recombinant LEKTI-1 fragments exhibit antimicrobial activity. Finally, we discuss the pathophysiological implications of LEKTI-1 in skin biology as well as its contribution to the pathogenesis of Netherton Syndrome and its potential involvement in atopic dermatitis.

[Pharmacy compounding of an omeprazole suspension]. / Preparation magistrale d'une suspension d'omeprazole.

The problems of preparation of different pharmaceutically compounded formulations of prescribed omeprazole suspensions are discussed. Problems that can be cited are: inadequate preparation, chemical and physical stability problems, taste problems and low bioavailability. The formulation of the omeprazole suspension is optimized, taking into account the cited problems. At the same time, some formulations are presented, ensuring chemical stability of omeprazole and its bioavailability.

Epidermal ceramidase activity regulates epidermal desquamation via stratum corneum acidification.

The acidic pH of the outer surface of the mammalian skin plays several important roles in the epidermal barrier function. The 2 endogenous pathways that are currently known to elicit this acidic pH are the generation of free fatty acids from phospholipids and the exchange of protons for sodium ions by non-energy-dependent sodium-proton exchangers. In this study, we propose a third endogenous pathway, i.e. epidermal ceramidase activity, generating free fatty acids from ceramides. By topical application of N-oleylethanolamine, a well-known ceramidase inhibitor, we could demonstrate a significant increase in the stratum corneum pH and a corresponding decrease in the epidermal free fatty acid content. Moreover, we could show that the resulting change in the apparent skin pH also provoked a delay in early barrier recovery and an increased epidermal desquamation, corresponding to earlier observations made for the already known endogenous mechanisms.

Effect of oral intake of choline-stabilized orthosilicic acid on skin, nails and hair in women with photodamaged skin.

Chronic exposure of the skin to sunlight causes damage to the underlying connective tissue with a loss of elasticity and firmness. Silicon (Si) was suggested to have an important function in the formation and maintenance of connective tissue. Choline-stabilized orthosilicic acid ("ch-OSA") is a bioavailable form of silicon which was found to increase the hydroxyproline concentration in the dermis of animals. The effect of ch-OSA on skin, nails and hair was investigated in a randomized, double blind, placebo-controlled study. Fifty women with photodamaged facial skin were administered orally during 20 weeks, 10 mg Si/day in the form of ch-OSA pellets (n=25) or a placebo (n=25). Noninvasive methods were used to evaluate skin microrelief (forearm), hydration (forearm) and mechanical anisotropy (forehead). Volunteers evaluated on a virtual analog scale (VAS, "none=0, severe=3") brittleness of hair and nails. The serum Si concentration was significantly higher after a 20-week supplementation in subjects with ch-OSA compared to the placebo group. Skin roughness parameters increased in the placebo group (Rt:+8%; Rm: +11%; Rz: +6%) but decreased in the ch-OSA group (Rt: -16%; Rm: -19%; Rz: -8%). The change in roughness from baseline was significantly different between ch-OSA and placebo groups for Rt and Rm. The difference in longitudinal and lateral shear propagation time increased after 20 weeks in the placebo group but decreased in the ch-OSA group suggesting improvement in isotropy of the skin. VAS scores for nail and hair brittleness were significantly lower after 20 weeks in the ch-OSA group compared to baseline scores. Oral intake of ch-OSA during the 20 weeks results in a significant positive effect on skin surface and skin mechanical properties, and on brittleness of hair and nails.

HS-GC-MS method for the analysis of fragrance allergens in complex cosmetic matrices.

Potential allergenic fragrances are part of the Cosmetic Regulation with labelling and concentration restrictions. This means that they have to be declared on the ingredients list, when their concentration exceeds the labelling limit of 10 ppm or 100 ppm for leave-on or rinse-off cosmetics, respectively. Labelling is important regarding consumer safety. In this way, sensitised people towards fragrances might select their products based on the ingredients list to prevent elicitation of an allergic reaction. It is therefore important to quantify potential allergenic ingredients in cosmetic products. An easy to perform liquid extraction was developed, combined with a new headspace GC-MS method. The latter was capable of analysing 24 volatile allergenic fragrances in complex cosmetic formulations, such as hydrophilic (O/W) and lipophilic (W/O) creams, lotions and gels. This method was successfully validated using the total error approach. The trueness deviations for all components were smaller than 8%, and the expectation tolerance limits did not exceed the acceptance limits of ± 20% at the labelling limit. The current methodology was used to analyse 18 cosmetic samples that were already identified as being illegal on the EU market for containing forbidden skin whitening substances. Our results showed that these cosmetic products also contained undeclared fragrances above the limit value for labelling, which imposes an additional health risk for the consumer.

Microrelief of the skin using a light transmission method.

The recently developed Skin Visiometer, based on light transmission through blue-coloured silicone replicas, was used to study skin microrelief. Calibrated metal plates displaying lines with depths between 6 and 361 microns, were used to determine the accuracy, sensitivity and reproducibility of the technique as well as the parameters of importance during measurement. The precision of the measurements was particularly good between 10 microns and 361 microns. The sensitivity of the method was between 10 and 20 microns. Replicas of volar forearm skin were taken from four groups (n = 15) of male and female volunteers in the age ranges 20 to 30 years and 55 to 65 years. In addition to the instrumental roughness parameters (Rz, Rt, Rm and Ra), the surface of the furrows, the number of primary and secondary lines and the number of intersections were determined. For both sexes, significantly lower values were observed for Rz, Rm and Rt in the younger age group than in the older age group. In addition, the numbers of primary and secondary lines and the number of intersections were higher, pointing to a more structured microrelief in younger forearm skin. Diurnal rhythm, the relative humidity of the measuring room and the position of the forearm were found to be significant factors, while room temperature and precleansing of the skin with mild products were not. Following the application of a hydrating cream (twice daily for 14 days) to the forearm skin of the older female age group, the Rz, Rt, Rm and Ra decreased, while the other parameters measured, except for the surface taken in by the lines, increased, indicating that the microrelief was modified towards the typical pattern observed in young skin.

Characterization of suspected illegal skin whitening cosmetics.

An important group of suspected illegal cosmetics consists of skin bleaching products, which are usually applied to the skin of the face, hands and décolleté for local depigmentation of hyper pigmented regions or more importantly, for a generalized reduction of the skin tone. These cosmetic products are suspected to contain illegal active substances that may provoke as well local as systemic toxic effects, being the reason for their banning from the EU market. In that respect, illegal and restricted substances in cosmetics, known to have bleaching properties, are in particular hydroquinone, tretinoin and corticosteroids. From a legislative point of view, all cosmetic products containing a prohibited whitening agent are illegal and must be taken off the EU market. A newly developed screening method using ultra high performance liquid chromatography-time off flight-mass spectrometry allows routine analysis of suspected products. 163 suspected skin whitening cosmetics, collected by Belgian inspectors at high risk sites such as airports and so-called ethnic cosmetic shops, were analyzed and 59% were classified as illegal. The whitening agents mostly detected were clobetasol propionate and hydroquinone, which represent a serious health risk when repeatedly and abundantly applied to the skin.

Development and validation of a fast chromatographic method for screening and quantification of legal and illegal skin whitening agents.

During the last years, the EU market is flooded by illegal cosmetics via the Internet and a so-called "black market". Among these, skin-bleaching products represent an important group. They contain, according to the current European cosmetic legislation (Directive 76/768/EEC), a number of illegal active substances including hydroquinone, tretinoin and corticosteroids. These may provoke as well local as systemic toxic effects, being the reason for their banning from the EU market. To control this market there is a need for a fast screening method capable of detecting illegal ingredients in the wide variety of existing bleaching cosmetic formulations. In this paper the development and validation of an ultra high pressure liquid chromatographic (UHPLC) method is described. The proposed method makes use of a Waters Acquity BEH shield RP18 column with a gradient using 25 mM ammonium borate buffer (pH 10) and acetonitrile. This method is not only able to detect the major illegal (hydroquinone, tretinoin and six dermatologic active corticosteroids) and legal whitening agents, the latter having restrictions with respect to concentration and application (kojic acid, arbutin, nicotinamide and salicylic acid), but can also quantify these in a run time of 12 min. The method was successfully validated using the "total error" approach in accordance with the validation requirements of ISO-17025. During the validation a variety of cosmetic matrices including creams, lotions and soaps were taken into consideration.