Hedgehog- and mTOR-targeted therapies for advanced basal cell carcinomas.

Basal cell carcinomas (BCCs) are the most frequent human cancer. Over 90% of all BCCs have a mutation in PTCH1 or smoothened, two conducting proteins of the Hedgehog pathway. They rarely progress deeply and metastasize; however, if they do, these advanced basal cell carcinoma become amenable to treatment by inhibiting the Hedgehog and the P13K-mTOR pathways. Such innovative drugs include vismodegib, cyclopamine, itraconazole, everolimus and a few other agents that are in early clinical development.

Protomyofibroblast Pathway in Early Thermal Burn Healing.

Wound healing following partial thickness thermal burns is commonly hampered by the risk of hypertrophic scarring. Skin myofibroblast (MF) density is commonly increased in postburn healing. The transition between fibroblast-like cells and α-smooth muscle actin (SMA)+ MF possibly begins with CD14+ monocytes, evolving to CD14+ CD34+ fibrocytes, followed by ß-SMA+ protomyofibroblast (PMF) maturation. Skin biopsies from 25 burn patients were collected about 1 and 4 weeks after injury. Immunohistochemistry was performed using monoclonal antibodies to α-SMA, ß-SMA, factor XIIIa, lysozyme, Mac 387, CD14, CD117 and Ulex europaeus agglutinin-1 (UEA-1). The set of Mac 387+ and CD14+ monocytes was accompanied by both CD34+ fibrocytes and factor XIIIa+ dendrocytes. By contrast, ß-SMA+ PMF were rare. Of note, α-SMA+ MF were more abundant at week 4 than at week 1 (p < 0.01). The UEA-1+ endothelial cells showed marked variations in their dermal distribution, irrespective of the densities in the other scrutinized cells. In conclusion, healing of partial thickness thermal burns involves a diversity of cell types including PMF. In the present samples, the PMF density remained low. © 2015 S. Karger AG, Basel.

Dermal ultrastructure in collagen VI myopathy.

The COL VI mutations are responsible for a spectrum of myopathies. The authors report cutaneous ultrastructural alterations in a patient with COL6A2 myopathy. The changes include variations in size of collagen fibrils, flower-like sections of collagen fibrils, as well as thickening of vessel and nerve basement membranes. Electron microscopy of a skin biopsy contributes to the diagnosis of COL VI myopathies.

Cyanoacrylate skin surface stripping and the 3S-Biokit advent in tropical dermatology: a look from Liège.

In the dermatopathology field, some simple available laboratory tests require minimum equipment for establishing a diagnosis. Among them, the cyanoacrylate skin surface stripping (CSSS), formerly named skin surface biopsy or follicular biopsy, represents a convenient low cost procedure. It is a minimally invasive method collecting a continuous sheet of stratum corneum and horny follicular casts. In the vast majority of cases, it is painless and is unassociated with adverse events. CSSS can be performed in subjects of any age. The method has a number of applications in diagnostic dermatopathology and cosmetology, as well as in experimental dermatology settings. A series of derived analytic procedures include xerosis grading, comedometry, corneofungimetry, corneodynamics of stratum corneum renewal, corneomelametry, corneosurfametry, and corneoxenometry.

Ustekinumab biotherapy and real-time psoriasis capacitance mapping: a pilot study.

In recent years, the treatment of moderate to severe psoriasis has benefited from the development of targeted biologicals. Assessing this new class of drugs calls for precise modalities of severity/improvement ratings of the disease. Bioengineering-driven dermometrology aims at improving objective and quantitative assessments of disease severity and treatment efficacy. Skin capacitance mapping/imaging is one of those emerging methods. Among its clinical applications, psoriasis capacitance mapping (PCM) was introduced in order to assess both skin scaliness and water trapping inside the stratum corneum (inflammatory serum deposits) on lesional skin. PCM was used for assessing the therapeutic effects of ustekinumab on target lesions of 5 psoriatic patients. The reduction in the inflammatory dampness of the stratum corneum was conveniently seen after a 1-month ustekinumab treatment. The present pilot study suggests that PCM could be used as a fast and convenient method for assessing the anti-inflammatory efficacy of ustekinumab and other biotherapies.

Dermal ultrastructure in low Beighton score members of 17 families with hypermobile-type Ehlers-Danlos syndrome.

The distinction between the Ehlers-Danlos syndrome hypermobile type (EDSH) and the benign joint hypermobility syndrome (BJHS) is unclear. The aim of the present study was to compare skin ultrastructural abnormalities of EDSH and BJHS among different families. Skin of 23 EDSH, 27 BJHS, and 41 asymptomatic subjects from 17 families was examined using transmission electron microscopy. Similar ultrastructural abnormalities were found irrespective of the Beighton score. Flower-like collagen fibrils represented the key change and elastic fibers were altered as well. Beighton score is a clinical parameter rating joint mobility that appeared unrelated to quantitative and qualitative collagen ultrastructural alterations in the skin. Some EDSH family members fit with BJHS diagnosis. BJHS possibly represents a mild variant of EDSH.

Challenging regional psoriasis and ustekinumab biotherapy: impact of the patterns of disease.

In some patients, psoriasis appears refractory to many treatments, particularly when the disease is confined to some specific body regions. In this respect, palmoplantar psoriasis and palmoplantar pustulosis are possibly related conditions in their immunopathomechanisms involving Il-12, IL-23, and Th17. Nail psoriasis and scalp psoriasis are two other particular psoriasis manifestations. Accordingly, ustekinumab was tested in a few of these patients. The present paper is limited to peer-reviewed case reports. Data were not supported by bioinstrumental assessments and controlled trials. Overall, they are indicative of potential efficacy. The cost-effectiveness and the risk-benefit assessments merit further investigations.

Ustekinumab in psoriasis immunopathology with emphasis on the Th17-IL23 axis: a primer.

Psoriasis is a chronic relapsing immunoinflammatory dermatosis that is commonly associated with systemic comorbidities. The pathogenic importance of interleukin (IL)-12 and IL-23 is beyond doubt, as well as the involvement of T helper cells (Th)1 and Th17 cells. There is upregulation of the p40 subunit shared by IL-12 and IL-23 and of the IL-23 p19 subunit, but not an increased expression of the IL-12 p35 subunit. This indicates that IL-23 appears more involved than IL-12 in the pathogenesis of psoriatic plaques. Ustekinumab is a fully human monoclonal antibody of the immunoglobulin (Ig) G1 class targeting the p40 subunit common to both IL-12 and IL-23, thus inhibiting both IL-12 and IL-23 receptor-mediated signalling. Ustekinumab is part of the recent biologic therapies active in psoriasis, autoimmune arthritides, and inflammatory bowel diseases.

Bioimpact of EGFR antagonists on the pilosebaceous follicles.

Cancer patients under targeted chemotherapy to the epidermal growth factor receptor (EGFR) frequently suffer from unusual skin adverse events. In the past, these changes were globally qualified as a rash. Our aim was to assess objectively by non invasive bioinstrumentation some early structural and functional skin changes associated with EGFR inhibitor treatment. A series of 27 cancer patients aged 58-66 years were assessed using two ultraviolet light emitting CCD cameras, Visioscan(®) and Visiopor(®). Assessments were performed on the foreheads at inclusion and therefore at weekly intervals for 2 months at most. No topical treatment was applied during the assessment period. The Visioscan(®) camera revealed specular light reflectance at the site of follicular plugging. The interfollicular stratum corneum showed occasional focal hyperkeratosis. These features increased in severity with the EGFR inhibitor treatment, indicating follicular involvement as an early adverse event of the therapy. The follicular fluorescence revealed by the Visiopor(®) camera remained unchanged over the treatment period. The present findings suggest an EGFR inhibitor-induced kerosis (follicular hyperkeratosis) possibly responsible for acneiform reactions.

Field melanin mapping of the hairless scalp.

BACKGROUND: Mottled subclinical melanoderma (MSM) is frequently seen on facial skin using the ultraviolet light enhanced visualization (ULEV) method. The corresponding aspect on the hairless scalp remains unknown. OBJECTIVE: To explore the field distribution of melanin on the scalp of fair-skinned Caucasian subjects. METHOD: The scalp was examined in 43 men with androgenic alopecia. The Visioscan(®) camera provided the ULEV pictures. Another optical (Visioface(®) Quick) device was used under white light illumination followed by colour contrast enhancement. This was reached after specific computer filtration of the cyan hue wavelengths. RESULTS: Under white light illumination, the scalp looked normal. MSM patterns were disclosed by both optical procedures as evenly scattered discrete patchy fields of hypermelanosis. The smaller rounded spots were restricted to the lips of the hair infundibula. Larger irregularly shaped spots predominated in the interfollicular areas. A few hypomelanotic spots were scattered over the scalp. CONCLUSION: The present observations based on dual optical methods possibly provide information about a patterned pathobiology of melanocytes on the scalp. The spotty MSM pattern looked similar to the reported aspects on the face. It somewhat resembled the widespread PUVA-induced lentiginosis.

Recent trends in specular light reflectance beyond clinical fluorescence diagnosis.

Under specific light illumination, particularly ultraviolet (UV) and near-UV light stimulation, the skin produces both specular light reflectance and, possibly, specific fluorescent emission. These properties offer diagnostic clues and disclose some peculiar functions of the skin. A series of superficial infections (erythrasma, some tinea capitis types, tinea/pityriasis versicolor, dermatophytoses, etc.) and pilosebaceous follicles enriched in Propionibacterium spp show fluorescence. This latter characteristic is downgraded or lost while on some anti-acne treatments. A quenching effect of fluorescence is observed following the application of sunscreens. The (pre)neoplastic areas prepared for methylaminolevulinate photodynamic therapy (MAL-PDT) show reddish fluorescence following drug metabolisation producing porphyrins by the abnormal activated cells. Of note, when using a recording sensitive CCD camera instead of casual visual observation, skin fluorescence may be superimposed on the specular reflectance of the incident light. With the current technology, these situations are not distinguished with confidence. Any harsh and scaly lesion appears brighter following yellowish specular light reflectance. Stratum corneum samplings collected on clear self-adhesive discs or cyanoacrylate skin surface strippings are conveniently examined ex vivo, taking advantage of the same optical properties.

Angiogenic fast-growing melanomas and their micrometastases.

Malignant melanoma (MM), particularly its fast-growing type, is prone to interstitial, intravascular and extravascular migratory metastases. There is no information linking their growth fraction, the configuration of the MM advancing edge, the extent in vascularity and the propensity to metastatic progression. The objective of this study was to determine the growth fraction, the size of vascularity and the contours of the progression border of 32 fast-growing MM with regard to the presence or absence of a micrometastatic spread inside the skin and overt metastases in the sentinel lymph nodes. In vivo high resolution colorimetry was performed as a clinical estimate of MM vascularity. Euclidean geometry and fractal analysis were used on immunohistochemical sections. The relative microvasculature profile area beneath MM, and the fractal dimension D of the MM frontline were assessed. The MIB/Ki-67 index was determined in MM cells. Value a* of colorimetry was similarly increased in the presence or absence of micro-metastases. No difference in growth fraction was revealed between these neoplasms. Correlations were found between vascularity and angiotropism, and between the micrometastatic process and the sentinel lymph node involvement. By contrast, no correlation was shown between vascularity and the fractal D dimension of the MM advancing edge. In sum, this study establishes a link between the extent of MM growth fraction, vascularity and the presence of dermal and nodal micrometastases in fast-growing MM.

Updating corneofungimetry: a bioassay exploring dermatomycoses and antifungal susceptibility.

Superficial dermatomycoses are frequent conditions in humans and animals. Specific treatment modalities have been designed using a variety of different antifungal compounds. The need for antifungal susceptibility testing (AST) has been growing steadily over the last two decades due to the extending number of newer antifungal agents. Objective inter- and intraindividual comparisons of their respective efficacies are nearly impossible to perform in vivo. Currently, a series of standardized AST methods and interpretative guidelines have been designed. However, their clinical relevance for dermatomycoses is not consistent. The corneofungimetry bioassay was designed to test comparatively a series of antifungals on pathogenic fungi growing on sheets of human stratum corneum. Computerized morphometric assessments bring numerical values allowing statistical comparisons. Variants of corneofungimetry address more specific aspects related to fungal cell adhesion, fungitoxicity and lipid-dependent fungi.

Epidermal field carcinogenesis in bald-headed: An attempt at finetuning early non-invasive detection.

Skin weathering and photoaging of the balding scalp have not attracted much investigative attention so far. However, the concept of field cancerization, in particular actinic field carcinogenesis, is likely applicable to this part of the body. The aim of the study was to finetune the epidermal actinic changes present on hairlessness scalp. The ultraviolet light-enhanced visualization (ULEV) method was used to assess a series of 50 healthy men older than 50 years with documented baldness for over 15 years. They were scrutenized looking for altered epidermal structures corresponding to photoaging-associated changes. Attention was focused on the faint mosaic melanoderma (FMM) and atypical scaliness. Observations were made on the scalp and forehead. FMM was recognized in each case. It presented either as a single manifestation of photoaging or it was associated with an unusual pattern of discrete rimmed scaliness. In this latter case histology and morphometry disclosed keratinocyte dysplasia. A similar scaly pattern was not seen on the forehead. Subtle skin surface changes were disclosed on long-standing sunexposed balding scalps. The scaly aspect was distinct from dandruff, seborrheic dermatitis or any other common inflammatory scalp dermatosis. The presently described changes had not previously been described during early balding. It is suggested that the presently described condition may be associated with or indicative for actinic field carcinogenesis and incipient keratinocyte dysplasia.

Molecular pathways supporting the proliferation staging of malignant melanoma (review).

The clinical diagnosis of cutaneous melanoma always calls for histological confirmation. In addition to the recognition of the classic aspects of the neoplasm, immunohistochemistry is determinant, in particular in the assessment of the size of the replicative compartment. Generally, the proliferation rate is indicative of the neoplastic progression and is related to the clinical growth rate of the neoplasm. It allows to distinguish high risk melanomas showing a high growth rate from those of lower malignancy associated with a restricted growth rate. In melanoma, the recruitment and progression of neoplastic cells in the cell cycle of proliferation have lost some of their controls that are normally processed by a series of key regulatory molecules. In addition, the apoptotic pathway counteracting any hyperproliferative activity is released of the dependency of specific regulated molecular mechanisms. This review summarizes the current knowledge on key molecular components involved in the deregulation of the growth fraction, cell proliferation and apoptosis in melanocytic neoplasms. The implication of cyclins and of the mitogen-activated protein kinase pathways are scrutinized. The involvement of neoplastic stem cells in the metastatic process is also discussed.

Highlighting the immunohistochemical profile of melanocytomas: review.

The histological assessment of atypical melanocytic neoplasms is mandatory to ensure proper diagnosis and treatment. However, for some atypical lesions, expert pathologists report only moderate concordance in the diagnosis. In addition, certain atypical neoplasms have been coined differently in the literature. These designations include among others atypical and metastasizing Spitz tumor, malignant Spitz naevus, borderline and intermediate melanocytic tumor, and melanocytic tumor of uncertain malignant potential (MELTUMP) or Spitzoid melanocytic tumor of uncertain malignant potential (STUMP). These neoplasms are grouped here under the heading melanocytoma. Such melanocytic lesions have a benign outcome but exhibit an atypical and worrisome aspect. Rare individual cases of melanocytomas can progress to locoregional disease (agminate melanocytomas), and even beyond. At times, the distinction between melanocytoma and melanoma is difficult and may even be impossible. However, multipronged immunohistochemistry can help define malignancy risk stratification and therapeutic guidelines.

Crossroads between actinic keratosis and squamous cell carcinoma, and novel pharmacological issues.

Actinic keratoses (AKs) and their derived squamous cell carcinomas are distinctive lesions forming a continuum in a multi-step carcinogenesis process. They are typically found on chronically sun exposed skin. AKs merit to be recognized as such and to be distinguished from squamous cell carcinomas both conceptually and for therapeutic implications. The histological differences between these lesions are well defined and should not be blurred. A brief review is presented about the biological features responsible for AKs and the clinicopathologically distinctive aspects of these lesions. In addition, recent findings are presented about pharmacotherapy using anti-epidermal growth factor receptors, imidazoquinolines, diclofenac-hyaluronan, and methyl aminolevulinate photodynamic therapy.

Analytic quantification of the bleaching effect of a 4-hydroxyanisole-tretinoin combination on actinic lentigines.

BACKGROUND: Solar lentigines represent a common feature of photoaging, particularly on the back of the hands. Bleaching agents are usually proposed to lighten the shade of the lesions. METHODS: The study was randomized and designed to assess the effect of a bleaching solution containing 2% mequinol (4-hydroxyanisole, 4HA) and 0.01% tretinoin (Solagé). The formulation was applied twice daily for 3 months on solar lentigines present on the back of one hand. The lesions on the other hand were treated with the ethyl alcohol vehicle which served as a control. Clinical diagnosis was confirmed using dermoscopy. In addition, objective measurements of the hypermelanosis were performed at 1-month intervals during and after treatment. Clinical assessments were used as well as narrow-band reflectance spectrophotometry, image analysis of video-recorded ultraviolet light-enhanced visualization (ULEV method) and photodensitometry of the corneomelametry test. RESULTS: The multipronged assessment of the lesional color demonstrated a significant lightening effect of the 4HA/tretinoin solution. This was demonstrated after 2 months of treatment and was maintained at least 2 months after stopping treatment. CONCLUSION: Both the visual ratings and the objective bioinstrumental methods indicate the rapid lightening effect of the 4HA/tretinoin formulation. After stopping treatment, the rate of repigmentation appeared to have slowed compared to the depigmentation phase.

Highlighting the rim of the perifollicular epidermal unit.

The perifollicular and interfollicular areas of normal skin may look similar. However, some physiological and pathological processes may specifically involve a thin perifollicular rim. This review illustrates some of the methods available for highlighting the rim of the perifollicular epidermal unit. Non invasive methods rely on dermoscopy, ultraviolet light enhanced visualization (ULEV), skin capacitance imaging and cyanoacrylate skin surface strippings (CSSS). Conventional histology and immunohistochemistry may also show specific perifollicular features without, however, revealing the aspects highlighted by the specific non invasive methods. The clinically relevant modifications consist of pigmentary and hyperkeratotic perifollicular changes.

Treatment of pyogenic granulomas with the Nd-YAG laser.

Pyogenic granuloma is a common vascular tumour that can be treated by various means. However, some large lesions and those located on some difficult-to-treat body sites may represent a difficult challenge to the clinician (residual pain after treatment, difficult to cover with a dressing, or risk of sequelae). We report the successful treatment of such lesions in three patients using the Nd-YAG laser.