The systemic influence of chronic smoking on skin structure and mechanical function.

One of the major functions of human skin is to provide protection from the environment. Although we cannot entirely avoid, for example, sun exposure, it is likely that exposure to other environmental factors could affect cutaneous function. A number of studies have identified smoking as one such factor that leads to both facial wrinkle formation and a decline in skin function. In addition to the direct physical effects of tobacco smoke on skin, its inhalation has additional profound systemic effects for the smoker. The adverse effects on the respiratory and cardiovascular systems from smoking are well known. Central to the pathological changes associated with smoking is the elastic fibre, a key component of the extracellular matrices of lungs. In this study we examined the systemic effect of chronic smoking (>40 cigarettes/day; >5 years) on the histology of the cutaneous elastic fibre system, the nanostructure and mechanics of one of its key components, the fibrillin-rich microfibril, and the micromechanical stiffness of the dermis and epidermis. We show that photoprotected skin of chronic smokers exhibits significant remodelling of the elastic fibre network (both elastin and fibrillin-rich microfibrils) as compared to the skin of age- and sex-matched non-smokers. This remodelling is not associated with increased gelatinase activity (as identified by in situ zymography). Histological remodelling is accompanied by significant ultrastructural changes to extracted fibrillin-rich microfibrils. Finally, using scanning acoustic microscopy, we demonstrated that chronic smoking significantly increases the stiffness of both the dermis and the epidermis. Taken together, these data suggest an unappreciated systemic effect of chronic inhalation of tobacco smoke on the cutaneous elastic fibre network. Such changes may in part underlie the skin wrinkling and loss of skin elasticity associated with smoking. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Mitochondrial dysfunction in affected skin and increased mitochondrial DNA in serum from patients with psoriasis.

Psoriasis is characterized by keratinocyte proliferation and chronic inflammation, but the pathogenesis is still unclear. Dysregulated mitochondria (mt) could lead to reduced apoptosis and extracellular secretion of mtDNA, acting as "innate pathogen" triggering inflammation. Serum was obtained from healthy volunteers and psoriatic patients. Mitochondrial DNA was extracted from the serum and amplified with quantitative PCR (qPCR). Punch biopsies were obtained from lesional and non-lesional psoriatic skin (10 cm apart) and from healthy volunteers, were placed in RNA later and were stored at -80°C until RNA was extracted and cDNA was synthesized; gene expression of uncoupling protein 2 (UCP2), Dynamin-related protein 1 (Drp1) and calcineurin, involved in the regulation of mitochondria function, was detected with qPCR. Mitochondrial DNA was significantly increased (7s, P = 0.0496 and Cytochrome B, CytB, P = 0.0403) in the serum of psoriatic patients (n = 63) as compared to controls (n = 27). Gene expression was significantly reduced for UCP2 (P = 0.0218), Drp1 (P = 0.0001) and calcineurin (P = 0.0001) in lesional psoriatic skin, as compared to non-lesional or control skin. Increased serum extracellular mtDNA in psoriatic patients and decreased expression of mitochondrial regulatory proteins in psoriatic skin suggest increased inflammation and reduced keratinocyte apoptosis, respectively. Inhibitors of mtDNA secretion and/or UCP2 stimulants may be potential treatment options.

Vismodegib persistence and discontinuation patterns in Greek patients from a real world setting.

Hedghehog pathway inhibitors have been successfully used for patients with locally advanced basal cell carcinomas. However, these treatments have been associated with various adverse events that may limit patient compliance. In this study, an association of patient and disease characteristics with drug compliance in a real clinical setting was made. 18 patients were included in the study. The average patient age was 78.39 years. The time that patients remained to treatment was, on average, 8.73 months. 72.2% of patients experienced at least one adverse event. At study cut-off, 11 out of 18 patients had discontinued treatment. The most common reason for discontinuation was reported "fatigue" from the treatment due to the type of AEs experienced (37.4%) and patient's choice after complete response achievement (30.8%). Factors that were associated with treatment discontinuation was: number of previous treatments, severity of AEs and patient age.

Phototherapy as a first-line treatment for early-stage mycosis fungoides: The results of a large retrospective analysis.

BACKGROUND: Phototherapy is one of the main treatments for mycosis fungoides (MF). In this study, we analyzed the efficacy and safety of phototherapy as a first-line treatment in patients with early-stage disease. METHODS: We analyzed treatment outcomes in a group of 227 early-stage patients. The chi-squared test, the parametric t test, and ANOVA test and the non-parametric tests of Mann-Whitney and Kruskal-Wallis were applied for data analysis. RESULTS: 55.9% of patients treated with UVB-NB reached complete remission (CR), while analog rates after PUVA treatment were 74.5% (P = .015). Patients with patch-stage disease showed better response rates to PUVA compared to UVB-NB therapy (CRs 56.7% vs 91.3%, P < .001). Regarding the latter, long-lasting disease was proven as an independent negative prognostic factor for treatment outcome. Phototypes I and II were found to be favorable prognostic factors for patients treated with PUVA. Maintenance treatment did not alter final relapse rates but led to prolonged time to relapse compared to no-maintenance treated cases (19.5 months, vs 32.3, P < .002). CONCLUSION: Our analysis indicates that PUVA leads to better responses and longer relapse-free intervals both in patch- and plaque-stage disease. UVB-NB could be a valid therapeutic alternative for patients with recent disease presentation.

Use of vismodegib for the treatment of multiple basal cell carcinomas in a patient with xeroderma pigmentosum.

A female patient with xeroderma pigmentosum and multiple basal cell carcinomas was treated with a hedgehog pathway inhibitor (vismodegib), which successfully treated the majority of her basal cell carcinomas while preventing the appearance of new lesions. The sum diameter of lesions showed a 61% decrease after 16.5 months of treatment, although after 18.5 months of treatment, a persistent lesion showed progression and metatypical characteristics; adverse events included persistent alopecia muscle cramps, dysgeusia, and amenorrhea. Despite these limitations, vismodegib may have a role in the treatment of some patients with xeroderma pigmentosum.

Quality of Life and Psychosocial Implications in Patients with Hidradenitis Suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a long-term skin disorder associated with high levels of psychological distress and significant life impact. OBJECTIVE: To evaluate the quality of life, depression, anxiety, loneliness, and self-esteem in patients with HS. METHODS: Ninety-four patients with HS were enrolled in the study. The quality of life, depression, anxiety, loneliness, and self-esteem of the patients were assessed using the Dermatology Life Quality Index (DLQI), the Hospital Anxiety and Depression Scale (HADS), the UCLA Loneliness Scale (UCLA-Version 3), and the Rosenberg Self-Esteem Scale (RSES), respectively. RESULTS: The DLQI mean score was 11.43 ± 6.61 in patients with HS. The patients with HS presented statistically significantly higher anxiety (6.41 ± 3.31 vs. 5.00 ± 1.59, p < 0.001), depression (5.45 ± 2.79 vs. 4.16 ± 1.54, p < 0.001), and loneliness and social isolation scores (42.86 ± 8.63 vs. 35.57 ± 6.17, p < 0.001) and lower self-esteem scores (18.91 ± 1.79 vs. 19.77 ± 2.53, p = 0.008) than the healthy controls. CONCLUSIONS: HS is a distressing, recurrent disease that impairs quality of life. We can suggest services that allow an integrated approach, which includes psychosocial support, offering the patients relief from isolation and an opportunity to share common experiences.

Combination of microneedling and 10% trichloroacetic acid peels in the management of infraorbital dark circles.

BACKGROUND: Dark circles (DC), seen in the periorbital area, are defined as bilateral, round, homogeneous pigmented macules whose aetiology is thought to be multifactorial. Available treatments include bleaching creams, topical retinoic acid, chemical peels, lasers, autologous fat transplantation, injectable fillers and surgery (blepharoplasty). OBJECTIVE: To evaluate the efficacy and safety of a combination of microneedling and 10% trichloroacetic acid (TCA) peels in the treatment of DC. MATERIALS AND METHODS: Thirteen female patients with mild to severe infraorbital DC were included in the study. The patients were aged between 21 and 61 years. They were treated with Automatic Microneedle Therapy System-Handhold and topical application of 10% TCA solution to each infraorbital area for five minutes. The effect was photo-documented and a Patient and Physician Global Assessment was evaluated. Safety was assessed by evaluating early and delayed adverse events. RESULTS: Almost all patients showed significant aesthetic improvement. Both Physician and Patient Global Assessment rated a fair, good or excellent response in 92.3%. The procedure was well tolerated. Mild discomfort, transient erythema and oedema were quite common during or immediately after the procedure. The patients were followed up regularly every month for four months, and no recurrence was recorded. CONCLUSION: Microneedling and 10% TCA constitute an innovative combination treatment for DC with encouraging results and minor side effects.

A case-control study of MC1R variants in Greek patients with basal cell carcinoma: increased risk independently of pigmentary characteristics.

Melanocortin 1 receptor (MC1R) gene variants are a major contributor to pigmentation characteristics and the modulation of sporadic basal cell carcinoma (BCC) risk. This is a hospital-based, case-control study to investigate the association of MC1R variants and pigmentary characteristics with the risk of BCC development in a Southern European population in Greece. In total, 141 patients with BCC and 166 controls were studied. Increased BCC risk was found for the presence of 2 or more MC1R variants (OR:3.07, 95% CI:1.13-8.34), or 2 or more variants of which at least 1 was major function (OR:7.15, 95% CI:1.37-5.52), after adjustment for the 'red hair colour' (RHC) phenotype. Increased BCC risk persisted in the presence of 2 or more MC1R variants (OR:4.15, 95% CI:1.35-12.72), after adjustment for potential confounding factors including skin color (P:0.237) and atypical nevi (OR:9.57, 95% CI:2.19-41.81, P:0.003). MC1R genotype is a risk factor for the development of BCC in Greek patients independently of pigmentary characteristics, and the combination of MC1R variants may modulate this risk.

In situ assessment of PI3K and PTEN alterations in mycosis fungoides: correlation with clinicopathological features.

Deregulated signalling through phosphatidylinositol 3-kinase (PI3K) pathway plays a critical role in tumour initiation and progression. We have already shown that AKT is activated in skin lesions in Mycosis Fungoides (MF) and we herein further investigate the frequency and clinical significance of PTEN and PI3K at the protein and at the DNA level as well as the presence of AKT1 mutations in skin lesions from 50 patients with MF clinical stages I-IV in relation to clinicopathological features. Increased p-AKT expression correlated with poor prognosis in plaques (P = 0.0198), whereas p-AKT was an independent predictor of poor survival in the entire cohort (P = 0.017, HR = 1.012). PTEN cytoplasmic expression was found low or absent in all 77.3% of cases and inversely correlated with advanced clinical stages (P = 0.0744). Molecular analysis showed no AKT1 mutation, no PI3KCA copy number gain, only 1 case with PI3KCA mutation in exon 9 and 3 cases with PTEN mutations (7%) in exons 7, 8 and 5. The latter correlated with disease (P = 0.0253) and progression (P < 0.0001) free survival in tumour stage. Although activation of PI3K/AKT signalling pathway due to PTEN alterations is rarely attributed to abnormalities in PTEN, PI3K, and AKT1 genes, PTEN mutations exert a negative effect on patients' prognosis with tumours.

Screening for asymptomatic scalp carriage in household contacts of patients with tinea capitis during 1997-2011: a retrospective hospital-based study.

For anthropophilic tinea capitis (TC), household spread and asymptomatic scalp carriage (ASC) is considered an important route of transmission and incomplete clearance. To investigate ASC in household contacts of patients diagnosed with TC in a tertiary hospital in Athens, Greece, we retrospectively reviewed the medical files of household contacts that were screened for ASC from 1997 to 2011. Only 34 household contacts of 15 index cases agreed to come for screening. Thirty-three (97%) household contacts were asymptomatic scalp carriers. The most commonly isolated species was Trichophyton violaceum (59%). There was a statistically significant association of ASC with the isolated dermatophyte species (T. violaceum, P-value: 0.029), and with the age of younger than 16 years old (P-value: 0.005), while there was no association with gender (P-value: 0.672). A small number of household contacts accepted to proceed for screening. ASC was found in nearly all screened household contacts and was associated with T. violaceum and younger age. The low number of household contacts that accepted screening may reflect the ignorance of the general population about the possibility of ASC among household contacts in case of a patient with TC.

First treatment of mycosis fungoides by total skin electron beam (TSEB) therapy in Greece.

BACKGROUND: Mycosis fungoides (MF), the most common subtype of cutaneous T-Cell Lymphoma (CTCL), is a rare chronic skin neoplasia. Total skin electron irradiation has been employed along with a variety of other topical or systemic treatments for MF management. AIM: To report the first case treated by TSEB irradiation protocol in Greece. MATERIALS AND METHODS: A fractionated 36 Gy total skin electron beam (TSEB) therapy was prescribed to a 65-years-old male patient with mycosis fungoides (MF), stage IIB, refractory to several treatments during a 20-year period. Dose uniform delivery was monitored by thermo-luminescence dosimetry. RESULTS AND DISCUSSION: The homogeneous skin dose distribution resulted in a complete clinical response. Limited, irradiation-oriented, side effects appeared. CONCLUSIONS: The first TSEB irradiation prescription in Greek medical chronicles was proved effective in this case of tumor stage MF (T3-IIB), which had been refractory to several single or combination treatments.

A comprehensive immunohistochemical approach of AKT/mTOR pathway and p-STAT3 in mycosis fungoides.

BACKGROUND: Although the expression pattern of phosphorylated (p)-mTOR pathway components has attracted scientific interest in several neoplasms, to our knowledge, there is no published information regarding its significance in mycosis fungoides (MF). OBJECTIVE: We sought to perform a comprehensive simultaneous assessment of key members of AKT/mTOR pathway along with p-extracellular signal-regulated kinase (ERK), NOTCH1, and p-STAT3 in patients with MF. METHODS: In all, 54 skin biopsy specimens (21 tumors, 30 plaques, and 3 folliculotropic MF) from 50 patients with MF were analyzed immunohistochemically for p-mTOR, its upstream p-AKT, its downstream effectors p-p70S6K and p-4E-BP1, and for p-ERK1/2, NOTCH1, and p-STAT3. RESULTS: p-mTOR was coexpressed with p-p70S6K in 67.3% of lesions, but coexpression with other molecules was less common. p-p70S6K and marginally NOTCH1 displayed higher H-scores in tumors than in plaques. Significant correlations were recorded between p-ERK and p-4E-BP1, as well as between NOTCH1 and p-p70S6K or p-4E-BP1. NOTCH1, p-4E-BP1, and p-p70S6K expression were associated with advanced stage. In survival analysis simultaneous overexpression of p-AKT and p-p70S6K, along with p-4E-BP1 positivity, adversely affected cancer-specific, disease-free, and progression-free survival in advanced-stage cases. LIMITATIONS: A limitation may be the small number of cases included in our investigation, precluding multivariate survival analysis. CONCLUSIONS: Activation of AKT/mTOR pathway in MF appears to be correlated with NOTCH1, p-ERK, and p-STAT3 and is implicated in the acquisition of a more aggressive phenotype. The combination of p-AKT, p-p70S6K, and p-4E-BP1 emerges as a significant potential prognostic marker in patients with advanced stage.

NMN: The NAD precursor at the intersection between axon degeneration and anti-ageing therapies.

The past 20 years of research on axon degeneration has revealed fine details on how NAD biology controls axonal survival. Extensive data demonstrate that the NAD precursor NMN binds to and activates the pro-degenerative enzyme SARM1, so a failure to convert sufficient NMN into NAD leads to toxic NMN accumulation and axon degeneration. This involvement of NMN brings the axon degeneration field to an unexpected overlap with research into ageing and extending healthy lifespan. A decline in NAD levels throughout life, at least in some tissues, is believed to contribute to age-related functional decay and boosting NAD production with supplementation of NMN or other NAD precursors has gained attention as a potential anti-ageing therapy. Recent years have witnessed an influx of NMN-based products and related molecules on the market, sold as food supplements, with many people taking these supplements daily. While several clinical trials are ongoing to check the safety profiles and efficacy of NAD precursors, sufficient data to back their therapeutic use are still lacking. Here, we discuss NMN supplementation, SARM1 and anti-ageing strategies, with an important question in mind: considering that NMN accumulation can lead to axon degeneration, how is this compatible with its beneficial effect in ageing and are there circumstances in which NMN supplementation could become harmful?

Childhood- and later-onset vitiligo have diverse epidemiologic and clinical characteristics.

BACKGROUND: Vitiligo onset during childhood is common. There are limited data regarding childhood-onset vitiligo. OBJECTIVE: We sought to provide an epidemiologic and clinical comparison between childhood- and later-onset vitiligo. METHODS: Two groups of patients were included in this cross-sectional study. Consecutive patients examined at the Vitiligo Clinic of Andreas Sygros Hospital for Skin and Venereal Diseases, Athens, Greece, from January 2005 to December 2009 with a disease onset before the age of 12 years were included in the childhood-onset group. The later-onset group included randomly selected patients who were examined at the same period and had a disease onset after the age of 12 years. After clinical examination, a standardized questionnaire was completed for each patient. RESULTS: In all, 126 patients were included in the childhood-onset and 107 patients in the later-onset group. Childhood-onset vitiligo: (1) involved different sites at initial presentation, (2) included more cases of segmental type, and (3) was characterized by a higher prevalence of allergic diseases and a lower prevalence of thyroid diseases. Longer duration of disease and a positive family history of thyroid disease were associated with the presence of thyroid disease only in the childhood-onset group. In the later-onset group, only female sex was associated with the presence of thyroid disease. LIMITATIONS: The study was conducted in a hospital specializing in skin diseases and a selection bias toward more severe vitiligo cases is possible. CONCLUSIONS: Childhood-onset vitiligo had distinct epidemiologic and clinical characteristics, compared with later-onset disease.

Azithromycin pulses for the treatment of epidermal growth factor receptor inhibitor-related papulopustular eruption: an effective and convenient alternative to tetracyclines.

BACKGROUND: Papulopustular eruption (PPE) is the most common cutaneous side effect of epidermal growth factor receptor inhibitors (EGFRIs). OBJECTIVE: To document the efficacy and safety of pulsed azithromycin doses in the treatment of EGFRI-related PPE. METHODS: A retrospective analysis of patients under EGFRIs who exhibited at least grade 2 PPE and were intolerant or resistant to tetracyclines was performed. Treatment consisted of pulsed azithromycin doses of 500 mg daily for 3 consecutive days per week for at least 2 weeks. RESULTS: Treatment with azithromycin showed a significant reduction in the number of lesions in 18/20 patients, with 11 showing complete resolution of the rash. No significant side effects were recorded. We did not observe any interactions with the targeted biological agents or any obvious compromise of the anticancer treatment. CONCLUSIONS: Weekly pulses of azithromycin are effective and promote increased patient adhesion to the treatment. A prospective study is needed to confirm efficacy and safety of this convenient treatment.

Management of cutaneous T-Cell lymphoma patients with extracorporeal photopheresis. The Hellenic experience.

Extracorporeal photopheresis (ECP) is an established therapy for cutaneous T-cell lymphoma (CTCL). The objective of this study was to further explore the clinical efficacy of ECP combined with immunomodulatory agents. Eighteen patients with histologically proven CTCL were followed-up after therapy with ECP, mainly combined with interferon-α or bexarotene. A total of 61% of patients responded to therapy (n=11; CR: 5, PR: 6). Median survival was 51 months, progression free survival was 28 months and response duration was 29 ± 23.9 months. ECP combined therapy was highly effective or had a palliative effect in CTCL resistant to previous treatments.

Determination of the protection efficacy and homogeneity of the distribution of sunscreens applied onto skin pre-treated with cosmetic products.

BACKGROUND: The efficacy of sunscreens depends decisively on the homogeneity of its distribution on the skin surface, which is sensitively reflected by two spectroscopic data - the factor of inhomogeneity and the sum transmission - measured after tape stripping. The aim of this study was to investigate the influence of a skin pre-treatment with body lotion on the layout of the formulations. METHODS: Six healthy volunteers were pre-treated using the body lotion, Nivea Body (Beiersdorf AG, Hamburg, Germany). The sunscreen was an oil/water (o/w) emulsion, Roc SPF 8 (RoC SA, Paris, France). The tape stripped tesa films were measured with a modified UV/VIS spectrometer Lambda 5 (PerkinElmer, Frankfurt/Main, Germany), the data of which were used to calculate both measurands. RESULTS: The obtained results made clear that the original spectroscopic data must be corrected taking into account the changed amounts of horny layer particles removed with the individual tape strips after pre-treatment. As a consequence of the correction, the factors of inhomogeneity as well as the sum transmissions confirm a more homogeneous distribution of the applied sunscreen. CONCLUSION: The findings confirm that the applied method is well suited to obtain information on the distribution of topically applied substances, and furthermore that the influence of the pre-treatment of the skin with the body lotion enhances the homogeneity of distribution and thus the sunscreen efficacy.

Two cases of hepatitis B in patients with moderate to severe psoriasis with ustekinumab.

BACKGROUND: Patients with psoriasis who are treated with systemic and biologic therapies may have an increased risk of infections, including hepatitis B virus (HBV). Cytokines that modulate CD4+ T cell subsets, including interleukin (IL)-12 and IL-23, have been suggested to play a role in the pathogenesis of HBV infection. OBJECTIVE: To report the first known cases of acute HBV infection in 2 ustekinumab-treated patients with psoriasis from a phase 3 (PHOENIX 1) and a phase 4 (TRANSIT) study. RESULTS: Both ustekinumab-treated patients generated an immune response toward HBV and experienced typical courses of infection, without progression to chronic HBV infection. CONCLUSION: Continued monitoring of liver-related adverse events in clinical trials, registries, and spontaneous reporting from the postmarketing setting will further contribute to understanding the role of ustekinumab in viral hepatitis.