Alternatives to animal testing in basic and preclinical research of atopic dermatitis

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease of increasing prevalence, especially in industrialized countries. Roughly 25% of the children and 1-3% of adults are affected. Although significant progress has been made in the understanding of the pathogenesis of AD, many aspects remain poorly understood. Moreover, there is a pressing need for improved therapeutic options. Studies to elucidate the pathophysiological pathways of AD and to identify novel therapeutic targets over the last few decades have been conducted almost exclusively in animal models. However, in vitro approaches such as 3D skin disease models have recently emerged due to an increasing awareness of distinct inter-species related differences that hamper the effective translation of results from animal models to humans. In addition, there is growing political and social pressure to develop alternatives to animal models according to the 3Rs principle (reduction, refinement and replacement of animal models). In this review, we briefly summarize commonly used animal models of AD and discuss the advancements and limitations of human-based in vitro models in AD research. Moreover, we address aspects where further improvements are urgently required.

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T-cell papulosis associated with B-cell malignancy: a distinctive clinicopathologic entity

Abstract

Background

A distinctive eruption referred to as "insect bite-like reaction", or "eosinophilic dermatosis of hematologic malignancy" has been described during the course of hematological B-cell malignancies (BCM). However, its clinical evolution, histopathological features and pathogenesis remain unclear.

Objectives

To characterize this eruption and to investigate its pathogenesis and relationship with the underlying BCM.

Methods

In this multicenter retrospective study of the French Study Group on Cutaneous Lymphomas, 37 patients with a BCM and a cutaneous eruption consisting in chronic and/or recurrent papules, papulo-vesicles and/or nodules were included. Clinical, histopathological, immunohistochemical and molecular data were reviewed.

Results

No significant insect bite history or seasonal predominance was recorded. Patients had pruritic papules (81%), papulo-vesicles (43%) and nodules (38%), often predominated in the head and neck region (84%), without complete remission periods in most cases (57%). The predominant associated BCM was chronic lymphocytic leukemia (73%). Histological and immunohistochemical review showed: a dense dermal lymphocytic infiltrate predominantly composed of T lymphocytes (100%), with frequent eosinophils (77.6%); a perivascular and periadnexial (most often pilotropic) pattern (77.6%), sometimes suggestive of a pilotropic mycosis fungoides; clusters of tumor B-cells were identified in 47% of cases using appropriate phenotyping markers. In 10/14 cases (71.4%) tested for B-cell IgH gene rearrangement, a B-cell clone was identified in skin lesions (identical to the blood clone in 9 cases), whereas no T-cell clone was present.

Conclusion

We propose the denomination "T-cell papulosis associated with B-cell malignancy" (TCP-BCM) for this distinctive eruption. Although resulting in various histopathological pictures, it can be easily recognized by clinicians, and may be identified by informed pathologists relying on some key features. An extravasation of tumor B-cells with skin-homing properties associated with a secondary, predominant, T-cell immune reaction could explain the clinico-pathologic aspect and the prolonged regressive and recurrent course of the disease.

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Marked pseudoepitheliomatous hyperplasia secondary to a red-pigmented tattoo: a case report

Abstract

Tattooing is gaining increasing popularity in developed countries in recent years. Adverse cutaneous reactions of many different types against coumponds in tattoo inks are being reported more and more often in medical literature,especially against red-pigmented tattoo. Delayed immune-mediated reactions can manifest in several ways and different histological patterns have been described

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Clinicopathological features and course of cutaneous protothecosis

Abstract

Background

Protothecosis is an uncommon infection caused by the achlorophyllic algae found more commonly in tropical areas. Only a limited number of cases have been reported.

Objective

We aimed to evaluate the clinicopathological features and treatment outcomes of cutaneous protothecosis.

Methods

We retrospectively identified 20 pathology-confirmed cases of cutaneous protothecosis based on skin biopsies in two tertiary medical centers in Taiwan from 1997 to 2015.

Results

The age of the patients at the time of diagnosis ranged from 48 to 85 years (mean age of 74 years). All lesions developed on the limbs. Twelve (60%) patients had adrenal insufficiency, but no patients had active malignancy at diagnosis. Interestingly, 4 (20%) patients had concurrent scabies infestation. Clinically, most lesions were erythematous plaques studded with punctate ulcers. Microscopically, the most common finding was granulomatous inflammation. Nineteen (95%) cases were successfully treated with itraconazole for 14 to 148 days with only one case of recurrence. Concomitant scabies should be suspected if pruritus is recalcitrant despite itraconazole treatment.

Conclusion

Despite its rarity, cutaneous protothecosis has become more significant due to an increased prevalence of immunocompromised individuals. Steroid overuse or iatrogenic adrenal insufficiency predisposes individuals to high-risk infections. Neglecting the disease leads to a chronic and incurable state. Protothecosis should be suspected in chronic eczematous and ulcerative plaques on the limbs refractory to conventional antibacterial and antiviral treatments, especially in patients with adrenal insufficiency. Clinical suspicion should be confirmed by skin biopsies, and confirmed cases can be successfully treated with itraconazole.

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Tracking actinic keratosis of face and scalp treated with 0.015% ingenol mebutate to identify clinical and dermoscopic predictors of treatment response

Abstract

Background

Ingenol mebutate (IngMeb) 0.015% gel is an approved field treatment option for non-hyperkeratotic non-hypertrophic actinic keratosis (AKs) of face and scalp. Efficacy of IngMeb has been assessed only on a clinical ground, in the majority of studies. Dermoscopy is a pivotal tool for the diagnosis of AK, while its role in evaluating the response to non-surgical therapies for AK has not been fully defined.

Objectives

Our study aims to determine if some dermoscopic features of AK of the face and scalp areas, may independently predict the response to IngMeb therapy.

Methods

Clinical and dermoscopic responses, one month after 0.015% IngMeb therapy, were retrospectively evaluated using a per-patient and per-lesion approach. Safety was evaluated through local skin reaction composite score calculation. Demographic, clinical and dermoscopic factors were then evaluated via univariate and multivariate logistic regression analysis to assess independent predictors of response.

Results

Fifty-five patients with 245 AKs were enrolled. Clinically, per-patient response evaluation identified 25 (45.4%) poor/partial and 30 (54.5%) complete responders, corresponding on a per-lesion approach to 66 (26.9%) and 179 (73.1%) AKs respectively. Dermoscopy re-classified 14 patients in the per-patient and 48 AKs in the per-lesion analysis from complete to poor/partial responders. Multivariate logistic regression analysis showed that AKs dermoscopically characterized by red pseudonetwork and located on the face were independently associated with a complete dermoscopic response to 0.015% IngMeb therapy; while microerosions were negative predictors.

Conclusion

Specific dermoscopic features of AK may predict the response to 0.015% IngMeb therapy, together with the location on the face.

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Cutaneous melioidosis: two cases of chronic primary forms

Abstract

Melioidosis is a bacterial infection due to Burkholderia pseudomallei. Systemic forms are well described and characterized by a high lethality rate up to 40% (1). In contrast cutaneous melioidosis (CM) is rarely described. CM can be primary and present either as acute or chronic forms, or secondary in case of generalized disease.

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A multicenter, prospective, observational study examining the impact of risk factors, such as BMI and waist circumference, on quality of life improvement and clinical response in moderate-to-severe plaque-type psoriasis patients treated with infliximab in routine care settings of Greece

Abstract

Background

Obesity has been associated with moderate-to-severe plaque psoriasis severity and PASI 75 response attainment of biologic therapies, but findings are inconsistent.

Objective

This study aimed to examine the association of body mass index (BMI) and waist circumference (WC) on disease severity, to identify potential patient characteristics associated with response attainment, and to assess the impact of infliximab on the patients' health-related quality of life (HRQoL) among infliximab-treated patients in the routine care setting of Greece.

Methods

This was a multicenter, prospective, observational study of adult moderate-to-severe plaque psoriasis patients who had initiated treatment with originator infliximab within 2 weeks prior to enrollment. Post-enrollment visits occurred at 14±4, 30±4 and 54±4 weeks following treatment onset.

Results

Between October-2012 and June-2014, 136 eligible patients (62.5% males) with a median age of 48.6 years, BMI of 29.6 kg/m² and WC of 107.0 cm at enrollment, were recruited by 21 dermatology hospital/private offices. All patients had received prior psoriasis treatment(s); 62.5% were biologic-naïve. Mean baseline psoriasis area severity index (PASI) and Dermatology Quality of Life Index (DLQI) scores were 23.4±13.6 and 15.0±8.3, respectively. A low correlation was observed between WC at enrollment and baseline PASI [rho=0.324 (p<0.001)]. Over a median 48.4 weeks of infliximab exposure, 89.3% of the per protocol set achieved a PASI 75 response. At 14-, 30-, and 54-weeks, the PASI 75 attainment rate was 66.4%, 74.8% and 76.6%, respectively; the clinically meaningful DLQI improvement (≥5 point decrease) rate was 68.9%, 75.7%, and 69.8%, respectively. BMI category and abdominal obesity at enrollment did not impact PASI 75 or DLQI improvement rate attainment.

Conclusion

In the routine care of Greece, infliximab reduced disease activity and improved the quality of life of moderate-to-severe psoriasis patients through one year of treatment, independent of their BMI and WC.

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Severe adverse cutaneous drug reactions to antiepileptic drugs: 18 years of experience in a tertiary referral dermatology clinic in Turkey

Abstract

Antiepileptic drugs (AEDs) are the mainstay of treatment for 1% of the human population suffering from epilepsy.¹ They are also increasingly used for several non-epileptic neurological conditions, such as trigeminal neuralgia, neuropathic pain syndromes, migraine and psychiatric disorders.² Three percent of patients who receive AEDs experience adverse cutaneous drug reactions (ACDR),³ which can range across a wide spectrum from mild to moderate eruptions, such as maculopapular rash and, urticaria, to severe and life-threatening conditions, such as drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).^1,4-5

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Bacterial community structure and abundances of antibiotic resistance genes in heavy metals contaminated agricultural soil

Abstract

Soil contamination with heavy metals is a worldwide problem especially in China. The interrelation of soil bacterial community structure, antibiotic resistance genes, and heavy metal contamination in soil is still unclear. Here, seven agricultural areas (G1–G7) with heavy metal contamination were sampled with different distances (741 to 2556 m) to the factory. Denaturing gradient gel electrophoresis (DGGE) and Shannon index were used to analyze bacterial community diversity. Real-time fluorescence quantitative PCR was used to detect the relative abundance of ARGs sul1, sul2, tetA, tetM, tetW, one mobile genetic elements (MGE) inti1. Results showed that all samples were polluted by Cadmium (Cd), and some of them were polluted by lead (Pb), mercury (Hg), arsenic (As), copper (Cu), and zinc (Zn). DGGE showed that the most abundant bacterial species were found in G7 with the lightest heavy metal contamination. The results of the principal component analysis and clustering analysis both showed that G7 could not be classified with other samples. The relative abundance of sul1 was correlated with Cu, Zn concentration. Gene sul2 are positively related with total phosphorus, and tetM was associated with organic matter. Total gene abundances and relative abundance of inti1 both correlated with organic matter. Redundancy analysis showed that Zn and sul2 were significantly related with bacterial community structure. Together, our results indicate a complex linkage between soil heavy metal concentration, bacterial community composition, and some global disseminated ARG abundance.

Epidemiologie ausgewählter endokriner Tumoren in Deutschland

Zusammenfassung

Der vorliegende Beitrag gibt einen Überblick über die Inzidenz- und Überlebensraten bösartiger Tumoren der Schilddrüse, Nebennierenrinde und neuroendokriner Tumoren in Deutschland. Die Ergebnisse beruhen auf den Daten der epidemiologischen Krebsregister der Bundesländer. In den Jahren 2012 bis 2014 wurden demnach in Deutschland jährlich etwa 7700 neuroendokrine Tumoren, 6160 bösartige Tumoren der Schilddrüse und 120 Nebennierenrindenkarzinome diagnostiziert. Ähnlich wie in vielen anderen industrialisierten Ländern war Mitte der 2000er Jahre ein deutlicher Anstieg des prognostisch günstigen papillären Schilddrüsenkarzinoms zu beobachten; die Inzidenzraten haben sich zuletzt jedoch stabilisiert. Von den neuroendokrinen Karzinomen treten etwas mehr als die Hälfte der Fälle im Verdauungstrakt auf. Von diesen sind wiederum 50 % der Tumoren gut differenziert (NET Grad 1 und 2) mit entsprechend hohen relativen Fünfjahresüberlebensraten zwischen 70 % und 90 % je nach Lokalisation. Bei den übrigen Formen sind die Überlebenschancen teilweise deutlich geringer mit Ausnahme der neuroendokrinen Karzinome (NEC) von Dünndarm und Appendix, deren Überlebensraten nur geringfügig niedriger liegen als bei den NET. Auffallend sind durchgehend höhere Überlebensraten für Frauen, die nicht alleine durch eine etwas günstigere Verteilung der histologischen Formen erklärt werden können.

Colorectal Cancer (CRC) Monitoring by Six-Monthly 18FDG-PET/CT: An Open-Label Multicentre Randomised Trial

Abstract

Background

¹⁸FDG-PET/CT has high sensitivity for detecting recurrences of colorectal cancer (CRC). Our objective was to determine whether adding routine 6-monthly ¹⁸FDG-PET/CT to our usual monitoring strategy improved patient outcomes and to assess the effect on costs.

Patients and Methods

In this open-label multicentre trial, patients in remission of CRC (stage II perforated, stage III, or stage IV) after curative surgery were randomly assigned (1:1) to usual monitoring alone (3-monthly physical and tumour marker assays, 6-monthly liver ultrasound and chest radiograph, and 6-monthly whole-body computed tomography) or with 6-monthly ¹⁸FDG-PET/CT, for 3 years. A multidisciplinary committee reviewed each patient's data every 3 months and classified the recurrence status as yes/no/doubtful. Recurrences were treated with curative surgery alone if feasible and with chemotherapy otherwise. The primary endpoint was treatment failure defined as unresectable recurrence or death. Relative risks (RR) were estimated, and survival was analysed using the Kaplan-Meier method, Log-Rank test, and Cox models. Direct costs were compared.

Results

Of the 239 enrolled patients, 120 were in the intervention arm and 119 in the control arm. The failure rate was 29.2% (31 unresectable recurrences and 4 deaths) in the intervention group and 23.7% (27 unresectable recurrences and 1 death), in the control group (RR = 1.23; 95%CI, 0.80-1.88; p=0.34). The multivariate analysis also showed no significant difference (hazards ratio, 1.33; 95%CI, 0.8-2.19; p=0.27). Median time to diagnosis of unresectable recurrence (months) was significantly shorter in the intervention group (7 [3-20] vs. (14.3 [7.3-27], p=0.016). Mean cost/patient was higher in the intervention group (18 192±27 679 €vs. 11 131±13 254 €, p<0.033).

Conclusion

¹⁸FDG-PET/CT, when added every six months, increased costs without decreasing treatment failure rates in patients in remission of CRC. The control group had very close follow-up, and any additional improvement (if present) would be small and hard to detect.

ClinicalTrials.gov identifier

NCT00624260

Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis

Abstract

Background

Recent efforts of genome-wide gene expression profiling analyses have improved our understanding of the biological complexity and diversity of triple negative breast cancers (TNBCs) reporting, at least 6 different molecular subtypes of TNBC namely Basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL) and luminal androgen receptor (LAR). However, little is known regarding the potential driving molecular events within each subtype, their difference in survival and response to therapy. Further insight into the underlying genomic alterations is therefore needed.

Patients and Methods

This study was performed using copy-number aberrations, somatic mutations and gene expression data derived from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA). TNBC samples (n = 550) were classified according to Lehmann's molecular subtypes using the TNBCtype online subtyping tool (http://cbc.mc.vanderbilt.edu/tnbc/).

Results

Each subtype showed significant clinic-pathological characteristic differences. Using a multivariate model, IM subtype showed to be associated with a better prognosis (HR = 0.68; CI = 0.46-0.99; p = 0.043) whereas LAR subtype was associated with a worst prognosis (HR = 1.47; CI = 1.0-2.14; p = 0.046). BL1 subtype was found to be most genomically instable subtype with high TP53 mutation (92%) and copy-number deletion in genes involved in DNA repair mechanism (BRCA2, MDM2, PTEN, RB1 & TP53). LAR tumours were associated with higher mutational burden with significantly enriched mutations in PI3KCA (55%), AKT1 (13%) and CDH1 (13%) genes. M and MSL subtypes were associated with higher signature score for angiogenesis. Finally, IM showed high expression levels of immune signatures and check-point inhibitor genes such as PD1, PDL1 and CTLA4.

Conclusion

Our findings highlight for the first time the substantial genomic heterogeneity that characterize TNBC molecular subtypes, allowing for a better understanding of the disease biology as well as the identification of several candidate targets paving novel approaches for the development of anti-cancer therapeutics for TNBC.

Next generation immunotherapies for lymphoma: one foot in the future

Abstract

Improved understanding of the interactions between cancer cells and the immune system combined with technological advances has led to the development of novel types of immunotherapies. These include checkpoint inhibitors (CPI), T cell engager antibodies (TCE), and Chimeric Antigen Receptor (CAR)-T cells which have demonstrated remarkable efficacy in B-cell malignancies, including anti-PD1 antibodies in Hodgkin lymphoma, and TCE and CAR-T cells in B-ALL, leading to their approval in these indications. Recent clinical data suggest that these immunotherapies may also benefit patients with other types of hematologic malignancies, particularly patients with Hodgkin and non-Hodgkin lymphomas. Here, we review the most recent clinical data regarding these different immunotherapies in patients with lymphoma. Ongoing and future studies should further define which immunotherapy may best apply to a given patient in order to provide a "personalized immunotherapy".

Genetic Landscape of Ultra-Stable Chronic Lymphocytic Leukemia Patients

Abstract

Background

Chronic lymphocytic leukemia (CLL) has a heterogeneous clinical course. Beside patients requiring immediate treatment, others show an initial indolent phase followed by progression and others do not progress for decades. The latter two subgroups usually display mutated IGHV genes and a favorable FISH profile.

Patients and Methods

Patients with absence of disease progression for over 10 years (11-30) from diagnosis were defined as ultra-stable CLL (US-CLL). Forty US-CLL underwent extensive characterization including whole exome sequencing (WES), ultra-deep sequencing and copy number aberration (CNA) analysis to define their unexplored genomic landscape. Microarray analysis, comparing US-CLL with non US-CLL with similar immunogenetic features (mutated IGHV/favorable FISH), was also performed to recognize US-CLL at diagnosis.

Results

WES was carried out in 20 US-CLL and 84 non-silent somatic mutations in 78 genes were found. When re-tested in a validation cohort of 20 further US-CLL, no recurrent lesion was identified. No clonal mutations of NOTCH1, BIRC3, SF3B1 and TP53 were found, including ATM and other potential progression driving mutations. CNA analysis identified 31 lesions, none with known poor prognostic impact. No novel recurrent lesion was identified: most cases showed no lesions (38%) or an isolated del(13q) (31%). The expression of 6 genes, selected from a gene expression profile analysis by microarray and quantified by droplet digital PCR on a cohort of 79 CLL (58 US-CLL and 21 non US-CLL), allowed to build a decision-tree capable of recognizing at diagnosis US-CLL patients.

Conclusions

The genetic landscape of US-CLL is characterized by the absence of known unfavorable driver mutations/CNA and of novel recurrent genetic lesions. Among CLL patients with favorable immunogenetics, a decision-tree based on the expression of 6 genes may identify at diagnosis patients who are likely to maintain an indolent disease for decades.

Assessment of the efficacy and tolerance of an innovative regenerative serum on cutaneous regeneration, following fractional laser procedure using Erbium:YAG

Summary

Introduction

Cutaneous regeneration, fractional laser, medical device, cellular proliferation cutaneous changes linked to photoaging are currently treated with physical treatments, such as fractional laser, which may induce epidermal alteration.

Objective

To determine the efficacy and safety of a regenerative serum (Matricium^®, Laboratoire Bioderma, France) after laser procedure.

Methods

Prospective, double-blind, controlled, and randomized study in subjects with photoaged skin. The regenerative serum of treatment was used after a fractional laser session twice daily for 2 months on 1 side of the face and the placebo on the other side. The main variable to determine efficacy was the improvement of clinical signs and histological and immunological results.

Results

A superior quality of epidermal regeneration on the treated side compared to the placebo side was observed. Likewise, a superior and faster clinical improvement on static wrinkles was observed on the hemiface on which the regenerative serum was used. After 60 days, the investigator and the subjects observed a moderate to significant improvement of the skin on the treated side and a mild to moderate improvement on the placebo side.

Histological examinations showed a superior thickness of epidermis and higher cellular proliferation rate (Ki67 markers) as well as a superior thickness of dermis with higher increase in elastin density with the regenerative serum compared to placebo.

Conclusion

The use of the regenerative serum after fractional laser on the face accelerated and improved the cutaneous regeneration on both the clinical and histological level and maximized the benefits of the laser procedure.

Japanese case of xeroderma pigmentosum complementation group C with a novel mutation

Increased risk of psoriasis following scabies infection: A nationwide population-based matched-cohort study

Abstract

Both scabies and psoriasis are pruritic inflammatory skin diseases. The clinical manifestations are similar and provocation of psoriasis by mite bite was reported. The association between scabies and psoriasis was not investigated before. We conducted this nationwide population-based matched-cohort study to describe if patients with a diagnosis of scabies have a different risk of developing new psoriasis. From the National Health Insurance Research Database of Taiwan, patients with scabies (n = 5137) were identified and matched for age and sex with non-scabies controls (n = 19 142). We tracked them for a 7-year period to identify the incidence of psoriasis. One hundred and ninety (0.8%) patients with newly diagnosed psoriasis were identified; 91 (1.8%) from the scabies group and 99 (0.5%) from the control group. Patients with scabies had a higher risk of subsequent psoriasis, with a crude hazard ratio of 3.45 and an adjusted hazard ratio (aHR) of 3.03 (95% confidence interval, 2.24–4.11). An increased risk for psoriasis among patients with scabies was observed (aHR, 3.03). Immunopathology involving the T-helper 17 cell-mediated inflammatory pathway may contribute to this association. Physicians may consider implementing assessments of psoriatic symptoms in patients with scabies.

Assessment of medication adherence and treatment satisfaction in Japanese patients with psoriasis of various severities

Abstract

Psoriasis is a chronic, relapsing, inflammatory keratotic skin disease. To elucidate the medication adherence and treatment satisfaction, we performed a questionnaire survey using the eight-item Morisky Medication Adherence Scale (MMAS-8) and nine-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) of 163 psoriatic patients who regularly visited hospitals or clinics. To assess the relationship between the MMAS-8/TSQM-9 outcomes and severity of psoriasis, two different clinical severity indices were used: the Psoriasis Area and the Severity Index (PASI) for disease severity and the Psoriasis Disability Index (PDI) for quality of life (QOL) impairment. The MMAS-8 score for oral medication was significantly higher than that for topical medication. The oral and topical MMAS-8 scores were significantly correlated with the PDI score, but not with the PASI score, indicating that QOL impairment lowered treatment motivation. All of the TSQM-9 domain scores (effectiveness, convenience and global satisfaction) were significantly correlated with both the PASI and PDI scores, suggesting that patients whose skin and QOL conditions were under good control had high satisfaction with treatment. Patients treated with biologics had higher satisfaction than those treated with non-biologics.

Successful management of steroid-resistant vascular tumors associated with the Kasabach–Merritt phenomenon using sirolimus

Abstract

Vascular tumors associated with Kasabach–Merritt phenomenon (KMP) are life-threatening and the mortality is as high as 10–30%. Steroids are considered the primary choice for drug therapy. However, there are many steroid-resistant cases. In the present study, analyzed data are presented to support the use of sirolimus in clinical practise for the treatment of corticosteroid-resistant vascular tumors with KMP in eight infants between June 2015 and April 2017 in a single hospital. The time to initial response was 6.8 ± 2.7 days. The average stabilization time for the platelet count was 19.1 ± 8.5 days. At the time of publication, the average duration of sirolimus treatment was 14.1 ± 4.0 months, and the average time for sirolimus treatment as a single agent was 12.6 ± 4.2 months. The side-effects were tolerable and included oral ulcer, fever, pain, skin rash and transient ascension of serum transaminase and cholesterol. Our study indicated that sirolimus therapy is an effective and safe method for the treatment of corticosteroid resistant vascular tumors associated with KMP in infants.

Association of elevated homocysteine levels and Methylenetetrahydrofolate reductase (MTHFR) 1298 A > C polymorphism with Vitiligo susceptibility in Gujarat

Vitiligo is one of the most common cosmetic disfigurement disorders caused due to loss of functional melanocytes from the epidermis [1]. The disease can affect individuals of any race or sex and manifests before the age of 20 years in approximately half of the patients [2]. Worldwide prevalence of vitiligo is about 0.06–2.28% of the population [3]. The etiology of vitiligo is complex, however, certain genetic predisposition factors and a number of potential precipitating events such as oxidative stress, autoimmunity, neurological factors etc.

Hidradenitis suppurativa, a review of pathogenesis, associations and management. Part 1

Abstract

Hidradenitis suppurativa is a chronic, painful, autoinflammatory condition resulting in nodules, abscesses and sinus tracts. We present an evidence-based review providing new understanding of the pathogenesis of hidradenitis suppurativa and associated comorbidities. By the nature of their speciality, dermatologists are uniquely positioned to investigate and treat patients with this condition. Data collected from a subspecialty hidradenitis suppurativa clinic (N = 106) and experiences thereof are discussed in this review.

Oil mixing behavior after an oil spill: identification conflicts of different fingerprints

Abstract

Clearing up whether spilled oil is mixed or not can strengthen the accuracy of oil spill identification. In the present study, the biomarkers in spilled oil samples were detected. The weathering modes of different types of diagnostic ratio and carbon isotope values of individual n-alkanes were also analyzed. The results showed that the diagnostic ratios of steroids, terpenes and aromatics, and weathering characteristics of carbon isotope composition (δ¹³C) of individual n-alkanes supported the idea that Dalian oil spill emerged from a single oil source. Furthermore, commonly used diagnostic ratios of n-alkanes indicated that the Dalian oil spill had undergone the oil mixing process. The different identifying outcomes indicate that some kinds of n-alkane-rich substance (such as oil dispersants) were mixed in the Dalian spilled oil and interfered with the routine diagnosis ratios of n-alkanes.

Examination of the skin barrier repair/wound healing process using a living skin equivalent (LSE) model and matrix-assisted laser desorption-ionization-mass spectrometry imaging (MALDI-MSI)

Abstract

Objective

Examination of the skin barrier repair/wound healing process using a living skin equivalent (LSE) model and matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) to identify lipids directly involved as potential biomarkers. These biomarkers may be used to determine whether an in vivo wound is going to heal for example if infected.

Methods

An in vitro LSE model was wounded with a scalpel blade and assessed at day 4 post wounding by histology and MALDI-MSI. Samples were sectioned at wound site and were either formalin fixed paraffin embedded (FFPE) for histology or snapped frozen (FF) for MSI analysis.

Results

The combination of using an in vitro wounded skin model with MSI allowed the identification of lipids involved in the skin barrier repair/wound healing process. The technique was able to highlight lipids directly in the wound site and distinguish differences in lipid distribution between the epidermis and wound site.

Conclusion

This novel method of coupling an in vitro LSE with MSI allowed in depth molecular analysis of the skin barrier repair/wound healing process. The technique allowed the identification of lipids directly involved in the skin barrier repair/wound healing process, indicating these biomarkers may be potentially be used within clinic. These biomarkers will help determine, which stage of the skin barrier repair/wound healing process the wound is in to provide the best treatment.

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Differential effects of secukinumab vs. ustekinumab for treatment of psoriasis on quality of life, work productivity and activity impairment: a structural equation modelling analysis

Abstract

Purpose

This study examined direct and indirect (mediated) effects of secukinumab vs. ustekinumab on quality of life, work productivity, and activity impairment based on psoriasis severity and symptoms.

Methods

Analyses were based on data from the CLEAR study. Structural equation modelling (SEM) examined the effects of secukinumab vs. ustekinumab on the Dermatology Life Quality Index (DLQI) and on the Work Productivity and Activity Impairment (WPAI) questionnaire using Psoriasis Area Severity Index (PASI) severity and symptoms (pain, itching, and scaling) as potential mediators. Analyses were conducted primarily for patients achieving PASI 90 response (indicating a 90% or greater reduction in PASI from baseline) at week 16 (repeated at week 52) and for PASI 50, 75, and 100.

Results

Results at weeks 16 and 52 showed that the effect of treatment on change in DLQI score was mediated by PASI 90 response and by improvements in itching and scaling. Achieving any PASI response as early as week 16 directly resulted in significantly better WPAI scores. At week 52, both PASI response and improvement in scaling directly resulted in significantly better WPAI scores. Pain, itching, and scaling were correlated (r = 0.51 to 0.68); improvement in any of these had a significant effect (directly or indirectly) on WPAI. All results favoured secukinumab over ustekinumab.

Conclusion

The results underscore the important role of both PASI response and reduction in symptoms on improvements in health-related quality of life and work and daily activity in favour of secukinumab vs. ustekinumab.

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How should minimally important change (MIC) scores for the Patient Oriented Eczema Measure (POEM) be interpreted? A validation using varied methods

Summary

Background

The Patient Oriented Eczema Measure (POEM), scored 0-28, is the core outcome instrument recommended for measuring patient-reported atopic eczema symptoms in clinical trials. To date, two published studies have broadly concurred that the MIC of the POEM is 3 points. Further assessment of the minimally important change (MIC) of POEM in different populations, and using a variety of methods, will improve interpretability of the POEM in research and clinical practice.

Objectives

To calculate the smallest detectable change in the POEM and estimate the MIC of the POEM using a variety of methods in a trial dataset of children with moderate to severe atopic eczema.

Methods

This study used distribution-based and anchor-based methods to calculate the MIC of the POEM in children with moderate to severe eczema.

Results

Data was collected from 300 children. The smallest detectable change was 2.12. The MIC estimates were 1.07 (0.2 SD) and 2.68 (0.5 SD) based on distribution-based methods, were 3.09 to 6.13 based on patient-reported anchor-based methods, and were 3.23 to 5.38 based on investigator-reported anchor-based methods.

Conclusions

We recommend the following thresholds are used to interpret changes in POEM scores: ≤ 2, unlikely to be a change beyond measurement error; 2.1 to 2.9, a small change detected that is likely to be beyond measurement error but may not be clinically important; 3 to 3.9, probably a clinically important change; 4+, very likely to be a clinically important change.

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In vivo dermoscopic and confocal microscopy multi-step algorithm to detect in situ melanomas

Summary

Background

Although several dermoscopic features of in situ melanoma (MIS) have been identified, data on confocal features for MIS are still lacking.

Objectives

To identify RCM (reflectance confocal microscopy) features of MIS and to develop a diagnostic score for MIS while combining dermoscopy and RCM.

Methods

120 MIS and 213 nevi (test set) were retrospectively analysed to assess the presence of dermoscopic and RCM criteria. Facial and acral lesions have been excluded. Spearman's correlation, univariate and multivariate regression models were performed to find features significantly correlated with MIS diagnosis. Multivariate results on the test set allowed the development of a multi-step algorithm, that was tested on a validation set counting 100 lesions.

Results

Dermoscopic atypical network and regression resulted as independent predicting factors for MIS diagnosis (OR=3.437, 95%CI=1.696-6.966 and OR=4.168, 95%CI=1.930-9.002 respectively). Significant confocal predictors for malignancy were epidermal pagetoid spread (OR=2.829, 95%CI=1.324-6.043) and junctional cytological atypia (OR=3.390, 95%CI=1.383-8.305 if focal, OR=8.439, 95%CI=3.213-22.165 if widespread). A multi-step diagnostic algorithm able to predict MIS with a sensitivity of 92.5% and a specificity of 61% was developed. The validation set confirmed the high diagnostic value (sensitivity 92%, specificity 58%).

Conclusions

An easy and reproducible multi-step algorithm for MIS detection is suggested, that can be routinely used in tertiary centres.

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Analysis of the skin mycobiome in adult patients with atopic dermatitis

Abstract

With the recent availability of culture-independent sequencing methods, studies have been conducted to analyze skin microorganisms present in patients with atopic dermatitis (AD). However, the database on the skin fungal communities, "mycobiome," has been relatively restrictive compared with the bacterial world. We aimed to comparatively analyze the overall skin mycobiome between patients with AD and healthy individuals in the Korean population. We analyzed skin swab samples obtained from the antecubital fossae of 8 patients with AD and 8 healthy controls. Using sequencing method followed by direct DNA extraction and molecular PCR, taxonomic compositions of fungi at stepwise level ranks were analyzed. The phylogenic marker used was internal transcribed spacer 2 regions of DNA. We observed the tendency of higher intra- and inter-personal taxonomic diversity at genus and species levels in AD samples. Non-Malassezia fungal diversity was also noticeable in the patient group compared with healthy controls. Malassezia globosa and Malassezia restricta were prevalent in all samples across both study groups, and some Malassezia species, including Malassezia sloofiae and dermatis characterized AD. Our data might provide a new insight into the mycobiome of adult AD, which contributes to building a systemic mycobiome database in AD.

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Seasonal changes in epidermal ceramides are linked to impaired barrier function in acne patients

Abstract

Acne skin demonstrates increased transepidermal water loss (TEWL) compared with healthy skin, which may be due, in part, to altered ceramide levels. We analysed ceramides in the stratum corneum of healthy and acne skin, and studied seasonal variation over the course of a year. Using ultraperformance liquid chromatography with electrospray ionisation and tandem mass spectrometry (UPLC/ESI-MS/MS), we identified 283 ceramides. Acne-affected skin demonstrated overall lower levels of ceramides, with notable reductions in CER[NH] and CER[AH] ceramides, as well as the acylceramides CER[EOS] and CER[EOH]; these differences were more apparent in the winter months. Lower ceramide levels reflected an increase in TEWL in acne, compared with healthy skin, which partly resolves in the summer. Individual ceramide species with 18-carbon 6-hydroxysphingosine (H) bases (including CER[N(24)H(18)], CER[N(26)H(18)], CER[A(24)H(18)], CER[A(26)H(18)]) were significantly reduced in acne skin, suggesting that CER[NH] and CER[AH] species may be particularly important in a healthy skin barrier.

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Predicting the Hearing Outcome in Sudden Sensorineural Hearing Loss via Machine Learning Models

Abstract

Objective

Sudden sensorineural hearing loss (SSHL) is a multifactorial disorder with high heterogeneity, thus the outcomes vary widely. The present study aimed to develop predictive models based on four machine learning methods for SSHL, identifying the best performer for clinical application.

Design

Single-center retrospective study.

Setting

Chinese People's liberation army (PLA) hospital, Beijing, China.

Participants

1220 in-patient SSHL patients were enrolled between June 2008 and December 2015.

Main outcome measures

An advanced deep learning technique, deep belief network (DBN), together with the conventional logistic regression (LR), support vector machine (SVM) and multilayer perceptron (MLP) were developed to predict the dichotomized hearing outcome of SSHL by inputting six feature collections derived from 149 potential predictors. Accuracy, precision, recall, F-score and the area under the receiver operator characteristic curves (ROC-AUC) were exploited to compare the prediction performance of different models.

Results

Overall the best predictive ability was provided by the DBN model when tested in the raw dataset with 149 variables, achieving an accuracy of 77.58% and AUC of 0.84. Nevertheless DBN yielded inferior performance after feature pruning. In contrast, the LR, SVM and MLP models demonstrated opposite trend as the greatest individual prediction powers were obtained when included merely three variables, with the ROC-AUC ranging from 0.79 to 0.81, and then decreased with the increasing size of input features combinations.

Conclusions

With the input of enough features, DBN can be a robust prediction tool for SSHL. But LR is more practical for early prediction in routine clinical application by using three readily available variables, i.e. time elapse between symptom onset and study entry, initial hearing level and audiogram.

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Botulinum toxin B suppresses the pressure ulcer formation in cutaneous ischemia-reperfusion injury mouse model: Possible regulation of oxidative and endoplasmic reticulum stress

With the aging of populations, the importance of prevention, treatment, and management of pressure ulcers (PUs), also known as decubitus ulcers, has been increasing more than ever. In the early phase of PU formation, non-blanchable erythema and/or purpuric lesions appear in the skin subjected to external pressure, and skin ulcers subsequently develop 2–3 weeks later [1]. Currently, there has been no evidence-based treatment in the early phase of PUs to prevent the development of skin ulcers. For example, only close observation and the use of protective film dressings on the lesion of early-phase PUs are recommended by the guidelines in the Japanese Dermatological Association (JDA) and the Japanese Society for Pressure Ulcers (JSPU) [2,3].

HSP72 functionally inhibits the anti-neoplastic effects of HDAC inhibitors

Histone deacetylase inhibitors (HDACi) enhance the acetylation of both histones and non-histone proteins, and induce apoptosis. They are potential therapeutic agents for the treatment of lymphoid neoplasms, but, with an overall remission rate of approximately 30%, they exhibit limited effectiveness [1–4]. The molecular mechanisms underlying the variability in HDACi sensitivity remain largely unknown; however, HR23B, a candidate biomarker for HDACi sensitivity [5], has been shown to regulate HDACi-induced apoptosis and autophagy [6].

Suppression of autophagy perturbs turnover of sequestosome-1/p62 in Merkel cells but not in keratinocytes

Autophagy is the main mechanism for the degradation of intracellular molecules and organelles via lysosomes. A decline of autophagic activity is associated with aging and aberrant levels of autophagy in various cell types have been linked to the initiation and progression of diseases [1,2]. To unravel roles of autophagy in epithelial cells of the skin in vivo, we have generated a mouse model [3] in which the essential autophagy gene Autophagy related 7 (Atg7) is deleted by the Cre-loxP system in keratin K14-positive cells that give rise to epidermis, skin appendages and Merkel cells.