Summary
Molecular diagnostics (MDx) has become an indispensable pillar of diagnostics in dermatology. Modern sequencing technologies allow for identification of rare genodermatoses, analysis of ...somatic mutations in melanoma are prerequisite for targeted therapies, and cutaneous infectious pathogens are quickly detected by PCR and other amplification methods. However, to push innovation in molecular diagnostics and tackle so far unmet clinical needs, research activities need to be bundled and the pipeline from idea to MDx product clearly rolled out. Only then, the requirements for technical validity and clinical utility of novel biomarkers can be fulfilled and the long‐term vision of personalized medicine will be realized.
Zusammenfassung
Die Molekulardiagnostik (MDx) ist zu einer unentbehrlichen Säule der Diagnostik in der Dermatologie geworden. Moderne Sequenzierungstechnologien ermöglichen die Identifizierung ...seltener Genodermatosen, die Analyse somatischer Mutationen beim Melanom ist Voraussetzung für zielgerichtete Therapien und infektiöse Erreger der Haut lassen sich durch PCR und andere Amplifikationsverfahren schnell nachweisen. Um allerdings Innovation in der Molekulardiagnostik voranzutreiben und bislang ungedeckte klinische Bedarfe zu decken, müssen die Forschungsaktivitäten gebündelt und die Pipeline von der Idee bis zum MDx‐Produkt klar strukturiert werden. Nur so können die Anforderungen an die technische Validität und den klinischen Nutzen neuartiger Biomarker erfüllt werden und die lang gehegte Vision von personalisierter Medizin verwirklicht werden.
Background
Atopic dermatitis (AD) is the most common inflammatory skin disease in children, with 30% of all those diagnosed developing chronic or relapsing disease by adolescence. Such disease ...persistence cannot yet be predicted. The aim of the present study was to predict the natural course of AD using clinical parameters and serum proteins.
Methods
Sera of 144 children with AD (age 0‐3 years) were analyzed for IgE and 33 cytokines, chemokines, and growth factors. Patient disease course until the age of 7 years was assessed retrospectively. Unsupervised k‐means clustering was performed to define disease endotypes. Identified factors associated with AD persistence at the age of 7 years were validated in children with AD in an independent cohort (LISA Munich; n = 168). Logistic regression and XGBoosting methods followed by cross‐validation were applied to predict individual disease outcomes.
Results
Three distinct endotypes were found in infancy, characterized by a unique inflammatory signature. Factors associated with disease persistence were disease score (SCORAD), involvement of the limbs, flexural lesion distribution at the age of 3 years, allergic comorbidities, and disease exacerbation by the trigger factors stress, pollen exposure, and change in weather. Persistence was predicted with a sensitivity of 81.8% and a specificity of 82.4%. Factors with a high impact on the prediction of persistence were SCORAD at the age of 3 years, trigger factors, and low VEGF serum levels.
Conclusion
Atopic dermatitis in infancy comprises three immunological endotypes. Disease persistence can be predicted using serum cytokines and clinical variables.
Three distinct endotypes are found in infant AD. Persistence of AD at the age of 7 years is predicted with a sensitivity and specificity >80%. Factors with a high impact on the prediction of persistence are SCORAD at the age of 3 years, milk crust, aggravation triggered by change in the weather, and low VEGF serum levels.
Abbreviations: AD, atopic dermatitis; SCORAD, scoring of atopic dermatitis; VEGF, vascular endothelial growth factor.
Abstract
Mechanistic insight into ageing may empower prolonging the lifespan of humans; however, a complete understanding of this process is still lacking despite a plethora of ageing theories. In ...order to address this, we investigated the association of lifespan with eight phenotypic traits, that is, litter size, body mass, female and male sexual maturity, somatic mutation, heart, respiratory, and metabolic rate. In support of the somatic mutation theory, we analysed 15 mammalian species and their whole‐genome sequencing deriving somatic mutation rate, which displayed the strongest negative correlation with lifespan. All remaining phenotypic traits showed almost equivalent strong associations across this mammalian cohort, however, resting heart rate explained additional variance in lifespan. Integrating somatic mutation and resting heart rate boosted the prediction of lifespan, thus highlighting that resting heart rate may either directly influence lifespan, or represents an epiphenomenon for additional lower‐level mechanisms, for example, metabolic rate, that are associated with lifespan.
Summary
Background and objectives
Molecular diagnostics (MDx) increasingly gains importance in dermatology and its application is a prerequisite for personalized medicine. The goal of this ...cross‐sectional study was to determine how MDx is implemented in dermatologists’ offices in the three fields of oncology, inflammation and infectiology and which hurdles office‐based dermatologists face in terms of MDx.
Methods
Physician members of the Association of the German Dermatologists (Berufsverband der Deutschen Dermatologen e. V.; BVDD) were surveyed via an online questionnaire on MDx.
Results
39.6 % of the 192 participants reported using MDx. Of these, the vast majority used MDx for diagnosing infectious diseases (86.5 % and 44.3 % of users perform MDx for detection of funghi and sexually transmitted diseases, respectively). Only a small minority applied MDx to answer oncological or immunological questions. The major obstacles for non‐users as compared to users were difficulties in implementation, lack of expertise as well as time, personnel, and technical availability. Reimbursement was a main issue in both groups.
Conclusions
Despite availability of specific therapies requiring precision medicine, MDx has not yet been broadly implemented in office‐based dermatology. To advance MDx, more needs to be done in terms of continuous education, availability of reliable and valid tests, and reimbursability.
Histopathological differentiation of early Mycosis Fungoides (MF) from benign chronic inflammatory dermatoses remains difficult and often impossible, despite the inclusion of all available diagnostic ...parameters.
To identify the most impactful histological criteria for a predictive diagnostic model to discriminate MF from atopic dermatitis (AD).
In this multicenter study, two cohorts of patients with either unequivocal AD or MF were evaluated by two independent dermatopathologists. Based on 32 histological attributes, a hypothesis-free prediction model was developed and validated on an independent patient's cohort.
A reduced set of two histological features (presence of atypical lymphocytes in either epidermis or dermis) was trained. In an independent validation cohort, this model showed high predictive power (95% sensitivity and 100% specificity) to differentiate MF from AD and robustness against inter-individual investigator differences.
The study investigated a limited number of cases and the classifier is based on subjectively evaluated histological criteria.
Aiming at distinguishing early MF from AD, the proposed binary classifier performed well in an independent cohort and across observers. Combining this histological classifier with immunohistochemical and/or molecular techniques (such as clonality analysis or molecular classifiers) could further promote differentiation of early MF and AD.
This essay reviews current approaches to establish novel molecular diagnostic tools for inflammatory skin diseases. Moreover, it highlights the importance of stratifying patients according to ...molecular signatures and revising current outdated disease classification systems to eventually reach the goal of personalized medicine.
Psoriasis is a T helper type 17–mediated immune disease. Initial triggers that lead to T helper type 17 production and inflammatory cell recruitment into skin are being delineated. Autoantigens that ...stimulate T helper type 17 cells are also being identified. A new and important piece of the puzzle indicates that keratinocytes not only amplify inflammation, but that they are essential for a full-blown IL-17–mediated psoriatic phenotype in mice.
Raster-scan optoacoustic mesoscopy (RSOM), also termed photoacoustic mesoscopy, offers novel insights into vascular morphology and pathophysiological biomarkers of skin inflammation in vivo at depths ...unattainable by other optical imaging methods. Using ultra-wideband detection and focused ultrasound transducers, RSOM can achieve axial resolution of 4 micron and lateral resolution of 20 micron to depths of several millimeters. However, motion effects may deteriorate performance and reduce the effective resolution. To provide high-quality optoacoustic images in clinical measurements, we developed a motion correction algorithm for RSOM. The algorithm is based on observing disruptions of the ultrasound wave front generated by the vertical movement of the melanin layer at the skin surface. From the disrupted skin surface, a smooth synthetic surface is generated, and the offset between the two surfaces is used to correct for the relative position of the ultrasound detector. We test the algorithm in measurements of healthy and psoriatic human skin and achieve effective resolution up to 5-fold higher than before correction. We discuss the performance of the correction algorithm and its implications in the context of multispectral mesoscopy.
PDF
