Clinicopathological Challenge: A New Article Type in Dermatopathology.

As the Editor-in-Chief of Dermatopathology, I have the great pleasure of announcing a new article type: "Clinicopathological Challenge" [...].

Annular papulovesicular lesions with a purpuric center in a female inpatient.

Epidermal multinucleated keratinocytes, or epidermal grape cells, in the absence of any viral infection, are an important histological finding and a clue for the diagnosis of dermatoses induced by external irritation or aggression, dermatitis artefacta, and facticial dermatitis. Thermal damage such as cryogenic injury is part of the spectrum of causes to be evoked in case of their presence.

The Leading Impact Journal in Dermatopathology.

As the Editor-in-Chief of Dermatopathology and the President of the European Society of Dermatopathology (ESDP), I have the great pleasure of celebrating the 10th anniversary of Dermatopathology, the only online journal in the field of cutaneous pathology and the official journal of the ESDP [...].

Development of an ex vivo porcine skin model for the preclinical evaluation of subcutaneously injected biomacromolecules.

Subcutaneous administration is used to deliver systemically-acting biotherapeutics, e.g. antibodies, and locally-acting biomacromolecules, e.g. hyaluronic acid. However, few preclinical models are available to evaluate post-injection behaviour in the tissue microenvironment. In vivo animal studies are costly, time-consuming, and raise obvious ethical concerns. In vitro models are cost-efficient, high-throughput solutions, but cannot simulate complex skin structure and biological function. An ex vivo model (containing hypodermis) with an extended culture period that enabled longitudinal studies would be of great interest for both the pharmaceutical and cosmeceutical industries. We describe the development of one such ex vivo model, using viable full-thickness porcine skin. Structural integrity was evaluated using a histological scoring system: spongiosis and epidermal detachment were identified as discriminating parameters. Ki67 and Claudin-1 expression reported on epidermal cell proliferation and barrier function, respectively and their expression decreased as a function of incubation time. After optimization, the system was used to investigate the fate/impact of subcutaneously administered hyaluronic acid (HA) formulations. The results showed that HA was localized at the injection site and adjacent adipocytes were well preserved during 5 days' incubation and confirmed that the full-thickness ex vivo porcine skin model could provide a platform for preclinical evaluation of subcutaneously injected biomacromolecules.

Wear and Thermal Behavior of TiAlN Thin Films onto Ti6Al4V Alloy Manufactured by Selective Laser Melting Method.

In this study, it was targeted to enhance the tribological and thermal properties of Ti6Al4V alloys, which were manufactured with three different build orientations and hatch spacing by using the selective laser melting (SLM) method and a traditional method (casting). In addition, the surfaces of the samples produced by these two methods were coated with the TiAlN thin film by using the cathodic arc physical vapor deposition (CAPVD) method. After the experimental investigations, the lowest wear rate was obtained for the 60-90° sample, and the highest microhardness value was measured as ∼1070 HV0.1 for the 90-45° sample. It was specified that the wear rate rose as the hatch spacing increased among the same build orientation Ti6Al4V alloys produced by SLM method. According to thermal analysis results, among the same hatch spacing values, it was determined that as the build orientation value increased, the specific heat capacity and thermal conductivity values decreased. Among the coated samples, the highest thermal conductivity and specific heat capacity values were obtained for casting samples as 5.63 (W/m·K) and 560.4 (J/kg·K), respectively.

Clonal expansion of intra-epithelial T cells in breast cancer revealed by spatial transcriptomics.

The spatial distribution of tumor-infiltrating lymphocytes (TIL) predicts breast cancer outcome and response to systemic therapy, highlighting the importance of an intact tissue structure for characterizing tumors. Here, we present ST-FFPE, a spatial transcriptomics method for the analysis of formalin-fixed paraffin-embedded samples, which opens the possibility of interrogating archival tissue. The method involves extraction, exome capture and sequencing of RNA from different tumor compartments microdissected by laser-capture, and can be used to study the cellular composition of tumor microenvironment. Focusing on triple-negative breast cancer (TNBC), we characterized T cells, B cells, dendritic cells, fibroblasts and endothelial cells in both stromal and intra-epithelial compartments. We found a highly variable spatial distribution of immune cell subsets among tumors. This analysis revealed that the immune repertoires of intra-epithelial T and B cells were consistently less diverse and more clonal than those of stromal T and B cells. T-cell receptor (TCR) sequencing confirmed a reduced diversity and higher clonality of intra-epithelial T cells relative to the corresponding stromal T cells. Analysis of the top 10 dominant clonotypes in the two compartments showed a majority of shared but also some unique clonotypes both in stromal and intra-epithelial T cells. Hyperexpanded clonotypes were more abundant among intra-epithelial than stromal T cells. These findings validate the ST-FFPE method and suggest an accumulation of antigen-specific T cells within tumor core. Because ST-FFPE is applicable for analysis of previously collected tissue samples, it could be useful for rapid assessment of intratumoral cellular heterogeneity in multiple disease and treatment settings.

Senotherapeutic Effect of Retinaldehyde and Hyaluronate Fragments in Dermatoporosis.

Cellular senescence is one of the important mechanisms of skin aging. In a recent study, we have shown that in patients with dermatoporosis, an extreme senescence condition of the skin, cells positive for p16Ink4a, a biomarker of senescence, were significantly increased in the epidermis. Senescent cells can develop a senescence-associated secretory phenotype (SASP) comprising pro-inflammatory cytokines, chemokines, and other soluble factors, leading to chronic inflammation and tissue dysfunction. These senescent cells and SASP pathways represent therapeutic targets for the development of senotherapeutics either by inducing selective cell death of senescent cells called senolytics, or suppressing markers of the SASP, called senomorphics. In this study where we conducted a retrospective immunohistochemical analysis of p16Ink4a expression in the skin samples of dermatoporosis patients included in a previous clinical study, we describe the senotherapeutic effect of retinaldehyde (RAL) and intermediate-size hyaluronate fragments (HAFi). Topical application of RAL and HAFi significantly reduced the number of p16Ink4a-positive cells in the epidermis and dermis in dermatoporosis patients which also showed a significant clinical improvement.

[Mpox (Monkeypox): from a dermatologist's point of view]. / Mpox (variole du singe) : l'œil du dermatologue.

Mpox (Monkeypox) was largely unknown in Switzerland before the outbreak that started in May 2022 and spread worldwide, including Europe and the Americas. This article reviews the clinical manifestations and treatment of this infection while emphasizing the importance of clinical observation. Rapid identification and diagnosis of cases allow a more efficient application of sanitary measures in order to prevent further spreading of the disease.

La mpox (variole du singe) était une maladie largement méconnue dans notre pays avant la poussée épidémique de mai 2022. Cette dernière a essaimé dans plusieurs pays, notamment en Europe et aux Amériques. Nous abordons ici les symptômes et signes cliniques ainsi que le traitement de cette maladie, tout en rappelant l'importance de l'observation clinique en médecine. Un diagnostic précoce des patients infectés permet une application plus efficace des mesures sanitaires afin de limiter la propagation.

Inflammation modulates intercellular adhesion and mechanotransduction in human epidermis via ROCK2.

Aberrant mechanotransduction and compromised epithelial barrier function are associated with numerous human pathologies including inflammatory skin disorders. However, the cytoskeletal mechanisms regulating inflammatory responses in the epidermis are not well understood. Here we addressed this question by inducing a psoriatic phenotype in human keratinocytes and reconstructed human epidermis using a cytokine stimulation model. We show that the inflammation upregulates the Rho-myosin II pathway and destabilizes adherens junctions (AJs) promoting YAP nuclear entry. The integrity of cell-cell adhesion but not the myosin II contractility per se is the determinative factor for the YAP regulation in epidermal keratinocytes. The inflammation-induced disruption of AJs, increased paracellular permeability, and YAP nuclear translocation are regulated by ROCK2, independently from myosin II activation. Using a specific inhibitor KD025, we show that ROCK2 executes its effects via cytoskeletal and transcription-dependent mechanisms to shape the inflammatory response in the epidermis.

Characteristics of long-survivor metastatic melanoma after polychemotherapy and interferon: a retrospective study.

BACKGROUND: The development of immunotherapy and tyrosine kinase inhibitors dramatically improved the prognosis of metastatic melanoma. Consequently, chemotherapy is now rarely used. Here, we describe the characteristics of long-surviving patients with metastatic melanoma treated with immunochemotherapy. MATERIAL AND METHODS: We retrieved retrospective clinical and pathological data for patients diagnosed with metastatic melanoma between January 1993 and December 2015 who received the CVD-INF (cisplatin, vinblastine, dacarbazine, and interferon α-2b) regimen at the Hôpitaux Universitaires de Genève. We estimated their progression-free survival and overall survival. This ad hoc study's primary aim was to describe the clinical and biological characteristics of long-term survivors, defined as patients surviving more than two years after immunochemotherapy initiation. The spatial distribution pattern of CD8+ T cells (inflamed, excluded, or desert) was immunohistochemically determined. RESULTS: Ninety patients received CVD-INF. Their median age at metastatic melanoma diagnosis was 55 years (20-75). Their median progression-free survival was 2.8 months, and median overall survival was 7.2 months. Eleven (12%) patients were long-term survivors. In multivariate analysis, central nervous system metastases (hazard ratio [HR]: 2.66; 95% confidence interval [CI]: 1.43-4.95; p = 0.001), multiple metastases (HR: 1.82; 95% CI: 1.01-3.29; p = 0.047), and elevated lactate dehydrogenase (LDH) (HR: 1.92; 95% CI: 1.12-3.30; p = 0.016) were independently associated with shorter survival. Most long-survivors (6/8; 75%) had a tumour-inflamed pattern compared to 25% of non-long survivors (5/20; Fisher's test p = 0.030). CONCLUSIONS: A subset of patients with metastatic melanoma and a tumour-inflamed phenotype treated with CVD-INF survived over two years. Factors associated with prolonged survival are consistent with those previously reported in metastatic melanoma.

Perforating Fibrous Histiocytoma Mimicking Keratoacanthoma: A Case Report.

A 31-year-old male presented with a firm, well-demarcated, erythematous, crateriform, and ulcerated nodule in the left lumbar region, which persisted for 3 months. Clinically, a keratoacanthoma was suspected. The histological analysis was consistent with perforating fibrous histiocytoma, a rare histopathologic variant of fibrous histiocytoma. To our knowledge, this is the third case reported in the literature.

In Memoriam-Martin C. Mihm, Jr.

Martin C [...].

Pseudo-Pemphigoid Gestationis Eruption Following SARS-CoV-2 Vaccination with mRNA Vaccine.

Auto-immune reactions, including auto-immune bullous disease, have been reported following SARS-CoV-2 virus vaccination. Few cases of bullous pemphigoid are described, but there has been no case of pemphigoid gestationis. We report the first case here.

IL-38 orchestrates proliferation and differentiation in human keratinocytes.

Interleukin (IL)-38 is a member of the IL-1 cytokine family with reported anti-inflammatory activity. The highest constitutive IL-38 expression is detected in the skin, where it is mainly produced by differentiating keratinocytes. However, little data are available regarding its biological functions. In this study, we investigated the role of IL-38 in skin physiology. We demonstrate here that dermal fibroblasts and epithelial cells of skin appendages, such as eccrine sweat glands and sebaceous glands, also express IL-38. Next, using two- and three-dimensional cell cultures, we show that endogenous expression of IL-38 correlates with keratinocyte differentiation and its ectopic overexpression inhibits keratinocyte proliferation and enhances differentiation. Accordingly, immunohistochemical analysis revealed downregulation of IL-38 in skin pathologies characterized by keratinocyte hyperproliferation, such as psoriasis and basal or squamous cell carcinoma. Finally, intracellular IL-38 can shuttle between the nucleus and the cytoplasm and its overexpression modulates the activity of the transcription regulators YAP and ID1. Our results indicate that IL-38 can act independently from immune system activation and suggest that it may affect the epidermis directly by decreasing proliferation and promoting differentiation of keratinocytes. These data suggest an important role of keratinocyte-derived IL-38 in skin homeostasis and pathologies characterized by epidermal alterations.

[Skin and pregnancy]. / Peau et grossesse.

Pregnancy has a substantial impact on the hormonal status of the organism, consequently influencing the physiology of the skin. This results in dermatoses that only occur during pregnancy, which can also improve or exacerbate pre-existing dermatoses. In this article, we explain the management of pregnancy-specific dermatoses : atopic eruption of pregnancy, polymorphic eruption of pregnancy, pemphigoid gestationis, impetigo herpetiformis, and intrahepatic cholestasis of pregnancy. It is essential to clearly distinguish these different dermatoses as some of them, such as pemphigoid gestationis, impetigo herpetiformis and intrahepatic cholestasis of pregnancy, can have fetal consequences and as result, need to be closely monitored by the obstetricians.

La grossesse a un impact considérable sur le statut hormonal de l'organisme, influençant ainsi la physiologie cutanée. Cela se traduit par des dermatoses qui ne se manifestent que pendant la grossesse. Cette dernière peut également améliorer ou exacerber des dermatoses préexistantes. Dans cet article, nous précisons la prise en charge des dermatoses spécifiques de la grossesse : l'eczéma atopique de la grossesse, l'éruption polymorphe gravidique, la pemphigoïde gestationnelle, l'impétigo herpétiforme et la cholestase intrahépatique gravidique. Il est important de distinguer ces dermatoses, puisque la pemphigoïde gestationnelle, l'impétigo herpétiforme et la cholestase intrahépatique gravidique présentent un risque fœtal et par conséquence nécessitent un suivi obstétrical rapproché.

Investigation of the Presence of SARS-CoV-2 in Aerosol After Dental Treatment.

AIMS: The objective of the present study was to investigate the presence of SARS-CoV-2 in aerosol and COVID-19 contamination distance asssociated with ultrasonic scaling and tooth preparation. METHODS: Twenty-four patients with COVID-19 were included in this study. Removal of supragingival plaque with ultrasonic instruments for 10 minutes and high-speed air-turbine using for the simulation of cutting the maxillary right canine tooth with a round diamond bur for 5 minutes were performed. Patients were randomly assigned to 2 groups: In group A, medium-volume suction was used during treatment. In group B, high-volume suction with an aerosol cannula was added to medium-volume suction. Prior to treatment, 5 glass petri dishes containing viral transport medium were placed in the operating room. After treatment, petri dishes were immediately delivered to a microbiology laboratory for real-time polymerase chain reaction (RT-PCR) analysis. RESULTS: RT-PCR test results were negative for all specimens in group B. However, 5 positive test results for COVID-19 were detected in group A specimens. CONCLUSIONS: Suction with an aerosol cannula is very important to prevent COVID-19 viral contamination via aerosol. In addition, a high-volume suction capacity (air volume) of 150 mm Hg or 325 L/min is sufficient for elimination of viral contamination. Thus, high-volume suction should be used during dental treatments in COVID-19 patients.

A New Case of Hybrid Epidermoid and Apocrine Cyst.

We described a new case of a hybrid epidermoid and apocrine cyst, known to be a rare histopathological entity. The cyst was located in the axillary region and completely excised, without complication. The diagnosis was made at the histological analysis, where we found a cystic lesion in the dermis, lined with both epidermoid and apocrine epithelium.

5-Hydroxymethylcytosine Loss in Conjunctival Melanoma.

AIMS: Conjunctival and cutaneous melanoma partially share similar clinical and molecular backgrounds. As 5-hydroxymethylcytosine (5-hmC) loss has been demonstrated in cutaneous melanoma, we decided to assess if similar changes were occurring in conjunctival melanoma. METHODS: 5-methylcytosine (5-mC), 5-hmC and TET2 were respectively identified by immunohistochemistry and RNA ISH in 40 conjunctival nevi and 37 conjunctival melanomas. Clinicopathological correlations were established. RESULTS: 5-mC, TET2 and 5-hmC were respectively identified in 67.5%, 95% and 100% of conjunctival nevi and in 81.1%, 35.1% and 54% of conjunctival melanomas. A significant 5-hmC and TET2 loss was identified in conjunctival melanoma comparing to nevus, as well as a significant correlation between TET2 and 5-hmC expression. In the melanomas, 5-hmC expression was only significantly associated with local lymphatic invasion, but not with other clinicopathological parameters. There was a correlation between TET2 expression and the localization of the tumors. 5-mC expression was not associated with any clinicopathological parameters. CONCLUSIONS: We identified a significant 5-hmC loss in conjunctival melanoma similar to cutaneous melanoma. This loss may possibly be attributed to TET2 loss or IDH1 mutations. 5-hmC loss in conjunctival melanoma may help in the differential diagnosis between atypical conjunctival nevus and conjunctival melanoma.