[Diabetes-related skin lesions : a frequently underdiagnosed problem]. / Lésions cutanées liées au diabète : une problématique souvent sous-diagnostiquée.

Skin disorders are common in diabetes, affecting both patients with type 1 and type 2 diabetes. These cutaneous manifestations can be classified into three categories: dermatoses associated with the presence of diabetes, cutaneous complications of diabetes (acute and chronic) and dermatoses linked to antidiabetic treatments. These conditions vary considerably in terms of severity (from insignificant cosmetic problems to life-threatening) and prevalence (from relatively frequent to rare). Despite the high prevalence of diabetes and associated skin disorders, the dermatological manifestations of diabetes are generally neglected and often under-diagnosed. Failure to diagnose and treat skin disorders at an early stage can lead to clinical worsening, whereas early detection and treatment can reduce the risk of serious complications.

Chez les personnes atteintes d'un diabète de type 1 ou 2, les atteintes cutanées sont fréquentes. Elles peuvent être classées en trois catégories : les dermatoses associées à la présence du diabète, ses complications cutanées (aiguës et chroniques) et les dermatoses liées aux traitements antidiabétiques. Ces atteintes varient considérablement en gravité (allant de préoccupations esthétiques banales à potentiellement mortelles) et en prévalence (relativement fréquentes à rares). Malgré la prévalence élevée du diabète et des atteintes cutanées associées, les manifestations dermatologiques sont généralement négligées et souvent sous-diagnostiquées. L'absence de diagnostic et de traitement à un stade précoce peut entraîner une aggravation clinique dermatologique. La détection et le traitement précoces de ces atteintes peuvent réduire le risque de complications graves.

Swiss Recommendations for Cutaneous Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer in Switzerland and worldwide. Most BCCs can be treated in a curative setting. However, patients can develop locally destructive and, rarely, metastatic tumors that require a different treatment approach. The clinical subtype of individual lesions provides prognostic information and influences management decisions. Surgical excision, topical therapies, and radiotherapy are highly effective in the majority of subtypes as well as in low- and high-risk diseases. For patients with low-risk diseases and superficial tumors not amenable to surgery, several nonsurgical alternatives are available. Systemic therapy is indicated for high-risk BCCs, which are not amenable to either surgery or radiotherapy. Hedgehog pathway inhibitors (HHI) are currently approved. Other therapeutic options such as immune checkpoint inhibitors show promising results in clinical trials. This first version of Swiss recommendations for diagnosis and management of BCC was prepared through extensive literature review and an advisory board consensus of expert dermatologists and oncologists in Switzerland. The present guidelines recommend therapies based on a multidisciplinary team approach and rate of recurrence for individual lesions. Based on the risk of recurrence, two distinct groups have been identified: low-risk (easy-to-treat) and high-risk (difficult-to-treat) tumors. Based on these classifications, evidence-based recommendations of available therapies are presented herein.

[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.

[Short telomere syndrome in adults: a rare entity that should be evoked]. / Syndrome des télomères courts chez l'adulte†: une entité rare qu'il faut savoir évoquer.

Short telomere syndrome (STS) is a group of rare, often underrecognized, diseases caused by defects in telomere-maintenance genes, leading to abnormal telomere shortening and associated with diverse multi-organ manifestations. In pediatric patients, STS typically presents with mucocutaneous or gastrointestinal lesions, bone marrow failure and neoplasia. In adulthood, aplastic bone marrow disease, liver disease and pulmonary fibrosis are classic clinical manifestations. At present, medical treatment options for STS remain limited. Danazol, a synthetic androgenic hormone, can slow down telomere shortening and thus limit the progression of the disease. Finally, hematopoietic, hepatic and pulmonary transplantation, sometimes combined, may be discussed in a multidisciplinary setting in certain situations.

Le syndrome des télomères courts (STC) est un groupe de maladies rares dues à un défaut dans les gènes de maintenance des télomères, provoquant leur raccourcissement anormal et des manifestations cliniques multiorganiques. Dans l'enfance, le STC se présente par des lésions mucocutanées et gastro-intestinales, une insuffisance médullaire et des néoplasies. À l'âge adulte, une atteinte médullaire aplasiante, hépatique, et une fibrose pulmonaire sont des manifestations cliniques classiques. Les options thérapeutiques pour le STC restent limitées. Le danazol, une hormone androgène synthétique, permet, parfois, de freiner le raccourcissement télomérique et de limiter la progression de la maladie. Finalement, les transplantations hématopoïétique, hépatique et pulmonaire sont discutées dans certaines situations de manière multidisciplinaire.

Skin Cancer Development in Solid Organ Transplant Recipients in Switzerland (Swiss Transplant Cohort Study).

IMPORTANCE: Skin cancer, in particular squamous cell carcinoma, is the most frequent malignancy among solid organ transplant recipients with a higher incidence compared to the general population. OBJECTIVE: To determine the skin cancer incidence in organ transplant recipients in Switzerland and to assess the impact of immunosuppressants and other risk factors. DESIGN: Prospective cohort study of solid organ transplant recipients in Switzerland enrolled in the Swiss Transplant Cohort Study from 2008 to 2013. PARTICIPANTS: 2,192 solid organ transplant recipients. MATERIALS AND METHODS: Occurrence of first and subsequent squamous cell carcinoma, basal cell carcinoma, melanoma and other skin cancers after transplantation extracted from the Swiss Transplant Cohort Study database and validated by medical record review. Incidence rates were calculated for skin cancer overall and subgroups. The effect of risk factors on the occurrence of first skin cancer and recurrent skin cancer was calculated by the Cox proportional hazard model. RESULTS: In 2,192 organ transplant recipients, 136 (6.2%) developed 335 cases of skin cancer during a median follow-up of 32.4 months, with squamous cell carcinoma as the most frequent one. 79.4% of skin cancer patients were male. Risk factors for first and recurrent skin cancer were age at transplantation, male sex, skin cancer before transplantation and previous transplantation. For a first skin cancer, the number of immunosuppressive drugs was a risk factor as well. CONCLUSIONS AND RELEVANCE: Skin cancer following solid organ transplantation in Switzerland is greatly increased with risk factors: age at transplantation, male sex, skin cancer before transplantation, previous transplantation and number of immunosuppressive drugs.

[Cutaneous visualization by different non-invasive skin imaging methods]. / La peau vue par différentes méthodes d'imagerie cutanée non invasive.

The development of in vivo skin imaging technologies has been booming for several decades. Their advantages are indisputable, especially as they are non-invasive. Their place is already well established in onco-dermatology and it is just a question of time for them to be used with success in other fields of dermatology, including pediatric dermatology. In this paper we will discuss 3 of these skin imaging techniques used in dermatology at the CHUV, including Optical Coherence Tomography (OCT), Reflectance Confocal Microscopy (RCM) and the most recent: Line-field Confocal Optical Coherence Tomography (LC-OCT).

Le développement de technologies d'imagerie cutanée in vivo est en plein essor depuis plusieurs dizaines d'années. Leurs avantages sont indéniables compte tenu notamment de leur caractère non invasif. Leur place est déjà bien établie en onco-dermatologie et leur utilité est également prometteuse dans beaucoup de domaines en dermatologie, y compris en dermatologie pédiatrique. Nous allons détailler ici trois de ces techniques utilisées en dermatologie au CHUV, à savoir la tomographie en cohérence optique (OCT), la microscopie confocale par réflectance (MCR) et la plus récente: la tomographie en cohérence optique confocale en champ linéaire (LC-OCT).

[Impact of COVID pandemic on the detection of skin cancer]. / Impact de la pandémie de Covid sur la détection des cancers de la peau.

In 2020, we have seen patients with neglected skin cancer in the context of the COVID pandemic. But what is the global health impact of the pandemic on skin cancer patients ? Is it as high as the delayed care of a heart infarct ? To answer this question, we have confronted a theoretic, a probabilistic and a scientific approach. These analyses allow us to conclude that the impact overall was moderate. It allows to draw general guidelines on the diagnosis and treatment of skin cancer for future pandemics.

En 2020, nous avons observé des cas de cancers de la peau négligés en raison de la pandémie de Covid-19. Mais quel est l'impact réel de la pandémie sur la détection des cancers de la peau en termes de santé publique ? Est-il aussi grand que celui d'une prise en charge retardée d'un infarctus du myocarde ? Pour répondre à cette question, nous avons confronté des approches théorique, probabilistique et scientifique. Ces analyses nous permettent de conclure que l'impact global a été heureusement faible. Elles permettent de tirer les grandes lignes directives qui sont à tenir dans le domaine de la prise en charge des cancers cutanés en temps de pandémie.

The proteolytic activity of the paracaspase MALT1 is key in T cell activation.

The paracaspase MALT1 is pivotal in antigen receptor-mediated lymphocyte activation and lymphomagenesis. MALT1 contains a caspase-like domain, but it is unknown whether this domain is proteolytically active. Here we report that MALT1 had arginine-directed proteolytic activity that was activated after T cell stimulation, and we identify the signaling protein Bcl-10 as a MALT1 substrate. Processing of Bcl-10 after Arg228 was required for T cell receptor-induced cell adhesion to fibronectin. In contrast, MALT1 activity but not Bcl-10 cleavage was essential for optimal activation of transcription factor NF-kappaB and production of interleukin 2. Thus, the proteolytic activity of MALT1 is central to T cell activation, which suggests a possible target for the development of immunomodulatory or anticancer drugs.

[Dermatofibrosarcoma protuberans†: clinico-pathological aspects and management]. / Dermatofibrosarcoma protuberans†: aspects clinico-pathologiques et prise en charge.

The dermatofibrosarcoma protuberans (DFSP) is the most common form of low-grade cutaneous sarcoma; its infiltrating growth occurs by fingerlike projections, which explain the high rate of recurrence in case of inappropriate surgical procedure. Based on an extensive review of the existing literature, we propose here to discuss the actual criteria for early recognition, diagnosis and optimal take of care of DFSP.

Le dermatofibrosarcoma protuberans (DFSP) est la forme la plus fréquente de sarcome cutané. Son caractère infiltrant du fait de projections tumorales digitiformes caractéristiques expose à un taux de récidive locale très élevé en cas de prise en charge chirurgicale inappropriée. Sur la base d'une revue extensive de la littérature existante, nous proposons ici de revoir les critères diagnostiques du DFSP ainsi que la prise en charge recommandée.

[ENT management of head and neck cutaneous melanoma]. / Prise en charge par l'ORL des mélanomes cutanés cervico-faciaux.

A quarter of cutaneous melanomas occur on the head and neck. Despite close collaboration between the dermatology, oncology, pathology, nuclear medicine and otorhinolaryngology departments, the survival of patients presenting with this type of melanomas remains inferior to that of other parts of the body. The morbidity of head and neck surgery significantly alters the quality of life. Therefore, specific multidisciplinary expertise is required. We present here the specificities of ENT management.

Un quart des mélanomes cutanés se présentent au niveau de la tête et du cou. Malgré une étroite collaboration entre les services de dermatologie, oncologie, pathologie, médecine nucléaire et oto-rhino-laryngologie (ORL), la survie des patients qui présentent ce type de mélanomes reste inférieure à celle des patients ayant un mélanome d'une autre partie du corps. La morbidité d'une chirurgie cervico-faciale modifie significativement la qualité de vie. Ainsi, une expertise spécifique multidisciplinaire est nécessaire. Nous présentons ici les spécificités de la prise en charge ORL des mélanomes cervico-faciaux.

[Artificial intelligence and the skin specialist]. / L'intelligence artificielle et le dermatologue.

Artificial intelligence's progress is spread on front pages of both lay and scientific journals. After Chess, after Go, before Dota2 and Starcraft, super-trained softwares have equaled or out-performed dermatologists. But what is the future of these computer programs and how will they change clinical practice for both the general practitioner and the skin specialist? It is time to ask these questions, even though the promises of these new technologies are not yet available.

Les progrès de l'intelligence artificielle s'étalent chaque jour dans les journaux laïques comme scientifiques. Après les échecs, après le jeu de Go, avant Dota2 et Starcraft, des programmes surentraînés ont fait aussi bien, voire mieux qu'un groupe de dermatologues. Mais quel est l'avenir de ces super-programmes et comment vont-ils changer la pratique médicale, pour le médecin de premier recours et pour le spécialiste ? Le temps est venu de se poser ces questions, même si les promesses de ces nouvelles technologies se refusent à nous pour l'instant.

Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity.

The protease activity of the paracaspase Malt1 has recently gained interest as a drug target for immunomodulation and the treatment of diffuse large B-cell lymphomas. To address the consequences of Malt1 protease inactivation on the immune response in vivo, we generated knock-in mice expressing a catalytically inactive C472A mutant of Malt1 that conserves its scaffold function. Like Malt1-deficient mice, knock-in mice had strong defects in the activation of lymphocytes, NK and dendritic cells, and the development of B1 and marginal zone B cells and were completely protected against the induction of autoimmune encephalomyelitis. Malt1 inactivation also protected the mice from experimental induction of colitis. However, Malt1 knock-in mice but not Malt1-deficient mice spontaneously developed signs of autoimmune gastritis that correlated with an absence of Treg cells, an accumulation of T cells with an activated phenotype and high serum levels of IgE and IgG1. Thus, removal of the enzymatic activity of Malt1 efficiently dampens the immune response, but favors autoimmunity through impaired Treg development, which could be relevant for therapeutic Malt1-targeting strategies.

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity.

Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma.

Evaluation of the National Swiss Skin Cancer Screening Campaign 2013: Do We Do the Right Thing.

BACKGROUND: Skin cancer prevention and screening programs are performed in many countries. Their benefit is discussed controversially. OBJECTIVE: Our aim is to evaluate the Skin Cancer Screening Program 2013 in Switzerland by following up screenees upon interventions. METHODS: Quality was assessed by personal follow-up via phone/e-mail of every patient that had been screened during this campaign and histological follow-up of all participants with suspicious skin lesions. RESULTS: Of the 1,087 screenees requiring interventions, 263 agreed to participate in the follow-up. We were able to obtain 66 histology reports. During this campaign 33 malignant lesions (8 melanomas) were removed. CONCLUSION: The overall melanoma detection rate in our free Skin Cancer Screening Program is comparable to those in European public activities. The costs of free screening programs compare favorably with the prevented potential therapeutic costs of late-stage melanoma. The low response rate of screenees agreeing to be followed up limits conclusions of this study.

[A new vision of skin]. / Une nouvelle vision de la peau.

As of today, the skin will never look the same. Indeed, several technologies allowing the observation of the skin at a microscopic level are now coming of age. This magnifies our visual acuity and thus our capacity to recognize various pathological processes. We herein present three different methods of non-invasive skin imaging we have worked with at the CHUV, which revolutionize the practice of dermatology. In vivo confocal microscopy, ex-vivo confocal microscopy and optical coherence tomography are complementary techniques that are now becoming essential for the modern management of skin cancers, among other uses.

Dès aujourd'hui, vous ne verrez plus la peau de la même manière. En effet, plusieurs technologies de microscopie sur peau intacte arrivent à maturité. Ceci décuple notre acuité visuelle, et donc notre capacité à reconnaître différents processus pathologiques. Nous présentons ici trois techniques d'imagerie cutanée non invasive avec lesquelles nous avons travaillé au CHUV, et qui sont en train de révolutionner la pratique de la dermatologie. Il s'agit de la microscopie confocale par réflectance in vivo ou ex vivo, et de la tomographie par cohérence optique, trois techniques complémentaires qui deviennent indispensables pour la prise en charge des cancers cutanés, mais dont l'utilité va bien au-delà.

Ingenol Mebutate 500 µg on the Cheekbones with Concomitant Conjunctivitis.

Ingenol mebutate induces strong inflammation after a single application already. This must be taken into account when prescribing the drug, as mistakes in the application may results in severe side effects. Here, we report the case of a 72-year-old woman who applied ingenol mebutate on the cheekbones and developed a pronounced conjunctivitis, needing topical corticosteroids. The treatment was intended for the actinic keratosis she had on the chest, and the regimen of 2 consecutive once daily applications of ingenol mebutate at 500 µg/g had been prescribed as registered. The inadvertent application on the thin skin of the cheekbones led to a pronounced inflammation. With topical steroids followed by fusidic acid, both conjunctivitis and skin inflammation resolved within a few days. The skin showed erythema for a few weeks, but after 3 months, the patient presented a perfectly smooth skin and was very happy with the cosmetic outcome. This suggests that the cheekbones are a sensitive site for ingenol mebutate, but that intense inflammation should not scare physician or patient, as clinical remission with excellent healing can still be expected.

Ingenol Mebutate 500 µg for Treatment of the Scalp in Refractory Field Cancerization.

Patients suffering from chronic lymphocytic leukemia often develop actinic keratosis (AK) and squamous cell carcinoma in sun-exposed areas. In these particular patients, who have a suboptimal immune function, AK treatment can be particularly challenging. We report the case of a patient who failed to respond to most AK treatments, including 5-FU, imiquimod and photodynamic therapy, but responded to ingenol mebutate. We started with 3 applications of 150 µg/g (registered treatment of the scalp) and also 2 applications of 500 µg/g (registered in for trunk and extremities). Both treatments were well tolerated, but only the latter led to significant clinical success. This suggests that 500 µg/g of ingenol mebutate may represent an interesting therapeutic option in patients with mild immunosuppression.

[Skin memory: the clinical implications]. / La mémoire dans la peau: implications cliniques.

Activated T lymphocytes give rise to daughter cells that can persist for decades in our body, while retaining their ability to provide a strong immune response. Recent advances have highlighted the fact that a significant portion of these memory cells are found directly in peripheral tissues and lack the capacity to migrate to the blood. We have recently shown that these cells, called Tissue Resident Memory T cells (T(RM)), play a major role in the immune response, regardless of the antigenic challenge. They have a backup of circulating central memory T cells (T(CM)) that bear the exact same T cell receptor. For the clinician, this knowledge is very useful as it allows a better understanding and better choice of therapeutics for several cutaneous diseases, such as contact dermatitis and cutaneous T cell lymphoma (Mycosis Fungoides vs Sezary).

Generation and characterization of function-blocking anti-ectodysplasin A (EDA) monoclonal antibodies that induce ectodermal dysplasia.

Development of ectodermal appendages, such as hair, teeth, sweat glands, sebaceous glands, and mammary glands, requires the action of the TNF family ligand ectodysplasin A (EDA). Mutations of the X-linked EDA gene cause reduction or absence of many ectodermal appendages and have been identified as a cause of ectodermal dysplasia in humans, mice, dogs, and cattle. We have generated blocking antibodies, raised in Eda-deficient mice, against the conserved, receptor-binding domain of EDA. These antibodies recognize epitopes overlapping the receptor-binding site and prevent EDA from binding and activating EDAR at close to stoichiometric ratios in in vitro binding and activity assays. The antibodies block EDA1 and EDA2 of both mammalian and avian origin and, in vivo, suppress the ability of recombinant Fc-EDA1 to rescue ectodermal dysplasia in Eda-deficient Tabby mice. Moreover, administration of EDA blocking antibodies to pregnant wild type mice induced in developing wild type fetuses a marked and permanent ectodermal dysplasia. These function-blocking anti-EDA antibodies with wide cross-species reactivity will enable study of the developmental and postdevelopmental roles of EDA in a variety of organisms and open the route to therapeutic intervention in conditions in which EDA may be implicated.