[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.

Primary prophylaxis with mTOR inhibitor enhances T cell effector function and prevents heart transplant rejection during talimogene laherparepvec therapy of squamous cell carcinoma.

The application of mammalian target of rapamycin inhibition (mTORi) as primary prophylactic therapy to optimize T cell effector function while preserving allograft tolerance remains challenging. Here, we present a comprehensive two-step therapeutic approach in a male patient with metastatic cutaneous squamous cell carcinoma and heart transplantation followed with concomitant longitudinal analysis of systemic immunologic changes. In the first step, calcineurin inhibitor/ mycophenolic acid is replaced by the mTORi everolimus to achieve an improved effector T cell status with increased cytotoxic activity (perforin, granzyme), enhanced proliferation (Ki67) and upregulated activation markers (CD38, CD69). In the second step, talimogene laherparepvec (T-VEC) injection further enhances effector function by switching CD4 and CD8 cells from central memory to effector memory profiles, enhancing Th1 responses, and boosting cytotoxic and proliferative activities. In addition, cytokine release (IL-6, IL-18, sCD25, CCL-2, CCL-4) is enhanced and the frequency of circulating regulatory T cells is increased. Notably, no histologic signs of allograft rejection are observed in consecutive end-myocardial biopsies. These findings provide valuable insights into the dynamics of T cell activation and differentiation and suggest that timely initiation of mTORi-based primary prophylaxis may provide a dual benefit of revitalizing T cell function while maintaining allograft tolerance.

Randomized phase II selection trial of FLASH and conventional radiotherapy for patients with localized cutaneous squamous cell carcinoma or basal cell carcinoma: A study protocol.

Background: Cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most prevalent skin cancers in western countries. Surgery is the standard of care for these cancers and conventional external radiotherapy (CONV-RT) with conventional dose rate (0.03-0.06 Gy/sec) represents a good alternative when the patients or tumors are not amenable to surgery but routinely generates skin side effects. Low energy electron FLASH radiotherapy (FLASH-RT) is a new form of radiotherapy exploiting the biological advantage of the FLASH effect, which consists in delivering radiation dose in milliseconds instead of minutes in CONV-RT. In pre-clinical studies, when compared to CONV-RT, FLASH-RT induced a robust, reproducible and remarkable sparing of the normal healthy tissues, while the efficacy on tumors was preserved. In this context, we aim to prospectively evaluate FLASH-RT versus CONV-RT with regards to toxicity and oncological outcome in localized cutaneous BCC and SCC. Methods: This is a randomized selection, non-comparative, phase II study of curative FLASH-RT versus CONV-RT in patients with T1-T2 N0 M0 cutaneous BCC and SCC. Patients will be randomly allocated to low energy electron FLASH-RT (dose rate: 220-270 Gy/s) or to CONV-RT arm. Small lesions (T1) will receive a single dose of 22 Gy and large lesions (T2) will receive 30 Gy in 5 fractions of 6 Gy over two weeks.The primary endpoint evaluates safety at 6 weeks after RT through grade ≥ 3 toxicity and efficacy through local control rate at 12 months. Approximately 60 patients in total will be randomized, considering on average 1-2 lesions and a maximum of 3 lesions per patients corresponding to the total of 96 lesions required. FLASH-RT will be performed using the Mobetron® (IntraOp, USA) with high dose rate functionality.LANCE (NCT05724875) is the first randomized trial evaluating FLASH-RT and CONV-RT in a curative setting.

Nutritional and metabolic characteristics of critically ill patients admitted for severe toxidermia.

INTRODUCTION: Drug-induced toxidermia is an idiosyncratic adverse skin reaction that may become life-threatening in a small portion of patients, requiring intensive care unit (ICU) admission. The treatment recommendations are extrapolated from those of major burns, while prospective data remain sparse. The objective was to observe the application of these recommendations in patients treated in a burn ICU. METHOD: Retrospective cohort study including patients requiring ICU between 2006 and 2020 in a tertiary university hospital. INCLUSION CRITERIA: Age >18 years. Patients were categorized as Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), or other toxidermia. VARIABLES: severity scores, body surface area (BSA) involvement, nutritional and metabolic variables, trace element status, outcome variables. Descriptive statistics: median [IQR]. RESULTS: Altogether 35 patients were included (27 SJS/TEN and 8 "other"), aged 58 [48; 69] years. Skin involvement was 45% [30; 60] of body surface, 17 patients required mechanical ventilation, and length of ICU stay was 16 [6.5; 26] days. Hospital mortality was 23%. Fluid resuscitation requirements were moderate, despite intense inflammation (admission CRP (144 [89; 218] mg/L). The first 2 weeks' energy and protein intakes were below recommendations (p < 0.0001), lowest with oral feeding. Indirect calorimetry showed high energy expenditure in 11 patients (30.4 [23.9; 35.5] kcal/kg) resulting in negative energy balances (mean -245 kcal/day). Copper and zinc levels were below reference range during the first week, the low copper values being a novel finding. CONCLUSION: Trace elements should be monitored. The cohort was underfed with intakes lower than our ICU protocols, partly explained by short intubation times, and mucocutaneous involvement complicating the management and placement of feeding tubes. Oral feeding was least efficient and may become an indication for supplemental parenteral nutrition in the absence of an enteral feeding tube. CLINICALTRIALS: gov Identifier: NCT05320653.

[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.

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.

[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.

Cutaneous presentation of enteropathy-associated T-cell lymphoma masquerading as a DUSP22-rearranged CD30+ lymphoproliferation.

DUSP22 gene rearrangements are recurrent in systemic and cutaneous ALK-negative anaplastic large cell lymphomas, rarely encountered in other cutaneous CD30+ lymphoproliferations, and typically absent in other peripheral T-cell lymphomas. We report the case of a 51-year-old woman, with longstanding celiac disease and a rapidly enlarging leg ulcer, due to a DUSP22-rearranged CD30+ T-cell lymphoproliferation. Subsequent history revealed an intestinal enteropathy-associated T-cell lymphoma (EATL). Identical monoclonal TR gene rearrangements and mutations in STAT3 and JAK1 typical of EATL were present in the cutaneous and intestinal lesions. No DUSP22 rearrangement was detected in the patient's intestinal tumour, nor in 15 additional EATLs tested. These findings indicate that DUSP22 rearrangements are not entirely specific of ALCLs, may rarely occur as a secondary aberration in EATL, and expand the differential diagnosis of DUSP22-rearranged cutaneous CD30+ lymphoproliferative disorders.

Comparison of ultra-high versus conventional dose rate radiotherapy in a patient with cutaneous lymphoma.

A patient with a cutaneous lymphoma was treated on the same day for 2 distinct tumors using a 15 Gy single electron dose given in a dose rate of 0.08 Gy/second versus 166 Gy/second. Comparing the two treatments, there was no difference for acute reactions, late effects at 2 years and tumor control.

Mutually exclusive lymphangiogenesis or perineural infiltration in human skin squamous-cell carcinoma.

Although tumor-associated lymphangiogenesis correlates with metastasis and poor prognosis in several cancers, it also supports T cell infiltration into the tumor and predicts favorable outcome to immunotherapy. The role of lymphatic vessels in skin squamous-cell carcinoma (sSCC), the second most common form of skin cancer, remains mostly unknown. Although anti-PD-1 therapy is beneficial for some patients with advanced sSCC, a greater understanding of disease mechanisms is still needed to develop better therapies. Using quantitative multiplex immunohistochemistry, we analyzed sSCC sections from 36 patients. CD8+ T cell infiltration showed great differences between patients, whereby these cells were mainly excluded from the tumor mass. Similar to our data in melanoma, sSCC with high density of lymphatic endothelial cells showed increased CD8+ T cell density in tumor areas. An entirely new observation is that sSCC with perineural infiltration but without metastasis was characterized by low lymphatic endothelial cell density. Since both, metastasis and perineural infiltration are known to affect tumor progression and patients' prognosis, it is important to identify the molecular drivers, opening future options for therapeutic targeting. Our data suggest that the mechanisms underlying perineural infiltration may be linked with the biology of lymphatic vessels and thus stroma.

[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.

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.

Therapeutic Potential of Targeting Malt1-Dependent TCR Downstream Signaling to Promote the Survival of MHC-Mismatched Allografts.

Strategies targeting T cells are the cornerstone of immunosuppression after solid organ transplantation. The transcription factor NF-κB is a key regulator of downstream T-cell activation and induction of inflammatory mediators; its full activation via antigen receptor engagement requires both the scaffold and the protease activity of the paracaspase Malt1. Experimental studies have highlighted that Malt1-deficient mice were resistant to experimental autoimmune encephalomyelitis, although they lacked peripheral regulatory T cells (Treg). Here, we compared targeting Malt1 versus using calcineurin inhibitors as immunosuppression in a stringent experimental transplantation model. We found that Malt1-deficiency impaired Th1-mediated alloresponses in vitro and in vivo and significantly prolonged MHC-mismatched skin allograft survival, compared to cyclosporine. However, it paradoxically enhanced Th17 differentiation in the transplantation setting. Interestingly, more selective inhibition of Malt1 protease activity in wild-type mouse and human peripheral T cells in vitro led to attenuation of alloreactive Th1 cells, while preserving preexisting Treg in the peripheral T-cell pool, and without promoting Th17 differentiation. Thus, there is a place for further investigation of the role of Malt1 signaling in the setting of transplantation.

[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.

[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.