Comparing Line-Field Confocal Optical Coherence Tomography and Reflectance Confocal Microscopy on the In Vivo Healing Process of Lesions Induced by Fractional Photothermolysis.

BACKGROUND: The advent of ablative fractional photothermolysis has revolutionized laser dermatology by providing a method to produce well-standardized, precise, and repeatable microscopic lesions. These wounds typically heal within 1-3 weeks, depending on the body site, with a minimal risk of permanent scarring. This positions ablative fractional photothermolysis as an exemplary in vivo model for studying the skin's wound healing processes. OBJECTIVES: This study aims to evaluate and compare the effectiveness of two noninvasive imaging techniques, reflectance confocal microscopy (RCM) and line-field confocal optical coherence tomography (LC-OCT), in assessing skin wound healing following microscopic injuries induced by ablative fractional photothermolysis. METHODS: The forearms of participating volunteers were treated and ablated with a CO2-Laser in a fractional pattern using varying power settings (2.5-10 mJ/MTZ). In vivo RCM and LC-OCT images were obtained at predefined time intervals post-laser treatment, ranging from 6 h to 14 days. RESULTS: Vertical visualization of the lesions through both imaging modalities revealed a healing process characterized by the upward and outward movement of microscopic epidermal necrotic debris, thereby reducing the depth of the injury while forming an external crust. LC-OCT imaging demonstrated more comprehensive results with fewer movement artifacts. Conversely, horizontal visualization with both techniques highlighted a gathering of keratinocytes around the wounds, indicating the initiation of the regenerative process. RCM provided superior image clarity in this horizontal plane. CONCLUSIONS: RCM and LC-OCT offer valuable and complementary noninvasive alternatives to conventional biopsy methods for the assessment and characterization of the skin's wound healing process post-ablative fractional photothermolysis. These findings underscore the potential of such imaging techniques in enhancing our understanding of the wound healing process. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05614557.

[Screening for cutaneous melanoma: little impact, major challenges]. / Dépistage du mélanome : peu d'impact, beaucoup de défis.

Routine screening for melanoma has never been shown to be effective. Here, we revisit this debate and the preconceived notion that the increased detection of early-stage melanoma should necessarily be followed within the same population by a reduction in the incidence of advanced stages, which is not supported by any evidence. The issue of overdiagnosis, which has been debated for several decades, is discussed in the light of screening practices. We illustrate with two of its common motives, why this practice is ineffective. Finally, we suggest that the risk of overdiagnosis has probably reached its climax over the last two decades, as the increasing sensitivity of skin-imaging tools has not been followed by a refinement of histopathologic diagnostic criteria.

Le dépistage systématique du mélanome n'a jamais fait la preuve de son efficacité. Nous rediscutons ici de cette question en revenant sur l'idée reçue que le dépistage accru des stades précoces de mélanome au sein d'une population devrait engendrer une diminution des formes avancées de la maladie, ce qui ne se vérifie pas dans les faits. La question débattue depuis plusieurs décennies du surdiagnostic est également discutée à la lumière des pratiques de dépistage. Nous illustrons par deux motifs fréquents de dépistage pourquoi cette pratique est inefficace. Nous suggérons que le risque de surdiagnostic a atteint son paroxysme au cours des deux dernières décennies dans la mesure où la sensibilité croissante des outils d'imagerie cutanée n'a pas été suivie d'un affinement des critères diagnostiques histopathologiques.

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.

Inhibition of the DAPKs-L13a axis prevents a GAIT-like motif-mediated HuR insufficiency in melanoma cells.

We previously showed that the adaptive response of BRAFV600-mutated melanoma cells to BRAF inhibition emerges from a subpopulation of cells expressing an intermittent lower level of the mRNA-binding protein HuR. In this study, following initial overexpression experiments in which we confirm our previous results, we use wild-type and mutants HuR full-length mRNA constructs and in vivo-interacting assays and demonstrate that a highly conserved interferon-γ-activated inhibitor of translation (GAIT)-like motif located upstream of the GU-rich elements of HuR major polyadenylation site (PAS2), interacts with constituents of the GAIT complex and affects HuR post-transcriptional expression regulation. Knockdown of the ribosomal protein L13a or the inhibition of the DAPK1-ZIPK axis involved in L13a phosphorylation, reduces the proportion of HuRLow cells at steady-state and attenuates the adaptive response of the whole melanoma-cell population to BRAF inhibition. These results have further potential therapeutic implications for disease conditions associated with HuR insufficient expression.

[BRAF inhibitors-induced paradoxical reactions and oncogenesis]. / Oncogenèse et réactions paradoxales aux inhibiteurs de BRAF.

Paradoxical oncogenesis and benign paradoxical proliferations occur in off-target rapidly regenerating labile tissues of patients treated for malignancies with small-molecule inhibitors of cell-signaling such as kinase inhibitors. These paradoxical proliferations, particularly well listed in patients treated with selective BRAF inhibitors carrying BRAF-mutated solid malignancies, have had their incidence reduced upon the advent of BRAF/MEK double blockade therapies. Mechanistically, the underlying molecular events involved in paradoxical proliferations in off-target tissues could prove to be as complex as those involved in the adaptive resistance of malignant cells to targeted therapies.

L'oncogenèse paradoxale et les proliférations bénignes paradoxales se produisent dans les tissus hors cibles à renouvellement rapide chez les patients traités pour des néoplasies par les petites molécules inhibitrices de la signalisation cellulaire que sont les inhibiteurs de kinases. Ces proliférations paradoxales, particulièrement bien décrites chez les patients atteints de tumeurs solides avec mutation BRAF et traités par des inhibiteurs sélectifs de BRAF, ont vu leur incidence diminuer avec la venue des traitements basés sur un double blocage de la voie ciblée. Du point de vue des mécanismes, les événements moléculaires impliqués dans les proliférations paradoxales des tissus hors cibles pourraient se révéler aussi complexes que ceux impliqués dans la résistance adaptative des cellules malignes à l'inhibition ciblée.

Drug-induced expression of the RNA-binding protein HuR attenuates the adaptive response to BRAF inhibition in melanoma.

Strategies that aim to limit the adaptive response to pathway inhibition in BRAF-mutated melanoma face the inherent limit of signaling redundancy and multiplicity of possible bypass mechanisms. Drug-induced expression of selected RNA-binding proteins, like the ubiquitously expressed HuR, has the potential to differentially stabilize the expression of many genes involved in the compensatory mechanisms of adaptive response. Here, we detect in BRAF-mutated melanoma cell lines having a higher propensity for adaptive response and in non-responding melanoma tumors, a larger proportion of HuRLow cells in the expression distribution of HuR. Using knockdown experiments, we demonstrate, through expression profiling and phenotypic assays, that increasing the proportion of HuRLow cells favors the adaptive response to BRAF inhibition, provided that the HuRLow state stays reversible. The MAPK dependency of melanoma cells appears to be diminished as the proportion of HuRLow cells increases. In single-cell assays, we demonstrate that the HuRLow cells display plasticity in their growth expression profile. Importantly, the adaptive over-proliferating cells emerge in the subpopulation containing the HuRLow cells. Therapeutic concentrations of lithium salts, although they moderately increase the global expression of HuR, are sufficient to suppress the HuRLow cells, induce an overall less resistant expression profile and attenuate in a HuR-dependent manner the adaptive response of melanoma cells in ex vivo assays. The therapeutic effectiveness of this approach is also demonstrated in vivo in mice xenografts. This study has immediate clinical relevance for melanoma therapy and opens a new avenue of strategies to prevent the adaptive response to targeted cancer therapy.

Skin cancer screening in Switzerland: Cross-sectional trends (1997-2012) in socioeconomic inequalities.

INTRODUCTION: Skin cancer is one of the most common malignancies. Despite controversy over its efficacy, skin cancer screening has become widespread although socioeconomic screening inequalities have been documented. Switzerland has the highest rate of melanoma in Europe but Swiss trends in skin cancer screening and social disparities have not been investigated. This study aims to evaluate trends in skin cancer screening and its association with socioeconomic indicators in Switzerland between 1997 and 2012. METHOD: We used data from four waves (from 1997 to 2012) of the population-based Swiss Health Interview Survey. Multivariable Poisson regressions with robust variance were used to estimate weighted prevalence ratio (PR) and 95% Confidence Intervals (CI) adjusting for demographics, health status and use of healthcare. RESULTS: This study included 60,764 participants with a mean age of 49.1 years (standard deviation (SD) 17.2) and 53.6% of women. Between 1997 and 2012, the weighted prevalence of ever life-time skin examination and skin examination in the current year increased by 38.2% and 35.3% respectively (p-value <0.001). Participants with a lower education level, lower income and living in non-metropolitan areas were less often screened than their counterparts. Educational differences in ever life-time skin examination increased over time (p-value for trend = 0.036). CONCLUSION: While skin cancer screening prevalence in Switzerland increased from 1997 to 2012, most social inequalities persisted over time and educational inequalities increased. Dermatologists should be alerted that populations with lower education should be given special attention.

[Recent advances in the adjuvant treatment of high-risk melanoma]. / Dermatologie: Avancées récentes du traitement adjuvant du mélanome à haut risque métastatique.

Despite tremendous therapeutic innovations during the last decade, the prognosis of metastatic melanoma remains uncertain. Adjuvant therapy following resection of high-risk melanoma is currently under intense investigation. Both small-molecules targeted therapy and immune checkpoint inhibitor therapy, initially developed for metastatic disease, have proven to be efficient in the adjuvant setting in phase 3 trials. The results of this research are already considered as practice-changing. In this article we summarize this ongoing clinical research and its consequences for the practical management of high-risk melanoma patients.

Malgré d'étonnants progrès thérapeutiques durant la dernière décennie, le pronostic des patients atteints de mélanome métastatique reste hautement incertain. Le traitement adjuvant du mélanome à haut risque de récurrence métastatique fait l'objet actuellement d'une recherche clinique très intense. Les deux approches thérapeutiques développées pour la prise en charge du mélanome métastatique, à savoir les thérapies ciblées par petites molécules et l'immunothérapie par inhibiteurs de point de contrôle immunitaire (immune checkpoint), ont montré leur efficacité en situation adjuvante dans plusieurs essais de phase 3. Ces données ont d'ores et déjà modifié nos pratiques de prise en charge des patients à haut risque. Dans cet article, nous résumons les principales données issues de cette recherche clinique et les nouvelles modalités de prise en charge qui en découlent.

Hu antigen R (HuR) heterogeneous expression quantification as a prognostic marker of melanoma.

BACKGROUND: Prognostic markers for melanoma, particularly for stage II disease, are needed for the risk-benefit evaluation of future adjuvant therapies. The mainly nuclear RNA-binding protein human antigen R (HuR) regulates the protein expression of thousands of mRNAs, its own heterogeneous expression could therefore reflect tumor heterogeneity and plasticity. Here, we evaluate its quantification in primary melanoma as a marker of metastatic outcome. METHODS: We conducted an immunohistochemistry-based automated quantification of HuR nuclear expression heterogeneity in primary melanomas, most with Breslow thickness ≥ 1 mm and calculated the dimensionless fourth moment, that is, the kurtosis of HuR (HuR K) expression distribution. Twelve tumors from patients with no metastatic disease were compared to a similar number of tumors from patients who had metastatic disease at 2 years follow up. RESULTS: HuR K value appeared significantly higher in the non-metastatic group comparatively to the metastatic group (P = 2.84 × 10-3 , 1-tailed Wilcoxon rank-sum test). Moreover, compared to the Breslow thickness, HuR K value appeared as a more robust marker of metastatic outcome (respective areas under receiver operating characteristic curves 0.84 and 0.87). CONCLUSION: Our data need confirmation on a large cohort, however strongly suggest that HuR expression heterogeneity quantification using kurtosis, could be used as a prognostic marker in 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.