[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.

The human antigen R as an actionable super-hub within the network of cancer cell persistency and plasticity.

In this perspective article, a clinically inspired phenotype-driven experimental approach is put forward to address the challenge of the adaptive response of solid cancers to small-molecule targeted therapies. A list of conditions is derived, including an experimental quantitative assessment of cell plasticity and an information theory-based detection of in vivo dependencies, for the discovery of post-transcriptional druggable mechanisms capable of preventing at multiple levels the emergence of plastic dedifferentiated slow-proliferating cells. The approach is illustrated by the author's own work in the example case of the adaptive response of BRAFV600-melanoma to BRAF inhibition. A bench-to-bedside and back to bench effort leads to a therapeutic strategy in which the inhibition of the baseline activity of the interferon-γ-activated inhibitor of translation (GAIT) complex, incriminated in the expression insufficiency of the RNA-binding protein HuR in a minority of cells, results in the suppression of the plastic, intermittently slow-proliferating cells involved in the adaptive response. A similar approach is recommended for the validation of other classes of mechanisms that we seek to modulate to overcome this complex challenge of modern cancer therapy.

Multistage Reconstruction of Large Arm Defect Using Keystone Type I Flap and Temporary Synthetic Skin Substitute.

Large arm defects remain a challenge to the reconstructive surgeon, as local and regional flaps are limited regarding size and free flaps have disadvantages such as poor color match, technical complexity, prolonged operative time, and the risk of total flap loss. Keystone flaps are fascia-based flaps and combine perforator-based vascularity with relative simplicity of nonmicrosurgical techniques and do not distort local anatomy in cases of malignant excision with wide defects. This article highlights the approach of a multistaged procedure to reconstruct a large arm defect using a keystone type I flap and a temporary synthetic skin substitute for closure in a patient referred to our department for wide resection of a large melanoma in situ on the posterior aspect of the left arm. The defect, measuring 14 cm × 8 cm, was initially reconstructed with a keystone type I flap. Part of the wound was temporarily covered with EpiGARD (Biovision GmbH, Ilmenau, Germany) to avoid excessive wound tension. One week later, the wound was partially narrowed, and a smaller EpiGARD was placed in office under local anesthesia. The multistaged approach was completed with direct closure 1 week later after removal of the smaller EpiGARD. No complications occurred and the result was satisfactory with a pleasing cosmetic result after an 8-month follow-up. In conclusion, the keystone flap allows reconstruction of large arm defects. Temporary synthetic skin substitute coverage can serve as a good addition for those cases where tension on the margins is observed at the price of a small in-office procedure.

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.

Rintala Flap and Posterior Perichondrial Cutaneous Graft: A Combined Approach for Nasal Tip Reconstruction.

Nasal tip reconstruction requires a meticulous approach due to the complexity of the nasal anatomy and its aesthetic importance. Many procedures have been described to restore this aesthetic unit, including the paramedian forehead flap, which is one of the workhorse flaps. However, despite excellent final outcomes, this procedure may be refused by patients, due to its temporary conspicuous appearance possibly associated with serious psychological implications, and the need of multiple interventions. We aimed to present an approach combining the Rintala flap and the posterior perichondrial cutaneous graft as a valuable alternative to treat large nasal tip defects.

Head and Neck Porocarcinoma: SEER Analysis of Epidemiology and Survival.

Porocarcinoma is a rare malignant adnexal tumor. Little is known about the location of the disease in the head and neck. Our aim is to offer the largest analysis of demographic, pathological, and treatment patterns of head and neck porocarcinoma in comparison with other locations of the neoplasm from an epidemiologically representative cohort. METHOD: The Surveillance, Epidemiology, and End Results program of the National Cancer Institute was searched for all cases of porocarcinomas diagnosed between 2000 and 2018. This database is considered representative of the US population. Demographic, pathological, and treatment variables were compared between the head and neck and other regions. Overall and disease-specific survival was calculated and compared between groups. RESULTS: 563 porocarcinomas were identified, with 172 in the head and neck. The mean age was 66.4 years. Males were more affected in the head and neck. Regional and distant invasion rates were low (2.9 and 2.3%, respectively). Local excision and Mohs surgery were the most frequent therapies. Five-year overall survival was 74.8%. Five-year disease-specific survival was 97%. CONCLUSIONS: Head and neck porocarcinoma affects more males than females. Regional or distant metastatic rates are low and overestimated in previous literature. Disease-specific mortality is low. Surgery remains the mainstay of treatment.

Survival outcomes and epidemiology of Merkel cell carcinoma of the lower limb and hip: A Surveillance, Epidemiology, and End Results analysis 2000-2018.

BACKGROUND: Merkel cell carcinoma of lower limb and hip skin is a rare skin tumor that has a high recurrence rate. OBJECTIVE: To assess epidemiology and survival outcomes of the lower limb and hip Merkel cell carcinoma, which are less addressed in the literature. METHODS: The Surveillance, Epidemiology, and End Results database was searched for all cases of skin Merkel cell carcinoma between 2000 and 2018. Demographic and clinicopathologic features were compared between lower limb and other skin localizations using the t test or χ2 test. The overall survival (OS) of lower limb Merkel cell carcinoma was calculated using the Kaplan-Meier method. Subgroups were compared using the log rank test. Multivariate cox regression was used to identify independent prognostic factors. RESULTS: In total, 976 patients were identified. The mean age was 72.7 years. The median OS was 68 months, better than that of other localizations. Older age, regional lymph node, and distant metastasis were associated with low OS. Surgery with >1-cm margins, when associated with radiotherapy, had the best OS. Age, tumor size, lymph node status, presence of metastasis, and treatment sequence were identified as independent prognostic factors. CONCLUSION: Lower limb and hip Merkel cell carcinomas have better OS than tumors in other skin localizations. In this dataset, the best OS was ensured using surgery with >1-cm margins and adjuvant radiotherapy.

[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.

A mutual information-based in vivo monitoring of adaptive response to targeted therapies in melanoma.

The mechanisms of adaptive resistance to genetic-based targeted therapies of solid malignancies have been the subject of intense research. These studies hold great promise for finding co-targetable hub/pathways which in turn would control the downstream non-genetic mechanisms of adaptive resistance. Many such mechanisms have been described in the paradigmatic BRAF-mutated melanoma model of adaptive response to BRAF inhibition. Currently, a major challenge for these mechanistic studies is to confirm in vivo, at the single-cell proteomic level, the existence of dependencies between the co-targeted hub/pathways and their downstream effectors. Moreover, the drug-induced in vivo modulation of these dependencies needs to be demonstrated. Here, we implement such single-cell-based in vivo expression dependency quantification using immunohistochemistry (IHC)-based analyses of sequential biopsies in two xenograft models. These mimic phase 2 and 3 trials in our own therapeutic strategy to prevent the adaptive response to BRAF inhibition. In this mechanistic model, the dependencies between the targeted Li2CO3-inducible hub HuR and the resistance effectors are more likely time-shifted and transient since the minority of HuRLow cells, which act as a reservoir of adaptive plasticity, switch to a HuRHigh state as they paradoxically proliferate under BRAF inhibition. Nevertheless, we show that a copula/kernel density estimator (KDE)-based quantification of mutual information (MI) efficiently captures, at the individual level, the dependencies between HuR and two relevant resistance markers pERK and EGFR, and outperforms classic expression correlation coefficients. Ultimately, the validation of MI as a predictive IHC-based metric of response to our therapeutic strategy will be carried in clinical trials.

Anti-PD-1-Induced Hidradenitis Suppurativa.

Mucocutaneous adverse events are commonly observed under immune checkpoint inhibitors (ICIs) therapy. Here, we report the case of a 43-year-old male patient with a stage IIIC melanoma disease who developed hidradenitis suppurativa (HS) three months after the beginning of an anti-PD-1 (nivolumab) adjuvant therapy. The patient had no comorbidities other than obesity and severe acne during adolescence. After an unsuccessful course of lymecycline while he was still treated with nivolumab, he gradually improved under zinc gluconate therapy and, more importantly, after nivolumab cessation. HS is a recurrent follicular inflammatory disease in the apocrine gland-bearing areas of the body often associated with obesity, metabolic syndrome, tobacco smoking, inflammatory bowel diseases, psoriasis, and arthritis. In our patient, the latency period between drug initiation and onset of HS symptoms and the improvement after immunotherapy discontinuation, argued strongly in favor of an anti-PD-1-induced HS. Anti-PD-1 therapies often trigger T cells-mediated adverse events that mimic Th17-mediated inflammatory and neutrophilic diseases. We suggest that HS, as other pustular skin reactions and ICIs-induced neutrophilic colitis, can be part of the anti-PD-1 mucocutaneous adverse event spectrum.

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.

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.

[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.

Recognition of early melanoma: a monocentric dermoscopy follow-up study comparing de novo melanoma with nevus-associated melanoma.

BACKGROUND: The earlier detection of melanomas occurring within preexisting nevi is theoretically possible using sequential dermoscopy. Characterizing the early follow-up changes of nevus-associated melanomas (NAMs) and differentiating them from those observed in de novo melanomas (DNMs) may help the earlier recognition of NAMs. METHODS: Using descriptive dermoscopic features to detect focal changes, we blindly evaluated retrospectively the baseline and follow-up images of 32 melanomas that were subsequently classified as histopathologically defined NAMs or DNMs. RESULTS: Correlates of growth, as structureless brown­black areas or clods, complemented each other for the identification of DNMs at baseline (structureless brown­black areas: 66.7% DNMs, 15% NAMs, P < 0.01; combined with clods, one or the other being present: 100% DNMs, 30% NAMs, P < 0.01) and when considering their baseline presence or their appearance at follow­up (100% DNMs, 35% NAMs, P < 0.01). Correlates of fibrosis, as white lines, when considering their baseline presence or their appearance at follow-up, were associated with NAMs (60%, 16.7% DNMs, P = 0.027). CONCLUSION: Significant differences, distinguishing NAMs from DNMs, were detected particularly when considering both baseline signs and follow-up changes. Earlier identification of NAMs and their subsequent improved histological characterization will help define the subgroup of high-risk patients, for whom comprehensive image monitoring may be beneficial.

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.