Immune sensing of nucleic acids in inflammatory skin diseases.

Endosomal and cytosolic nucleic acid receptors are important immune sensors required for the detection of infecting or replicating viruses. The intracellular location of these receptors allows viral recognition and, at the same time, avoids unnecessary immune activation to self-nucleic acids that are continuously released by dying host cells. Recent evidence, however, indicates that endogenous factors such as anti-microbial peptides have the ability to break this protective mechanism. Here, we discuss these factors and illustrate how they drive inflammatory responses by promoting immune recognition of self-nucleic acids in skin wounds and inflammatory skin diseases such as psoriasis and lupus.

Anatomical exposure patterns of skin to sunlight: relative contributions of direct, diffuse and reflected ultraviolet radiation

Summary Background  The dose-response between ultraviolet (UV) exposure patterns and skin cancer occurrence is not fully understood. Sun-protection messages often focus on acute exposure, implicitly assuming that direct UV radiation is the key contributor to the overall UV exposure. However, little is known about the relative contribution of the direct, diffuse and reflected radiation components. Objective  To investigate solar UV exposure patterns at different body sites with respect to the relative contribution of the direct, diffuse and reflected radiation. Methods  A three-dimensional numerical model was used to assess exposure doses for various body parts and exposure scenarios of a standing individual (static and dynamic postures). The model was fed with erythemally weighted ground irradiance data for the year 2009 in Payerne, Switzerland. A year-round daily exposure (08:00-17:00 h) without protection was assumed. Results  For most anatomical sites, mean daily doses were high (typically 6·2-14·6 standard erythemal doses) and exceeded the recommended exposure values. Direct exposure was important during specific periods (e.g. midday during summer), but contributed moderately to the annual dose, ranging from 15% to 24% for vertical and horizontal body parts, respectively. Diffuse irradiation explained about 80% of the cumulative annual exposure dose. Acute diffuse exposures were also observed during cloudy summer days. Conclusions  The importance of diffuse UV radiation should not be underestimated when advocating preventive measures. Messages focused on avoiding acute direct exposures may be of limited efficiency to prevent skin cancers associated with chronic exposure.

Identification of Multiple Mechanisms of Resistance to Vemurafenib in a Patient with BRAFV600E-Mutated Cutaneous Melanoma Successfully Rechallenged after Progression.

PURPOSE: To investigate the mechanism(s) of resistance to the RAF-inhibitor vemurafenib, we conducted a comprehensive analysis of the genetic alterations occurring in metastatic lesions from a patient with a BRAF(V600E)-mutant cutaneous melanoma who, after a first response, underwent subsequent rechallenge with this drug. EXPERIMENTAL DESIGN: We obtained blood and tissue samples from a patient diagnosed with a BRAF(V600E)-mutant cutaneous melanoma that was treated with vemurafenib and achieved a near-complete response. At progression, he received additional lines of chemo/immunotherapy and was successfully rechallenged with vemurafenib. Exome and RNA sequencing were conducted on a pretreatment tumor and two subcutaneous resistant metastases, one that was present at baseline and previously responded to vemurafenib (PV1) and one that occurred de novo after reintroduction of the drug (PV2). A culture established from PV1 was also analyzed. RESULTS: We identified two NRAS-activating somatic mutations, Q61R and Q61K, affecting two main subpopulations in the metastasis PV1 and a BRAF alternative splicing, involving exons 4-10, in the metastasis PV2. These alterations, known to confer resistance to RAF inhibitors, were tumor-specific, mutually exclusive, and were not detected in pretreatment tumor samples. In addition, the oncogenic PIK3CA(H1047R) mutation was detected in a subpopulation of PV1, but this mutation did not seem to play a major role in vemurafenib resistance in this metastasis. CONCLUSIONS: This work describes the coexistence within the same patient of different molecular mechanisms of resistance to vemurafenib affecting different metastatic sites. These findings have direct implications for the clinical management of BRAF-mutant melanoma. Clin Cancer Res; 19(20); 5749-57. ©2013 AACR.

Nouvelles armes thérapeutiques contre le mélanome de stade IV [New therapeutic weapons in stage IV melanoma].

The treatment of stage IV melanoma has been revolutionized over the last years with the development of immunotherapies that, for the first time, have shown a significant benefit in overall survival, as well as with extremely effective targeted therapies, that also led to improved survival. These results are the fruits of an important translational research effort that allowed a rational approach with a very fast clinical development. The treatment of metastatic melanoma is, therefore, an illustration of the new paradigms of modern molecular research in oncology. In this review, we will present the various agents that have made the proof of their clinical benefit, as well as the scientific discoveries that allowed their development. Some of the remaining questions will be touched upon with the ongoing clinical trials. Inclusion of patients in these studies remains the top priority to improve on the clinical care.

Methylation of CpG island promoters in uveal melanoma.

BACKGROUND: Inactivation of tumour-related genes by promoter hypermethylation is a common epigenetic event in the development of a variety of tumours. AIM: To investigate in primary uveal melanoma the status of promoter methylation of genes thought to be involved in tumour development: p16, TIMP3, RASSF1, RARB, FHIT, hTERT and APC. METHODS: Gene promoter methylation was studied by methylation-sensitive single-strand conformation analysis and dot-blot assay in a series of 23 primary uveal melanomas. All DNA samples were obtained from paraffin-embedded formalin-fixed tissue blocks. RESULTS: hTERT promoter methylation was found with a relatively high frequency (52%). Promoter methylation of p16, TIMP3, RASSF1, RARB, FHIT and APC was a rare event. For none of these genes did promoter methylation exceed 15% of tumour samples, and, for some genes (FHIT and APC), no methylation was found at all. Furthermore, promoter methylation was absent in 39% (9/23) of cases. In only 22% (5/23) of cases was hypermethylation of at least two promoters observed. CONCLUSIONS: Promoter methylation of hTERT is a regular event in uveal melanoma. Hypermethylation of the other genes studied does not seem to be an essential element in the development of this tumour. As promoter methylation of APC, RASSF1 and RARB is often observed in cutaneous melanoma, these results suggest that different epigenetic events occur in the development of cutaneous and uveal melanoma.

Estimating the contribution of occupational solar ultraviolet exposure to skin cancer

BACKGROUND: Exposure to solar ultraviolet (UV) light is the main causative factor for skin cancer. Outdoor workers are at particular risk because they spend long working hours outside, may have little shade available and be bound to take their lunch at their workplace. Despite epidemiological evidence of a doubling in risk of squamous cell carcinoma in outdoor workers, the recognition of skin cancer as an occupational disease remains scarce. OBJECTIVE: To assess occupational solar UV doses and its contribution to skin cancer risk. METHODS: A numerical model (SimUVEx) was used to assess occupational and lunch break exposures, characterize exposure patterns and anatomical distribution. Risk of squamous cell carcinoma (SCC) was estimated from an existing epidemiological model. RESULTS: Horizontal body locations received 2.0-2.5 times more UV than vertical locations. Dose associated to lunch outdoor every day was similar to outdoor work one day per week but only half of a seasonal worker. Outdoor workers are associated with an increased risk of SCC but also of frequent acute episodes. CONCLUSION: Occupational solar exposure contributes largely to the overall lifetime UV dose, resulting in an excess risk of SCC. The magnitude of the estimated excess in risk supports the recognition of SCC as an occupational disease.

FDG PET and MR imaging in patients with liver metastases from uveal melanoma : results from a pilot study

Le présent travail a eu comme but la comparaison de la performance de deux méthodes d'imagerie diagnostique pour la détection de métastases hépatiques du mélanome uvéal : la tomographie d'émission par positons au F-18-fluorodésoxyglucose (TEP FDG) couplée à la tomodensitométrie (TDM) et l'imagerie par résonance magnétique (IRM). Dans cette étude rétrospective, nous avons analysé les données radiologiques de patients inclus dans une étude multicentrique randomisée de phase III de l'Uveal Melanoma Group of the European Organization for Research and Treatment of Cancer (EORTC). L'IRM s'est révélée nettement plus sensible que le FDG-PET/CT pour mettre en évidence les métastases hépatiques notamment de taille infra-centimétrique. Néanmoins, l'analyse des changements de l'accumulation du traceur métabolique par les métastases hépatiques au cours du traitement suggère la possibilité d'évaluer, de manière précoce, la réponse des métastases hépatiques à la chimiothérapie. Le nombre de cas étudiés est trop faible pour déterminer la précision et la valeur clinique d'une telle évaluation mais les résultats obtenus dans cette étude pilote justifient une étude plus étendue.

Successes and limitations of targeted cancer therapy in melanoma.

The treatment of stage IV melanoma has witnessed a very impressive pace of innovation in recent years, to a point where the management of these patients has very little in common to what was standard practice 5 years ago. If the gain in overall survival, the high response rates or the induction of a significant fraction of long survivors are all very exciting news for our patients and their families, the path that led to these discoveries is as important. Rather than empirical, the development of these new strategies has been extremely rational, based on state-of-the-art basic biology and immunology, exemplary translational research and, finally, hypothesis-driven targeted trials that led to rapid approval. In this review, we will cover all the new targeted therapies that have emerged as the results of these translational programs, focusing mainly on signaling pathway- and immune checkpoint-targeted therapies. Taken collectively, these new developments set the bar for a new paradigm in future translational and clinical research in both melanoma as well as other tumor types.

Recommandations suisses pour la prise en charge des cancers cutanés chez les patients transplantés d'organe [Swiss clinical practice guidelines for skin cancer in organ transplant recipients]

Swiss clinical practice guidelines for skin cancer in organ transplant recipients Transplant patients have increased over the last decades. As a consequence of long-term immunosuppression, skin cancer, in particular squamous cell carcinoma (SCC), has become an important problem. Screening and education of potential organ transplant recipients (OTRs) regarding prevention of sun damage and early recognition of skin cancer are important before transplantation. Once transplanted, OTRs should be seen yearly by a dermatologist to ensure compliance with sun avoidance as well as for treatment of precancerosis and SCC. Early removal is the best treatment for SCC. Reduction of immunosuppression, switch to mTOR inhibitors and chemoprevention with acitretin may reduce the incidence of SCC. The dermatological follow-up of OTRs should be integrated into a comprehensive post-transplant management strategy.

Prognostic value of sentinel node biopsy in 327 prospective melanoma patients from a single institution

Résumé Etude de la valeur pronostique de la biopsie du ganglion sentinelle dans une étude prospective monocentrique de 327 patients atteints de mélanome malin But II s'agit de confirmer la validité de la biopsie du ganglion sentinelle, d'en définir la morbidité, d'investiguer les facteurs prédictifs pour le statut du ganglion sentinelle ainsi que de déterminer les facteurs pronostiques pour la survie sans récidive et la survie spécifique liée à la maladie. Matériel et méthode D'octobre 1997 à décembre 2004, 327 patients consécutifs présentant un mélanome cutané primaire des membres, du tronc et de la tête, sans adénopathie clinique ni métastase à distance ont été inclus. La biopsie du ganglion sentinelle a été réalisée selon la triple technique (lymphoscintigraphie, colorant bleu vital et sonde de détection gamma). Les paramètres et la survie ont été évalués par différentes analyses de régression logistique multiple selon Cox et la survie évaluée selon Kaplan Meier. Résultats Vingt-trois pour cent des patients présentaient au moins un ganglion sentinelle métastatique, ce qui était associé de façon significative à l'épaisseur selon Breslow (p<0.001). Le taux de succès de la biopsie du ganglion sentinelle était de 99.1% et sa morbidité de 7.6%. Avec une durée médiane de suivi de 33 mois, la survie sans récidive à 5 ans était de 43% pour les patients avec un ganglion sentinelle positif et de 83.5% pour ceux avec un ganglion sentinelle négatif. La survie spécifique liée à la maladie à 5 ans était de 49% pour les patients avec un ganglion sentinelle positif et de 87.4% pour ceux avec un ganglion sentinelle négatif. Le taux de faux négatif de la biopsie du ganglion sentinelle était de 8.6%. L'analyse multivariée a démontré que la survie sans récidive était significativement péjorée par :l'épaisseur selon Breslow (RR=5.6, p<0.001), un ganglion sentinelle positif (RR=5.0, p<0.001), et le sexe masculin (RR=2.9, p=0.001). La survie spécifique liée à la maladie était significativement diminuée par : un ganglion sentinelle métastatique (RR=8.4, p<O.OOI), le sexe masculin (RR=6.1, p<0.001), l'épaisseur selon Breslow (RR=3.2, p=0.013), et la présence d'une ulcération (RR=2.6, p=0.015). Conclusion La biopsie du ganglion sentinelle est une procédure fiable avec une haute sensibilité (91.4%) et une faible morbidité (7.6%). L'épaisseur selon Breslow était le seul facteur prédictif significatif pour le statut du ganglion sentinelle. La survie sans récidive était péjorée selon un ordre décroissant par :l'épaisseur selon Breslow, un ganglion sentinelle métastatique, et le sexe masculin. De façon similaire la survie spécifique liée à la maladie était péjorée par : un ganglion sentinelle métastatique, le sexe masculin, l'épaisseur selon Breslow, et une ulcération. Ces données renforcent le statut du ganglion sentinelle en tant que puissant moyen pour évaluer le stade tumoral ainsi que le pronostic.

Mutations in NDUFB11, Encoding a Complex I Component of the Mitochondrial Respiratory Chain, Cause Microphthalmia with Linear Skin Defects Syndrome.

Microphthalmia with linear skin defects (MLS) syndrome is an X-linked male-lethal disorder also known as MIDAS (microphthalmia, dermal aplasia, and sclerocornea). Additional clinical features include neurological and cardiac abnormalities. MLS syndrome is genetically heterogeneous given that heterozygous mutations in HCCS or COX7B have been identified in MLS-affected females. Both genes encode proteins involved in the structure and function of complexes III and IV, which form the terminal segment of the mitochondrial respiratory chain (MRC). However, not all individuals with MLS syndrome carry a mutation in either HCCS or COX7B. The majority of MLS-affected females have severe skewing of X chromosome inactivation, suggesting that mutations in HCCS, COX7B, and other as-yet-unidentified X-linked gene(s) cause selective loss of cells in which the mutated X chromosome is active. By applying whole-exome sequencing and filtering for X-chromosomal variants, we identified a de novo nonsense mutation in NDUFB11 (Xp11.23) in one female individual and a heterozygous 1-bp deletion in a second individual, her asymptomatic mother, and an affected aborted fetus of the subject's mother. NDUFB11 encodes one of 30 poorly characterized supernumerary subunits of NADH:ubiquinone oxidoreductase, known as complex I (cI), the first and largest enzyme of the MRC. By shRNA-mediated NDUFB11 knockdown in HeLa cells, we demonstrate that NDUFB11 is essential for cI assembly and activity as well as cell growth and survival. These results demonstrate that X-linked genetic defects leading to the complete inactivation of complex I, III, or IV underlie MLS syndrome. Our data reveal an unexpected role of cI dysfunction in a developmental phenotype, further underscoring the existence of a group of mitochondrial diseases associated with neurocutaneous manifestations.