Activin promotes skin carcinogenesis by attraction and reprogramming of macrophages.

Activin has emerged as an important player in different types of cancer, but the underlying mechanisms are largely unknown. We show here that activin overexpression is an early event in murine and human skin tumorigenesis. This is functionally important, since activin promoted skin tumorigenesis in mice induced by the human papillomavirus 8 oncogenes. This was accompanied by depletion of epidermal γδ T cells and accumulation of regulatory T cells. Most importantly, activin increased the number of skin macrophages via attraction of blood monocytes, which was prevented by depletion of CCR2-positive monocytes. Gene expression profiling of macrophages from pre-tumorigenic skin and bioinformatics analysis demonstrated that activin induces a gene expression pattern in skin macrophages that resembles the phenotype of tumor-associated macrophages in different malignancies, thereby promoting angiogenesis, cell migration and proteolysis. The functional relevance of this finding was demonstrated by antibody-mediated depletion of macrophages, which strongly suppressed activin-induced skin tumor formation. These results demonstrate that activin induces skin carcinogenesis via attraction and reprogramming of macrophages and identify novel activin targets involved in tumor formation

Clinical experience with combination BRAF/MEK inhibitors for melanoma with brain metastases: a real-life multicenter study

BRAF and MEK kinase inhibitors can be highly effective in treating BRAF-mutant melanomas, but their safety and activity in patients with active/symptomatic brain metastases are unclear. We sought to shed light on this open clinical question. We conducted a multicenter retrospective study on real-life patients with melanoma and active brain metastases treated with combination BRAF/MEK inhibitors. A total of 65 patients were included (38 men and 27 women; median age: 49 years). Of them, 53 patients received dabrafenib/trametinib, 10 received vemurafenib/cobimetinib, one received encorafenib/binimetinib, and one received vemurafenib/trametinib. We did not observe any unexpected treatment-related safety signals in our cohort. Overall, 17 patients continued on therapy through the cutoff date. After initiation of therapy, steroid dose could be decreased in 22 of 33 patients (11 tapered off entirely), anticonvulsants were stopped in four of 21, and narcotics were stopped in four of 12. Median progression-free survival from the start of therapy was 5.3 months (95% confidence interval: 3.6-6.1), and median overall survival was 9.5 months (95% confidence interval: 7.7-13.5). A total of 20 patients were surviving at the cutoff date. Univariate analysis of age, sex, ulceration status, thickness, stage, location, or lactate dehydrogenase did not reveal significant predictors of progression-free survival or overall survival within our cohort, but multivariate analysis suggested that older age, lower risk location of original lesion, and nodular melanoma are poor prognostic indicators. Combination therapy with BRAF/MEK inhibitors is a viable treatment option for patients with BRAF-mutant melanoma and brain metastases, but further studies should help to define the optimal treatment approach in this population

Evolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling

Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression

Aktuelle Systemtherapien bei fortgeschrittenem Melanom Neue Medikamente – neue Kombinationen

Seit 2010 hat sich die systemische Therapie des metastasierten Melanoms drastisch verändert. Nachdem in klinischen Studien jahrzehntelang nahezu keinerlei Überlebensvorteil durch systemische Therapieoptionen gezeigt werden konnte, stehen heute mit den spezifischen Kinasehemmern und den Immuntherapien mit Checkpoint-Inhibitoren Behandlungsmethoden zur Verfügung, die zu einem verlängerten Überleben und einer verbesserten Lebensqualität beitragen

Angioimmunoblastic T-Cell Lymphoma Mimicking Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome)

Angioimmunoblastic T-cell lymphoma (AITCL) is a rare, aggressive lymphoma which derives from follicular helper T cells, commonly affecting the elderly population. It accounts for 2% of all non-Hodgkin lymphomas, with a reported 5-year overall survival rate of less than 30%. Very often, the clinical picture of AITCL encompasses systemic symptoms such as generalized lymphadenopathy, hepatosplenomegaly, skin rash, anemia, and polyclonal hypergammaglobulinemia. Here we report on the case of a female patient who presented with clinical features resembling drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) prior to the definitive diagnosis of AITCL. The index of suspicion for cutaneous manifestations of lymphoma, and especially AITCL, must be high, particularly in atypical clinical courses of drug eruptions or if skin lesions relapse and are refractory to standard high-dose systemic corticosteroids

Evolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling

Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression