Subject(s)
Meningococcal Infections/diagnosis , Pneumococcal Infections/diagnosis , Purpura Fulminans/microbiology , Skin/pathology , Aged , Biopsy/methods , Fatal Outcome , Female , Humans , Male , Middle Aged , Neisseria meningitidis/isolation & purification , Polymerase Chain Reaction/methods , Skin/microbiology , Streptococcus pneumoniae/isolation & purificationABSTRACT
The cyclic AMP (cAMP) signaling pathway is critical in melanocyte biology for regulating differentiation. It is downregulated by phosphodiesterase (PDE) enzymes, which degrade cAMP itself. In melanoma evidence suggests that inhibition of the cAMP pathway by PDE type 4 (PDE4) favors tumor progression. For example, in melanomas harboring RAS mutations, the overexpression of PDE4 is crucial for MAPK pathway activation and proliferation induced by oncogenic RAS. Here we showed that PDE4D is overexpressed in BRAF-mutated melanoma cell lines, constitutively disrupting the cAMP pathway activation. PDE4D promoted melanoma invasion by interacting with focal adhesion kinase (FAK) through the scaffolding protein RACK1. Inhibition of PDE4 activity or inhibition of PDE4D interaction with FAK reduced invasion. PDE4D expression is increased in patients with advanced melanoma and PDE4D-FAK interaction is detectable in situ in metastatic melanoma. Our study establishes the role of PDE4D in BRAF-mutated melanoma as regulator of cell invasion, and suggests its potential as a target for preventing metastatic dissemination.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Focal Adhesion Kinase 1/metabolism , Melanoma/pathology , Mutation/genetics , Proto-Oncogene Proteins B-raf/genetics , Apoptosis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Differentiation , Cell Movement , Cell Proliferation , Cyclic Nucleotide Phosphodiesterases, Type 4/genetics , Focal Adhesion Kinase 1/genetics , Humans , Melanocytes/cytology , Melanocytes/metabolism , Melanoma/genetics , Melanoma/metabolism , Neoplasm Invasiveness , Neoplasm Staging , Phosphorylation , Prognosis , Signal Transduction , Tumor Cells, CulturedABSTRACT
BACKGROUND: Sentinel lymph-node (LN) biopsy (SLNB) is a valuable tool to assess the regional LN status in Merkel cell carcinoma (MCC). However, its prognostic value is still debated. This study was undertaken to assess SLNB usefulness for MCC management and to determine the impact of SLNB status on disease-free survival (DFS) and overall survival (OS) by comparing SLNB-positive versus -negative patients according to demographic, clinical and treatment characteristics. PATIENTS AND METHODS: In this retrospective, multicenter observational study, SLNB was proposed to all patients referred for clinically N0 MCC. Treatment schedule consisted of wide-margin surgical resection of primary MCC followed by adjuvant radiation therapy (aRT) to the primary site and, for SLNB-positive patients, radical LN dissection followed by regional aRT. Univariate and multivariate analyses determined factors associated with DFS and OS. RESULTS: Among 87 patients with successful SLNB, 21 (24.1%) were SLNB-positive. Median follow-up for the entire series was 39 months; respective 3-year DFS and OS rates were 73% and 81.4%, respectively. Univariate analysis (all patients) identified SLNB-negativity as being associated with prolonged OS (P = 0.013) and aRT (all sites considered) was associated with longer DFS (P = 0.004) and OS (P = 0.018). Multivariate analysis (all patients) retained SLNB status and aRT (all sites considered) as being associated with improved DFS (P = 0.014 and 0.0008) and OS (P = 0.0020 and 0.0019). Moreover, for SLNB-negative patients, tumor-bed irradiation was also significantly associated with prolonged DFS (P = 0.006) and OS (P = 0.014). CONCLUSIONS: The present study demonstrates that SLNB-negativity is a strong predictor of longer DFS and OS in stage I and II MCC patients. The similar benefit for aRT on tumor bed observed in this study has to be confirmed by a prospective study. The results advocate for SLNB being considered to all MCC patients.
Subject(s)
Carcinoma, Merkel Cell/radiotherapy , Prognosis , Radiotherapy, Adjuvant , Sentinel Lymph Node Biopsy , Adult , Aged , Aged, 80 and over , Carcinoma, Merkel Cell/pathology , Carcinoma, Merkel Cell/surgery , Disease-Free Survival , Female , Humans , Lymph Node Excision , Male , Middle Aged , Neoplasm Staging , Retrospective Studies , Sentinel Lymph Node/pathology , Sentinel Lymph Node/surgery , Treatment OutcomeABSTRACT
Helical tomotherapy is a recent modality of intensity-modulated, rotational irradiation being developed for treatment of an increasing number of malignancies. It allows delivering an accurate treatment while sparing critical organs thus optimizing the therapeutic ratio. In particular, it allows treating some tumour locations that could not be efficiently irradiated through more conventional irradiation devices. We report the usefulness of this approach for the treatment of complex lesions such as circumferential cutaneous lymphoma of the trunk.
