Discoidin domain receptors: A promising target in melanoma.

The discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family that signals in response to collagen and that has been implicated in cancer progression. In the present study, we investigated the expression and role of DDR1 in human melanoma progression. Immunohistochemical staining of human melanoma specimens (n = 52) shows high DDR1 expression in melanoma lesions that correlates with poor prognosis. DDR1 expression was associated with the clinical characteristics of Clark level and ulceration and with BRAF mutations. Downregulation of DDR1 by small interfering RNA (siRNA) in vitro inhibited melanoma cells malignant properties, migration, invasion, and survival in several human melanoma cell lines. A DDR tyrosine kinase inhibitor (DDR1-IN-1) significantly inhibited melanoma cell proliferation in vitro, and ex vivo and in tumor xenografts, underlining the promising potential of DDR1 inhibition in melanoma.

Three-stage folded forehead flap for nasal reconstruction: Objective and subjective measurements of aesthetic and functional outcomes.

BACKGROUND: The three-stage folded forehead flap (FFF) proved to be a simple and readily available method of lining replacement. To date, no clinical trial has evaluated the outcomes of the FFF on the nose shape and function. METHODS: Patients undergoing a full-thickness unilateral alar reconstruction with a forehead flap between January of 2010 and December of 2015 were included for analysis. Patients were divided into two groups: The FFF group included patients that had a unilateral alar reconstruction using a three-stage FFF; the standard forehead flap (SFF) group included patients that had a reconstruction using a two-stage forehead flap in combination with another method for lining reconstruction. The following objective measurements were performed: the alar thickness, nostril and hemi-nose areas, and nostril height. Subjective evaluation of the results was performed using the NAFEQ score. Independent raters also evaluated the appearance of the nose. RESULTS: Thirty-one patients were included: 15 in the FFF group and 16 in the SFF group. In both groups, the reconstructed ala was thicker than that on the normal side, the reconstructed nostril was smaller than the normal nostril, and the reconstructed hemi-nose was bigger than the normal side. Moreover, 84% of the patients were satisfied with their total nasal functioning. All the patients were satisfied with their total nasal appearance. CONCLUSION: The FFF showed objective, subjective, aesthetic, and functional results comparable to other lining reconstruction techniques.

EMMPRIN/CD147 is an independent prognostic biomarker in cutaneous melanoma.

CD147 has been implicated in melanoma invasion and metastasis mainly through increasing metalloproteinase synthesis and regulating VEGF/VEGFR signalling. In this study, the prognostic value of CD147 expression was investigated in a cohort of 196 cutaneous melanomas including 136 consecutive primary malignant melanomas, 30 lymph nodes, 16 in-transit and 14 visceral metastases. A series of 10 normal skin, 10 blue nevi and 10 dermal nevi was used as control. CD147 expression was assessed by immunohistochemistry, and the association of its expression with the clinicopathological characteristics of patients and survival was evaluated using univariate and multivariate statistical analyses. Univariate analysis showed that high CD147 expression was significantly associated with metastatic potential and with a reduced overall survival (P < 0.05 for both) in primary melanoma patients. CD147 expression level was correlated with histological factors which were associated with prognosis: Clark level, ulceration status and more particularly with Breslow index (r = 0.7, P < 10(-8) ). Multivariate analysis retained CD147 expression level and ulceration status as predicting factors for metastasis and overall survival (P < 0.05 for both). CD147 emerges as an important factor in the aggressive behaviour of melanoma and deserves further evaluation as an independent prognostic biomarker.

Mature cytotoxic CD56(bright)/CD16(+) natural killer cells can infiltrate lymph nodes adjacent to metastatic melanoma.

Melanomas are characterized by high metastatic potential, with regional lymph node representing the most frequent site of early dissemination in this disease. These regional lymph nodes also represent the primary site for differentiation of natural killer (NK) cells. Although blood-derived NK cells can efficiently lyse melanoma cells isolated from metastatic lymph node (M-LN), there has been no study of the properties of the most disease-relevant NK cells isolated from M-LN in patients with melanoma. Here, we report that M-LN contains 0.5% to 11% of CD56(bright) NK cells among CD45(+) hematopoietic cells present and that this cell population surrounds tumor cell clusters in M-LN. This NK cell population was characterized by expression of CD62L, chemokine receptors, and high levels of natural cytotoxicity receptors (NCR), NK group 2 D (NKG2D), and DNAX accessory molecule 1 (DNAM-1). Expression of NCR-NKp30 and NKG2D correlated negatively with percentages of tumor cells in M-LN. Interestingly, M-LN contained a unique subset of mature CD56(bright)CD16(+) NK cells displaying coregulated expression of NCR and NKG2D activating receptors. Ex vivo analyses suggested that M-LN-derived NK cells were inactive but could be activated by appropriate cytokine signals [interleukin (IL)-2 or IL-15], and could lyse metastatic melanoma cells in a highly efficient manner compared with blood-derived NK cells. Taken together, the results offer evidence that adjuvant immunotherapy that targets NK cells in M-LN for activation may improve treatment of patients with sentinel lymph node-positive melanoma.

Phenotypic and functional characteristics of blood natural killer cells from melanoma patients at different clinical stages.

Melanomas are aggressive skin tumors characterized by high metastatic potential. Immunotherapy is a valuable alternative for metastatic melanoma patients resistant to chemotherapy. Natural Killer (NK) cells are efficient anti-tumor cytotoxic effectors. We previously showed that blood NK cells from stage IV metastatic melanoma patients display decreased NK receptors and that chemotherapy modifies the functional status of blood NK cells. To investigate the role of NK cells along melanoma progression, we have here studied NK cells from patients at different stages of the disease. First, we showed that ex vivo NK cells from certain stage III-IV patients displayed low degranulation potential. Using a dynamic label-free assay, we found that immunoselected IL-2 activated blood NK cells from patients efficiently lysed melanoma cells through NKp46 and NKG2D receptors, independently to the clinical stage. Moreover, the ex vivo phenotype of circulating NK cells from 33 patients (stage I to IV) was extensively analyzed. NK cells from patients displayed higher variability in the percentages of Natural Cytotoxicity Receptors (NCR) and Natural Killer Group 2D (NKG2D) receptor expression compared to donor NK cells. The main defect was the decreased expression of NCR1 (NKp46) by NK cells from metastatic patients. Interestingly, we found a positive correlation between the NK cell percentages of NKp46 and the duration of stage IV in melanoma patients. Finally, we showed that NK cells infiltrated primary melanomas and displayed a predominant peritumoral distribution. These results are new arguments for the development of NK-based therapies in melanoma patients.

Perforator-based chimaeric thoracodorsal flap for foot reconstruction.

The reconstruction of severe defects of the ankle and foot is a challenge. The ideal solution should combine a thin skin flap on the dorsum to allow shoe fitting and a muscle flap with a split-thickness skin graft on the weight-bearing area. Perforator-based thoracodorsal chimaeric flaps allow us to achieve these two goals with minimal donor-site morbidity. We present a reconstruction of an extended circumferential defect of the ankle with an exposed heel using a chimaeric thoracodorsal perforator flap with a serratus muscle flap. The skin flap was transferred on the dorsal foot, whereas the serratus anterior muscle was transferred on the exposed heel. Postoperative recovery was uneventful and the patient began full weight bearing after 3 months. Twelve months after reconstruction, natural shape and walking function were successfully achieved.