Metastases are the major cause of death from melanoma, a skin cancer which has the fastest rising incidence of any malignancy in the Western world. Molecular pathways that drive melanoblast migration in development are believed to underpin the movement and ultimately the metastasis of melanoma. Here we show that mice lacking P-Rex1, a Rac-specific Rho GTPase guanine nucleotide exchange factor (GEF), have a melanoblast migration defect during development evidenced by a white belly. Moreover, these P-Rex1−/− mice are resistant to metastasis when crossed to a murine model of melanoma. Mechanistically, this is associated with P-Rex1 driving invasion in a Rac-dependent manner. P-Rex1 is elevated in the great majority of human melanoma cell lines as well as tumor tissue. We conclude that P-Rex1 plays an important role in melanoblast migration and cancer progression to metastasis in mice and humans.

Purpose To improve velocity–to-noise ratio (VNR) and dynamic velocity range at 4D flow MRI by using dual-velocity encoding (dual-venc) with k-t GRAPPA acceleration. Materials and Methods A dual-venc 4D flow MRI sequence with k-t GRAPPA acceleration was developed using a shared reference scan followed by three-directional low- and high-venc scans (TR/TE/FA=6.1ms/3.4ms/15°, temporal/spatial resolution=43.0ms/1.2×1.2×1.2mm3). The high-venc data was used to correct for aliasing in the low-venc data, resulting in a single dataset with the favorable VNR of the low-venc but without velocity aliasing. The sequence was validated at a 3 Tesla MRI Scanner in phantom experiments and applied in 16 volunteers to investigate its feasibility for assessing intracranial hemodynamics (net flow and peak velocity) at the major intracranial vessels. In addition, image quality and image noise was assessed in the in-vivo acquisitions. Results All 4D flow MRI scans were acquired successfully with an acquisition time of 20±4min. The shared reference scan reduced the total acquisition time by 12.5% compared to two separate scans. Phantom experiments showed 51.4% reduced noise for dual-venc compared to high-venc and an excellent agreement of velocities (ρ=0.8, p<0.001). The volunteer data showed decreased noise in dual-venc data (54.6% lower) compared to high-venc, and improved image quality, as graded by two observers: less artifacts (P<0.0001), improved vessel conspicuity (P<0.0001), and reduced noise (P<0.0001). Conclusion Dual-venc 4D flow MRI exhibits the superior VNR of the low-venc acquisition and reliably incorporates low- and high-velocity fields simultaneously. In-vitro and in-vivo data demonstrate improved flow visualization, image quality and image noise.

Adrenalectomy for metastasis, with intent to prolong survival, should be offered to patients with favorable tumor biology, such as those with significant DFI. The oncological outcome from LA appears similar to that from OA.

BackgroundCutaneous melanoma is the deadliest skin cancer, with an increasing incidence and mortality rate. Currently, staging of patients with primary melanoma is performed using histological biomarkers such as tumor thickness and ulceration. As disruption of the epigenomic landscape is recognized as a widespread feature inherent in tumor development and progression, we aimed to identify novel biomarkers providing additional clinical information over current factors using unbiased genome-wide DNA methylation analyses.MethodsWe performed a comprehensive DNA methylation analysis during all progression stages of melanoma using Infinium HumanMethylation450 BeadChips on a discovery cohort of benign nevi (n = 14) and malignant melanoma from both primary (n = 33) and metastatic (n = 28) sites, integrating the DNA methylome with gene expression data. We validated the discovered biomarkers in three independent validation cohorts by pyrosequencing and immunohistochemistry.ResultsWe identified and validated biomarkers for, and pathways involved in, melanoma development (e.g., HOXA9 DNA methylation) and tumor progression (e.g., TBC1D16 DNA methylation). In addition, we determined a prognostic signature with potential clinical applicability and validated PON3 DNA methylation and OVOL1 protein expression as biomarkers with prognostic information independent of tumor thickness and ulceration.ConclusionsOur data underscores the importance of epigenomic regulation in triggering metastatic dissemination through the inactivation of central cancer-related pathways. Inactivation of cell-adhesion and differentiation unleashes dissemination, and subsequent activation of inflammatory and immune system programs impairs anti-tumoral defense pathways. Moreover, we identify several markers of tumor development and progression previously unrelated to melanoma, and determined a prognostic signature with potential clinical utility.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0851-3) contains supplementary material, which is available to authorized users.

A single acquisition of 4D flow MRI characterized local morphological and haemodynamic differences between groups along the aorta. BAV showed altered haemodynamics when compared with TAV in spite of having similar aorta dimensions. Maximal aorta diameter was associated with age, PV, and normalized flow displacement.