Application of circulating cell-free tumor DNA profiles for therapeutic monitoring and outcome prediction in genetically heterogeneous metastatic melanoma

PURPOSE Circulating cell-free tumor DNA (ctDNA) reflects the heterogeneousspectrum of tumor-specific mutations, especially in systemic disease. We validated plasma-based assays that allow the dynamic quantitative detection of ctDNA as a prognostic biomarker for tumor load and prediction of therapy response in melanoma. MATERIALS and METHODS We analyzed plasma-derived ctDNA from a large training cohort (n = 96) of patients with advanced-stage melanoma, with assays for the BRAFV600E and NRASQ61 driver mutations as well as TERTC250T and TERTC228T promoter mutations. An independent patient cohort (n = 35) was used to validate the utility of ctDNA monitoring under mitogen-activated protein kinase–targeted or immune checkpoint therapies. RESULTS Elevated plasma ctDNA level at baseline was an independent prognostic factor of disease progression when compared with serum S100 and lactate dehydrogenase levels in multivariable analyses (hazard ratio [HR], 7.43; 95% CI, 1.01 to 55.19; P = .05). The change in ctDNA levels during therapy correlated with treatment response, where increasing ctDNA was predictive for shorter progression-free survival (eg, for BRAFV600EctDNA, HR, 3.70; 95% CI, 1.86 to 7.34; P < .001). Increasing ctDNA levels predicted disease progression significantly earlier than did routine radiologic scans (P < .05), with a mean lead time of 3.5 months. NRAS-mutant ctDNA was detected in a significant proportion of patients with BRAF-mutant tumors under therapy, but unexpectedly also at baseline. In vitro sensitivity studies suggested that this represents higher-than-expected intratumoral heterogeneity. The detection of NRASQ61 ctDNA in baseline samples of patients with BRAFV600E mutation who were treated with mitogen-activated protein kinase inhibitors significantly correlated with shorter progression-free survival (HR, 3.18; 95% CI, 1.31 to 7.68; P = .03) and shorter overall survival (HR, 4.08; 95% CI, 1.57 to 10.58; P = .01). CONCLUSION Our results show the potential role of ctDNA measurement as a sensitive monitoring and prediction tool for the early assessment of disease progression and therapeutic response in patients with metastaticmelanoma

New Opportunities in the Soft X-Ray Absorption to Characterize the Adsorbate Bonding

One of the important applications of XAS in the soft X-ray regime is the ability to measure the EXAFS of light elements, like carbon, nitrogen, etc. up to sulfur and chlorine. These elements, adsorbed on metal surfaces, are the most important constituents for the investigation of gas-metal interactions. One decade ago, the surface EXAFS "world was harmonic", the nearest neighbor distances were determined within the harmonic approximation, R did not change with temperature, and the coordination number N was determined from measurements at a single temperature. Recently, SEXAFS data were taken as a function of T and at various angles of X-ray incidence. This advance, in combination with multiple scattering analysis and full simulation computer codes, allows to routinely determine the pair distribution function up to the third moment. We relate in general terms the Einstein temperature, the local static disorder and thermal expansion to the ionic versus covalent bonding, shape of effective pair potentials and adsórbate induced surface reconstruction. Furthermore, these low Z systems are ideal candidates to detect unambiguously the photoelectron backscattering by interstitial charge densities (AXAFS)

Surface Atomic-XAFS for Nitrogen Atoms on Copper

The presence of oscillatory structures in the atomic x-ray absorption background is reported for the first time for surface EXAFS of c(2x2)N/Cu(100) and (2x3)N/Cu(110). The experimental data for N/Cu(110) are compared to FEFF7 calculations of the oscillating atomic background µ0(E). For the two systems it is found that the AXAFS peak in the Fourier transform increases by a factor of two as the N-atom is adsorbed closer to the surface plane

Magnetic Coupling of Ni, Cu and Co Bi- and Trilayers Probed by Magnetic Circular X-Ray Dichroism

Using magnetic circular X-ray dichroism (MCXD), Co/Ni, Cu/Co and Cu/Ni trilayers and Co/Cu/Ni and Ni/Cu/Co trilayers grown on a Cu(00l) substrate were investigated. The Co layers were about 2 monolayers (ML) and the Ni layers were between 1.5 and 4.5 ML thick. It was observed that, for Co/Ni bilayers, the entire system has only one Curie temperature, TC. After having been covered by 2-7 ML Cu, Ni and Co films exhibit a significantly lower TC . For trilayers, different Curie temperatures were determined for Ni and Co when separated by a 2-6 ML Cu spacer. The coupling of Ni and Co layers was found to be both ferromagnetic and antiferromagnetic, depending on the spacer thickness and the order of the layers