No abstract

Purpose: Circulating tumor DNA (ctDNA) provides a novel approach for detecting tumor burden and predicting clinical outcomes of hepatocellular carcinoma (HCC). Here, we performed a thorough evaluation of HCC circulating genetic features and further fully integrated them to build a robust strategy for HCC monitoring and prognostic outcome assessment. Experimental Design: We performed target sequencing and low-coverage whole-genome sequencing on plasma samples collected from 34 long-term follow-up patients with HCC to capture tumor somatic SNVs and CNVs, respectively. Clinical information was also obtained to evaluate the prognostic performance of ctDNA comparing with clinically applied protein biomarkers. Results: All plasma samples before surgery showed somatic genetic variations resembling corresponding tumor tissues. During follow-up, SNVs and CNVs dynamically changed correlating to patients' tumor burden. We integrated the comprehensive ctDNA mutation profiles to provide a robust strategy to accurately assess patients' tumor burden with high consistence comparing with imaging results. This strategy could discover tumor occurrence in advance of imaging for an average of 4.6 months, and showed superior performance than serum biomarkers AFP, AFP-L3%, and Des-Gamma-Carboxy Prothrombin (DCP). Furthermore, our strategy could precisely detect minimal residual disease (MRD) in advance and predict patients' prognostic outcomes for both relapsefree survival (P ¼ 0.001) and overall survival (P ¼ 0.001); further combining ctDNA with DCP could increase the sensitivity for MRD detection. Conclusions: We demonstrated that plasma CNV and SNV levels dynamically correlated with patients' tumor burden in HCC. Our strategy of comprehensive mutation profile integration could accurately and better evaluate patients' prognostic risk and detect tumor occurrence in advance than traditional strategies.

S U M M A R YGreen's functions of the indirect effects of atmospheric loading is formulated taking into account the effect of the atmospheric thickness. This is a modification of the classic paper by Farrell that formulated the indirect effects of ocean loading by approximating the loading mass as a thin layer. Atmospheric loading differs from ocean loading in the ways in which gravitational attraction and pressure act. In the case of ocean loading, because both the gravitational attraction and the pressure can be considered to arise from the mass located at the surface of the Earth, the effects of both are treated together and are included in the load Love numbers defined for the problem. In the case of atmospheric loading, if the atmospheric thickness is taken into account, because the mass is distributed over a large elevation and the pressure is exerted at the surface of the Earth, defining a set of load Love numbers including both effects of gravitational attraction and pressure is no longer possible. In this paper, the indirect effects of gravitational attraction and pressure of atmospheric loading are formulated separately by introducing load Love numbers for each of them respectively. Asymptotic expressions of the various load Love numbers one order of magnitude more accurate than those given be Farrell are obtained by searching for the asymptotic solutions of their governing ordinary-differential equations. These are used to improve the convergence of the Legendre sums in the various Green's functions. We find that the consideration of the atmospheric thickness has a negligible effect when compared with the simple thin-layer approximation.