Fig. 1: Study design and digoxin treatment response assessment.
a, Study flow chart. b, Representative images of a single CTC and homotypic and heterotypic CTC clusters (scale bar, 10 µm), stained with EpCAM, HER2 and EGFR (green) and CD45 (magenta). c,d, LME random coefficients showing a negative association between treatment and the average size of all CTC clusters (c) and among homotypic (regression coefficient −0.20, 95% CI −0.76 to 0.35) or heterotypic (regression coefficient −0.31, 95% CI −1.21 to 0.59) clusters, separately (d). LME coefficients are also shown for control nonrandomized patients, not receiving digoxin therapy (regression coefficient 0.48, 95% CI −0.10 to 1.07 for homotypic clusters; regression coefficient −0.06, 95% CI −0.70 to 0.58 for heterotypic clusters). The cross bar in d represents the LME fixed-effect coefficient. e, The average cluster size at baseline and posttreatment (day 3 or day 7) paired by patient (n = 9). The boxes represent the lower quantile, median and upper quantile. The vertical lines show the range of values, and the gray lines connect paired values. P values were calculated using the one-sided paired t-test. f, The fold change of the average CTC cluster size post- over pretreatment in treated patients. In control patients, the fold change of the average CTC cluster size at day 3 or day 7 (according to smaller cluster size) over baseline is shown. Each point represents an individual patient, and the cross bar represents the median. P values were calculated using the one-sided Wilcoxon rank-sum test. g, Negative association between digoxin levels and normalized size of CTC clusters at day 7 (linear regression P = 0.14, β = −4.65). The points represent individual patients, the line represents the linear regression model and the shaded area represents the 95% CI of the fitted line. CTCAE, Common Terminology Criteria for Adverse Events; BM, bone marrow; ECG, electrocardiogram; SAE, serious adverse event. Panel a was created with BioRender.com.
