Use of integrated imaging and serum biomarker profiles to identify subclinical dysfunction in pediatric cancer patients treated with anthracyclines

Figures

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  Fig. 1. Study Cohort and Diagram. CMRI: cardiac magnetic resonance imaging; ALL: acute lymphocytic leukemia; AML: acute myeloid leukemia. Twenty patients (10–22 years) were prospectively enrolled between January 2013 and November 2014. Seventeen subjects completed visit 1 (30–60 mg/m2) and thirteen completed the remaining study visits (125–175 mg/m2, 200–250 mg/m2, 275–325 mg/m2, after max AC dose and 1 year after max AC dose)

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  Fig. 2. Schematic diagram demonstrating the three dimensional circumferential-radial-longitudinal coordinate system used for strain calculation. ERR; Peak mid radial strain magnitude; ECC: Peak global circumferential strain magnitude; ELL: Peak global longitudinal strain magnitude. Each element of strain is, simply, a measurement of the fractional or the percent change of length in a specific direction where Lo is the original fiber length before tag deformation and L is the current length

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  Fig. 3. Plasma profiling for specific determinants of inflammation and signaling. a Plasma profiling for specific determinants of inflammation and ECM remodeling were examined in referent normal subjects and those undergoing initial AC treatment, designated here as Visit 1 in tabular format. The plasma TIMP-1 and 2 levels at this AC treatment time point were not different from referent controls, and while IL-10 and IL-8/IL-10 ratios fell in the AC treatment group at Visit 1, these did not reach statistical significance. b Due to the high incidence of plasma TIMP-3 and TIMP-4 levels were fell below analytical detection limits, a categorical analysis was performed using a Chi Square analysis. A significant shift in the proportion of detectable TIMP-3 and TIMP-4 in plasma samples taken from the initial AC treatment time point occurred (*p < 0.05). c In contrast to the analyte shown in Table A, significant shifts in plasma MMP-2, − 7 and − 9 occurred at AC treatment Visit 1 when compared to referent control values (*p < 0.05)

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  Fig. 4. Plasma profiling for specific determinants of inflammation and signaling. A number of inflammatory signaling pathways were profiled in plasma samples taken from age matched referent normal subjects and at the initial visit following AC treatment- identified as Visit 1. While robust signals for the soluble IL, TNF and VEGF receptors were detected in both referent normal and Visit 1 samples many soluble receptor analytes were similar between groups and summarized in Table A. On the other hand, specific soluble receptors/pathways were significantly different from referent control values and are shown in Figure 2-2B. These included the soluble receptors for IL-1, -2, and -4. A relative reduction in sRage and sVEGFR3 occurred in Visit 1 samples with an increase in Sgp130. (*p < 0.05 vs Visit 1 values). Normal: referent normal; MMP-2: Matrix metallopeptidase 2; MMP-7: Matrix metallopeptidase 7; MMP-9: Matrix metallopeptidase 9; IL-8: Interleukin 8; sVEGFR3: Fms-related tyrosine kinase 4; sgp130: Interleukin 6 signal transducer; sIL-1RII: Interleukin 1 receptor, type II; sIL-2Ra: Interleukin 2 receptor, alpha; sIL-4R: Interleukin 4 receptor

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  Fig. 5. Plasma profiling changes from Visit 1 to last available visit in AC treated patients. The relative change in ECM and inflammatory pathways were computed as a function of Visit 1 and the final visit in the AC treated patients. Those with a significant shift from Visit 1 are shown here and identify that continued shifts in determinants of inflammatory signaling and ECM remodeling occurred at later AC treatment time points. (*p < 0.05 vs Visit 1 values)