Page 1 |
Save page Remove page | Previous | 1 of 186 | Next |
|
small (250x250 max)
medium (500x500 max)
Large (1000x1000 max)
Extra Large
large ( > 500x500)
Full Resolution
All (PDF)
|
This page
All
|
TRANSFUSIONAL IRON, ANTHRACYCLINES AND CARDIAC OUTCOMES IN
CHILDHOOD CANCER SURVIVORS
By
Kathleen Ruccione
______________________________________________________________________
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PREVENTIVE MEDICINE)
August 2013
Copyright 2013 Kathleen Ruccione
Object Description
| Title | Transfusional iron, anthracyclines and cardiac outcomes in childhood cancer survivors |
| Author | Ruccione, Kathleen S. |
| Author email | kruccione@chla.usc.edu;kruccione@chla.usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Preventive Medicine (Health Behavior) |
| School | Keck School of Medicine |
| Date defended/completed | 2013-04-02 |
| Date submitted | 2013-07-23 |
| Date approved | 2013-07-23 |
| Restricted until | 2013-07-23 |
| Date published | 2013-07-23 |
| Advisor (committee chair) | RIchardson, Jean |
| Advisor (committee member) |
Jordan-Marsh, Maryalice Krailo, Mark Rohrbach, Luanne Siegel, Stuart E. Wood, John C. |
| Abstract | Background: Childhood cancer survivors receiving multiple packed red blood cell (PRBC) transfusions may be at increased risk for iron deposition in vital organs such as the heart, thereby increasing risk of serious late effects due to organ dysfunction with associated symptoms, which may diminish their health-related quality of life (HRQOL). ❧ Purpose: To determine the prevalence, distribution and severity of transfusional iron deposition in heart, liver and pancreas among a cohort of childhood cancer survivors, and to characterize the prevalence, distribution and severity of cardiac dysfunction and pathological remodeling among a cohort of childhood cancer survivors; to assess HRQOL using validated patient-reported outcome (PRO) measures in a cohort of childhood cancer survivors. ❧ Methods: Design: single institution cross-sectional study of childhood cancer survivor cohort. Organ tissue iron was quantified by magnetic resonance imaging (MRI). Iron status by serum markers and hemachromatosis gene mutation status were assessed, as were cardiac biomarkers. Study subjects participated in a structured interview during which they (and their parent/guardian, if available), completed the validated PRO measures of HRQOL and fatigue in English or Spanish; a brief Cardiac Health Form was also completed. In addition to data acquired from laboratory and MRI evaluations obtained for this study, disease/treatment and demographic information was abstracted from medical records. Data analysis included descriptive approaches for data summarization and regression modeling for estimation and testing. ❧ Results: Seventy-five patients were enrolled (median age 14 years, range 8-25.6 years at evaluation); slightly more than half were male (40/75) and most were Hispanic/Latino (45/75). Median follow up time was 4.2 years. Cancer diagnoses included ALL/AML (n=33) and solid tumors (n=42). Sixty-seven patients had received PRBC transfusions (median=11, range=1-47), with median cumulative PRBC transfusion volume (cPRBCv) of 2727 mL (range, 300-14224 mL), and median cPRBCv adjusted for body weight of 90.6 mL/kg (range, 3.6-391.9). Forty-eight (64%) study participants had received anthracycline chemotherapy as part of their treatment plan, with a median dose of 293mg/m² (range, 50-739mg/m²). Study 1: Based on liver R2* (n=73) and cardiac T2* (n=74), tissue iron concentration (mean, median, range in mg/g) was calculated for liver (2.6, 1.2, 0.9-23.7) and heart (0.7, 0.6, 0.5-0.9). No iron calibration exists for pancreas; pancreas R2* results (mean, median, range in Hz) were 30.2, 26, 18-128 (n=72). Liver iron concentration (LIC) was elevated in 36 (58.9%) patients and pancreas R2* was abnormal in 34 (47.2%) patients, respectively. No abnormal cardiac iron concentrations were observed. Statistically significant correlations between liver R2* and pancreatic R2* were found. Both hepatic and pancreatic R2* were significantly positively correlated with serum iron, iron binding capacity, serum ferritin, and cRBCv. HFE C282Y and H63D mutation status was normal in 72/75 and 63/75, respectively. Predictors of LIC found to be significant in univariate analyses included diagnosis of AML or solid tumor, older age at diagnosis/age at MRI, greater treatment intensity, higher cumulative anthracycline dose, and higher adjusted cPRBCv. In the final reduced multivariate model there were statistically significant positive associations between elevated LIC and higher cPRBCv (p<0.0001) and older age at diagnosis (p<0.0001). Study 2: Seventy-four study participants completed cardiac MRI examination. There were two males in the study sample whose left ventricular ejection fraction (LVEF) was ≤50%, a level which would trigger clinical cardiology assessment and consideration of medical intervention. Predictors of lower LVEF found to be significant in univariate analyses included race/ethnicity (being Caucasian/non-Hispanic or other), diagnosis of AML or solid tumor, older age at diagnosis or at MRI evaluation, greater treatment intensity, higher cumulative anthracycline dose, use of dexrazoxane, larger body surface area, taller height at MRI evaluation, higher serum ferritin, and higher serum iron. Two reduced multivariate models had nearly identical model statistics but slightly different implications: in one model there were statistically significant associations between lower LVEF and higher cumulative anthracycline dose (p=0.003) and older age at MRI (p=0.009); in the other model there were statistically significant associations between lower LVEF and the variables of higher cumulative anthracycline dose (p=0.005) and taller height at MRI (p=0.006). Study 3: Seventy study participants and 63 parents completed PedsQL™ Generic Core Scales; 71 study subjects and 63 parents completed PedsQL™ Fatigue Scales. On average, childhood cancer survivors in this study had HRQOL total scores, physical health summary scores and psychosocial health summary scores that were approximately midway between those of pediatric patients with cancer in active treatment and those of healthy children. In general, participants rated their overall HRQOL as good, but there were subsets (13-17%) whose scores were ≥1 SD below the mean, indicating at-risk status for diminished HRQOL. Study participants endorsed more fatigue symptoms on every scale than did healthy children. On subscales within the fatigue measure, subjects reported the fewest symptoms of general fatigue, followed by sleep-rest fatigue, and they reported the most symptoms of cognitive fatigue. In univariate analyses, factors found to be statistically significantly associated with higher self-rated psychosocial HRQOL included endorsement of fewer symptoms of fatigue and higher self-rated physical health. Risk factors for lower self-rated physical health were female sex and lower LVEF. In multivariate analysis older age at evaluation (p=0.0003), higher self-rated physical health (p< 0.0001) and endorsement of fewer symptoms of fatigue (p< 0.0001) were predictive of higher self-rated psychosocial HRQOL. A statistically significant positive linear relationship was observed between patient self-report and parent proxy report on all aspects of HRQOL and fatigue in this study, although there was cross-informant variance in ratings of individual items on study measures. Participants self-rated their HRQOL slightly higher, but endorsed more fatigue symptoms than did their parents’ proxy-reports. ❧ Conclusion: These studies are the first to examine the prevalence of transfusional iron deposition and cardiac dysfunction by MRI, and to evaluate associated HRQOL among a relatively large sample of childhood cancer survivors. Study 1 demonstrated the feasibility of using non-invasive MRI assessment of iron deposition in several organ systems in one MRI session. Nearly 60% had elevated liver iron concentration and nearly half had abnormal pancreatic R2* results. Findings point to the need for development of tailored monitoring/management guidelines for childhood cancer patients/survivors at risk of liver/pancreatic damage due to iron overload (e.g., tracking, staging algorithms), provide evidence for adding iron overload to late effects surveillance guidelines, and indicate the need for exploration of the additive risk of liver/pancreatic damage from specific chemotherapeutic exposures, as well as for the design of patient education interventions to minimize further liver/pancreatic damage. Study 2 demonstrated the feasibility of assessing cardiac structure and function by MRI relatively early in the survivorship trajectory. Higher cumulative dose of anthracycline chemotherapy was associated with lower LVEF, which was confirmatory of previous studies. In contrast to most other published studies, older age and taller height at MRI evaluation were identified as risk factors. A new finding was that higher serum ferritin and serum iron were associated with lower LVEF. Study findings support the need for ongoing clinical surveillance of childhood cancer survivors at risk for adverse cardiac outcomes, and health education regarding survivors’ individualized survivorship care plans and modifiable risk factors for heart health. Study 3: Most study participants rated their HRQOL as good, but a significant subset may have increased risk for impaired HRQOL. Protective factors for psychosocial HRQOL included older age, endorsement of fewer symptoms of fatigue, and higher self-rated physical health. Risk factors for poorer physical health were female sex and lower LVEF. Study findings point to the importance of systematic assessment of HRQOL, fatigue and other symptoms using validated PRO measures and obtaining information from both patient and parent whenever possible during survivorship care, when there is a window of opportunity for targeted interventions to mitigate adverse effects of the cancer experience. The study provides a baseline for future comparisons that may help to better understand the dynamic nature of the psychosocial impact of cancer during the first years of post-treatment survivorship. ❧ Taken together, the three studies indicate a need for further research to advance understanding of the biologic mechanisms of iron overload, including genetic/genomic/epigenetic parameters that may mediate organ iron uptake. Prospective, longitudinal studies are needed that: (1) link assessment of organ iron content to organ function and to development of associated morbidity/mortality; (2) begin at the inception of cancer treatment, and include large sample sizes as well as additional relevant biological measures such as pubertal status, traditional cardiovascular risk factor assessment, and cardiotoxicity-related genetic analyses; (3) explore HRQOL risk and protective factors, and identify/evaluate targeted interventions aimed at minimizing adverse effects of cancer treatment such as fatigue to maximize healthy survivorship. |
| Keyword | childhood cancer survivors; iron overload; transfusional iron |
| Language | English |
| Format (imt) | application/pdf |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | Ruccione, Kathleen S. |
| Physical access | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-RuccioneKa-1824.pdf |
| Archival file | uscthesesreloadpub_Volume7/etd-RuccioneKa-1824-0.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | TRANSFUSIONAL IRON, ANTHRACYCLINES AND CARDIAC OUTCOMES IN CHILDHOOD CANCER SURVIVORS By Kathleen Ruccione ______________________________________________________________________ A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PREVENTIVE MEDICINE) August 2013 Copyright 2013 Kathleen Ruccione |
