Adipokines, Inflammation, and Adiposity in Hematopoietic Cell Transplantation Survivors.

Adult survivors of acute leukemia in childhood have a higher-than-expected frequency of obesity and are at increased risk for metabolic syndrome and early mortality from cardiovascular disease (CVD). Adipose tissue has been recognized as an endocrine and paracrine organ that secretes various adipokines involved in metabolic regulation and inflammatory processes. In this study, we examined inflammatory factors (IL-6 and TNF-α) and adipokines (adiponectin, leptin), in addition to body composition and adiposity, in cancer survivors who underwent hematopoietic cell transplantation (HCT) during childhood compared with sibling controls. Over 2-year survivors of HCT for hematologic malignancies during childhood were recruited from 2 institutions along with a control population of siblings. Participants underwent evaluation for body composition, anthropometric measurements, and assessment of CVD risk factors and adipokines. Cases were stratified by radiation exposure in the preparative regimen (total body irradiation [TBI] + central nervous system [CNS] irradiation, TBI only, chemotherapy only) and adjusted least squares means were estimated for each adipokine and adjusted by age, sex, race, Tanner stage, and percent fat mass (PFM) percentiles (0-24, 25-74, 75+). A total of 151 HCT survivors and 92 siblings underwent evaluation. Significant differences in mean adipokine levels were detected between survivors and siblings; leptin was significantly higher and adiponectin significantly lower in HCT survivors who received TBI with or without CNS irradiation compared with siblings. IL-6 was significantly higher in all groups of HCT survivors compared with siblings. Body mass index (BMI) was similar in survivors and controls, although PFM was significantly higher in all groups of HCT survivors and lean body mass (LBM) was lower in survivors who received TBI with or without CNS radiation compared with siblings. HCT survivors showed an unfavorable profile of inflammation, adipokines, and adiposity, despite similar BMI as controls. Higher PFM and lower LBM may contribute to these findings. TBI exposure is correlated with greater severity of these observations. Increasing LBM may represent a tangible target for mitigating the high cardiometabolic risks of HCT survivors.

Impact of Hematopoietic Cell Transplantation on Cardiovascular Risk Factors and Insulin Sensitivity.

The use of hematopoietic cell transplantation (HCT) for treating malignant conditions in children has increased over the past five decades, leading to a growing population of long-term survivors.This population of childhood HCT survivors faces increased risks of adverse medical effects due to cancer treatments, including adverse cardiovascular disease (CVD) risk factors such as metabolic syndrome, insulin resistance. but the impact of exposure to HCT preparative conditioning regimen has not been clearly delineated. These risk factors, including obesity, dyslipidemia, hypertension, and insulin resistance (IR), are significant contributors to premature cardiovascular disease and represent a leading cause of non-relapse deaths in childhood cancer and HCT survivors. This study aimed to assess the early development of CVD risk factors and their relationship to insulin resistance in a large population of pediatric and young adult HCT survivors of childhood hematologic malignancies. The study compared their cardiovascular risk profiles, insulin resistance (measured by euglycemic hyperinsulinemic clamp studies), and body composition (determined by dual X-ray absorptiometry - DXA) with a cohort of sibling controls. We enrolled 151 HCT recipients (26.36 ±0.90 years at study enrollment; time since HCT of 2.6-31.5 years) and 92 sibling controls to complete at cardiovascular risk assessment including insulin sensitivity by hyperinsulinemic euglycemic clamp, anthropometry, body composition by dual X-ray absorptiometry, blood pressure, and serum biomarkers. We used linear models to test for mean differences in all continuous outcomes between survivors and siblings, accounting for intra-family correlations with generalized estimating equations. Recipients of HCT were found to have lower insulin sensitivity and more likely to have adverse CVD risk factors in comparison to their healthy siblings. Significantly higher percent fat mass and visceral adipose tissue, and significantly lower lean body mass were noted in HCT recipients than sibling controls despite having a similar body mass index between the two groups. Total body irradiation in the conditioning regimen was one of the strongest factors associated with lower insulin sensitivity, dyslipidemia and abnormal body composition leading to sarcopenic obesity. This study reveals that pediatric and young adult HCT survivors are more insulin resistant and have a higher prevalence of adverse cardiovascular risk factors compared to sibling controls. The presence of cardiovascular risk factors at a relatively young age raises concerns about an escalating trajectory of cardiovascular disease in this population. Therefore, regular monitoring of HCT survivors for cardiometabolic risk factors and early intervention will be crucial for preventing cardiovascular-related complications in the future. The findings underscore the importance of survivorship care for pediatric and young adult HCT survivors, with a focus on managing cardiovascular risk factors and promoting a healthy lifestyle to mitigate long-term adverse effects. Early identification and targeted interventions can significantly improve the long-term health outcomes of this vulnerable population, reducing the burden of cardiovascular disease and related complications.

Morbidity and mortality in long-term survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study.

The contribution of specific cancer therapies, comorbid medical conditions, and host factors to mortality risk after pediatric Hodgkin lymphoma (HL) is unclear. We assessed leading morbidities, overall and cause-specific mortality, and mortality risks among 2742 survivors of HL in the Childhood Cancer Survivor Study, a multi-institutional retrospective cohort study of survivors diagnosed from 1970 to 1986. Excess absolute risk for leading causes of death and cumulative incidence and standardized incidence ratios of key medical morbidities were calculated. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of risks for overall and cause-specific mortality. Substantial excess absolute risk of mortality per 10,000 person-years was identified: overall 95.5; death due to HL 38.3, second malignant neoplasms 23.9, and cardiovascular disease 13.1. Risks for overall mortality included radiation dose ≥ 3000 rad ( ≥ 30 Gy; supra-diaphragm: HR, 3.8; 95% CI, 1.1-12.6; infradiaphragm + supradiaphragm: HR, 7.8; 95% CI, 2.4-25.1), exposure to anthracycline (HR, 2.6; 95% CI, 1.6-4.3) or alkylating agents (HR, 1.7; 95% CI, 1.2-2.5), non-breast second malignant neoplasm (HR, 2.6; 95% CI 1.4-5.1), or a serious cardiovascular condition (HR, 4.4; 95% CI 2.7-7.3). Excess mortality from second neoplasms and cardiovascular disease vary by sex and persist > 20 years of follow-up in childhood HL survivors.

Modifiable risk factors associated with bone deficits in childhood cancer survivors.

BACKGROUND: To determine the prevalence and severity of bone deficits in a cohort of childhood cancer survivors (CCS) compared to a healthy sibling control group, and the modifiable factors associated with bone deficits in CCS. METHODS: Cross-sectional study of bone health in 319 CCS and 208 healthy sibling controls. Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DXA). Generalized estimating equations were used to compare measures between CCS and controls. Among CCS, multivariable logistic regression was used to evaluate odds ratios for BMD Z-score ≤ -1. RESULTS: All subjects were younger than 18 years of age. Average time since treatment was 10.1 years (range 4.3 - 17.8 years). CCS were 3.3 times more likely to have whole body BMD Z-score ≤ -1 than controls (95% CI: 1.4-7.8; p = 0.007) and 1.7 times more likely to have lumbar spine BMD Z-score ≤ -1 than controls (95% CI: 1.0-2.7; p = 0.03). Among CCS, hypogonadism, lower lean body mass, higher daily television/computer screen time, lower physical activity, and higher inflammatory marker IL-6, increased the odds of having a BMD Z-score ≤ -1. CONCLUSIONS: CCS, less than 18 years of age, have bone deficits compared to a healthy control group. Sedentary lifestyle and inflammation may play a role in bone deficits in CCS. Counseling CCS and their caretakers on decreasing television/computer screen time and increasing activity may improve bone health.

Psychological outcomes of siblings of cancer survivors: a report from the Childhood Cancer Survivor Study.

OBJECTIVE: To identify risk factors for adverse psychological outcomes among adult siblings of long-term survivors of childhood cancer. METHODS: Cross-sectional, self-report data from 3083 adult siblings (mean age 29 years, range 18-56 years) of 5 + year survivors of childhood cancer were analyzed to assess psychological outcomes as measured by the Brief Symptom Inventory-18 (BSI-18). Sociodemographic and health data, reported by both the siblings and their matched cancer survivors, were explored as risk factors for adverse sibling psychological outcomes through multivariable logistic regression. RESULTS: Self-reported symptoms of psychological distress, as measured by the global severity index of the BSI-18, were reported by 3.8% of the sibling sample. Less than 1.5% of siblings reported elevated scores on two or more of the subscales of the BSI-18. Risk factors for sibling depression included having a survivor brother (OR 2.22, 95% CI 1.42-3.55), and having a survivor with impaired general health (OR 2.15, 95% CI 1.18-3.78). Siblings who were younger than the survivor reported increased global psychological distress (OR 1.81, 95% CI 1.05-3.12), as did siblings of survivors reporting global psychological distress (OR 2.32, 95% CI 1.08-4.59). Siblings of sarcoma survivors reported more somatization than did siblings of leukemia survivors (OR 2.07, 95% CI 1.05-3.98). CONCLUSIONS: These findings suggest that siblings of long-term childhood cancer survivors are psychologically healthy in general. There are, however, small subgroups of siblings at risk for long-term psychological impairment who may benefit from preventive risk-reduction strategies during childhood while their sibling with cancer is undergoing treatment.

Assessment of selection bias in clinic-based populations of childhood cancer survivors: a report from the childhood cancer survivor study.

BACKGROUND: It is not known to what extent prevalence estimates of late effects among childhood cancer survivors derived from clinic based samples represent the actual estimates that would be derived if the entire population of childhood cancer survivors was recruited and evaluated for a particular outcome. PROCEDURE: In a large retrospective cohort study of childhood cancer survivors, the Childhood Cancer Survivor Study (CCSS), the prevalence of chronic health conditions among participants who reported being seen in a cancer center or long-term follow-up clinic was compared to the prevalence of chronic conditions in the entire cohort. RESULTS: When compared to survivors who had no medical care in the previous 2 years, survivors accessing medical follow-up were significantly more likely to have chronic health conditions. Relative risks of reporting a chronic health condition were 1.4 (95% CI: 1.3-1.5) if seen in a cancer center or long-term follow-up clinic and 1.2 (95% CI: 1.1-1.3) if seen in a general medical care setting. Estimates derived from only those childhood cancer survivors who were seen in a cancer center or long-term follow-up clinic overestimate the prevalence of any chronic disease by 9.3% (95% CI: 7.0-11.6). CONCLUSIONS: Applying chronic condition prevalence estimates from a clinical population to the general population of childhood cancer survivors must be undertaken with caution. Survivorship research must maintain a high level of scientific rigor to ensure that results reported in the literature are interpreted within the appropriate context.

Cancer prevention and screening practices of siblings of childhood cancer survivors: a report from the Childhood Cancer Survivor Study.

BACKGROUND: To compare the skin and breast/cervical cancer prevention/screening practices of adult siblings of childhood cancer survivors with controls and to identify modifying factors for these practices. METHODS: Cross-sectional, self-report data from 2,588 adult siblings of 5+ year survivors of childhood cancer were analyzed to assess cancer prevention/screening practices. Two age, sex, and race/ethnicity-matched samples (N = 5,915 and N = 37,789) of the Behavioral Risk Factor Surveillance System participants served as the comparison populations. Sociodemographic and cancer-related data were explored as modifying factors for sibling cancer prevention/screening practices through multivariable logistic regression. RESULTS: Compared with controls, siblings were more likely to practice skin cancer prevention behaviors: use of protective clothing [OR, 2.85; 95% confidence interval (CI), 2.39-3.39], use of shade (OR, 2.11; 95% CI, 1.88-2.36), use of sunscreen (OR, 1.27; 95% CI, 1.14-1.40), and wearing a hat (OR, 1.77; 95% CI, 1.58-1.98). No differences were noted for breast/cervical cancer screening including mammography and Pap testing. Having less than a high school education and lack of health insurance were associated with diminished cancer prevention/screening behaviors. Survivor diagnosis, treatment intensity, adverse health, chronic health conditions, and second cancers were not associated with sibling cancer prevention/screening behaviors. CONCLUSIONS: Siblings of cancer survivors report greater skin cancer prevention practices when compared with controls; however, no differences were noted for breast/cervical cancer screening practices. Access to care and lack of education may be associated with decreased cancer prevention/screening behaviors. Interventions are needed to address these barriers. IMPACT: Research should be directed at understanding the impact of the cancer experience on sibling health behaviors.