INTRODUCTION:
The use of hematopoietic cell transplantation (HCT) for the treatment of malignant conditions in children has increased over the past 5 decades.1 Along with the larger number of children who have undergone HCT, survival after HCT has significantly increased, resulting in a growing population of long-term survivors.2 As childhood HCT survivors progress to adulthood, clinical and epidemiological research is focusing on long-term adverse medical effects from cancer treatment to characterize and understand the ramifications of curative cancer directed therapy,3 including metabolic syndrome or combinations of cardiovascular disease (CVD) risk factors (obesity, dyslipidemia, hypertension, insulin resistance [IR]). All are known to be potent contributors to the development of premature CVD in adults4 and represent a leading cause of non-relapse deaths in childhood cancer and HCT survivors.5–8
Previous studies have demonstrated an increased prevalence of metabolic syndrome in both pediatric and adult HCT survivors.5,9–12 In a large single-institution study of 1,885 1-year HCT adult survivors treated with total body irradiation (TBI), the prevalence of CVD risk factors was significantly higher among HCT survivors compared with the general population.9 In a study of CVD risk factors in childhood survivors of HCT who had received TBI, the cumulative incidence of CVD risk factors, except obesity, increased by 1.7- to 3.2-fold from 5 to 10 years post-TBI.6
From indirect measures of IR, some studies suggest that cancer and HCT survivors may be at higher risk for IR and subsequent CVD, but the direct relationship to body composition has not been well delineated. This study focused on the development of CVD risk factors and their relationship to insulin sensitivity. We undertook a comprehensive assessment in a large population of children and young adult HCT survivors of childhood hematologic malignancies and compared their CVD risk profiles, insulin sensitivity (as measured by euglycemic hyperinsulinemic clamp studies), and body composition determined by dual X-ray absorptiometry (DXA) with a cohort of sibling controls.13
MATERIALS AND METHODS
The study was approved by the Institutional Review Board and Human Subjects Committee at the University of Minnesota and the Fred Hutchinson Cancer Center/Seattle Children’s Hospital. Consent and assent were obtained from all participants as appropriate.
Study Participants
Cancer HCT:
HCT Eligible subjects were transplanted for a hematologic malignancy between 1975 and 2008, less than age 22 years at diagnosis, and were at least 10 years old at the time of entry into this study, to comply with the study procedures. Full details of the recruitment strategy and participation data have been previously published.14 Eligible subjects were randomly ordered and 154 subjects were recruited. Subsequently, 3 patients were found to be ineligible at the time of study due to previously undiagnosed diabetes (n=1), severe hypertension (n=1), and multiple medical issues (n=1) that required immediate medical treatment such that they were unable to complete study procedures. This left the final study population of 151 subjects. (Figure 1)
Figure 1:
Consort diagram
Sibling Controls:
The control group consisted of eligible healthy siblings who were ≥10 years old at study entry and who had never had a malignancy or HCT. Based on a pre-determined frequency matched enrollment scheme, siblings were recruited with the intent to represent the age and sex distribution of HCT recipients. Selection of the sibling closest in age to the subject was preferred, although not required, and having a sibling was not a requirement for participation. Siblings were chosen as the control population to obtain greater similarity to HCT recipients in genetics, lifestyle, and environment/geographical trends.
Study Procedures
Participants underwent a 2-day examination at either the University of Minnesota Clinical Research Center or the Pediatric Clinical Research Center at Seattle Children’s Hospital. Measurements for height and weight were taken at the start of the visit and the body mass index (BMI) was calculated as weight in kilograms (kg) divided by height in meters-squared (m2). Waist circumference was measured in duplicate midway between the anterior superior iliac spine and the lower rib margin directly over the skin, the method used in all earlier studies from our group designed to measure the site of natural waist and the level of minimal abdominal width, considered the level of the smallest circumference around the waist. Tanner stage was assessed by study investigators and assigned according to pubic hair development in boys and breast and pubic hair development in girls. Body composition (percent fat mass, total fat mass, visceral adipose tissue, total lean mass) were assessed by DXA (GE Healthcare Lunar Prodigy scanner; Madison, WI, USA) using enCORE software version 9.3. The two GE Healthcare Lunar Prodigy DXA scanners were cross-calibrated using a custom-built phantom that calibrated bone, fat, and lean tissue masses. No significant differences were observed between the two scanners. The average of two manual blood pressure measurements using a random zero sphygmomanometer from the right arm of rested, seated subjects was used in analyses.
Hyperinsulinemic euglycemic clamps were conducted after a 10- to 12-hour overnight fast as previously described.15 Intravenous catheters were inserted in an arm vein for infusion of potassium phosphate, insulin, and glucose and in a contralateral vein for blood sampling. Baseline insulin and glucose levels were determined from samples drawn at −5 and 0 minutes before beginning the insulin and glucose infusions. Insulin infusion was started at time 0 at a rate of 1 mU/kg/min for 3 hours. An infusion of 20% glucose was given and adjusted to maintain euglycemia (serum glucose level of 100 mg/dL [5.6 mmol/L]) with plasma glucose determined every 10 minutes. Insulin sensitivity (M) was determined by the amount of glucose required to maintain euglycemia in the final 40 minutes of the clamp study and expressed as mg/kg/min of glucose with adjustment for lean body mass (Mlbm) obtained from DXA.16 Lower Mlbm values are indicative of lower insulin sensitivity (i.e., greater insulin resistance).
Plasma glucose was analyzed at the bedside with a Beckman Glucose Analyzer II (Beckman Instruments, Fullerton, California). Serum insulin was determined with a chemiluminescence immunoassay (Immulite Insulin DPC, Los Angeles, California). Serum lipid levels were analyzed from fasting blood samples obtained at the time catheters were placed for the clamp, with a Vitros 5600 (Ortho-Clinical Diagnostics, Inc, Rochester, New York). Low-density lipoprotein (LDL) cholesterol was calculated with the Friedewald equation.
Statistical Analysis
Fisher Exact tests and t-tests were used to compare demographic characteristics between survivors and siblings. The key outcomes examined in analyses were: Mlbm, systolic blood pressure (SBP) (mmHg), diastolic blood pressure (DBP) (mmHg), mean waist circumference (cm), high-density lipoprotein cholesterol (HDL) (mg/dL), low-density lipoprotein cholesterol (LDL) (mg/dL), triglycerides (mg/dL), blood glucose (mg/dL), insulin (μU/mL), percent fat mass (PFM), visceral adipose tissue (VAT) (g), and lean body mass (LBM) (kg), all analyzed as continuous measures. Linear multivariable regression models were used to test for mean differences (MD) in outcomes between survivors (in total and subgroups defined by treatments) and siblings, accounting for intra-family correlations with generalized estimating equations. Among survivors, multivariable linear regression models were employed to compare mean values of continuous outcomes between mutually exclusive treatment groups (TBI and central nervous system irradiation [TBI+CNS], TBI without CNS irradiation [TBI/no CNS], and no TBI nor CNS irradiation [chemo only]). All models were adjusted for age, sex, race, and Tanner stage. An additional model for each non-body size outcomes was estimated with PFM added to the variables in the first model. SAS version 9.4 and R version 3.5.3 were used in these analyses.
RESULTS
Characteristics of Study Participants
Participants included 151 HCT recipients (26.36 ±0.90 years, minimum-maximum 10-50.5 years, referred to as survivors) and 92 sibling controls (22.20 ± 0.92 years, minimum-maximum 10.5-48 years) at study visit (Table 1). Age at most recent HCT ranged from 6 months to 32.6 years, and time since HCT was 2.6-31.5 years. There were no significant differences in age at study, sex distribution, race, Tanner stage or BMI between survivors and sibling controls, though survivors had higher PFM percentiles. Most survivors had an original cancer diagnosis of either acute lymphoblastic leukemia (ALL) (31.1%) or acute myeloid leukemia (AML) (44.3%). On the basis of overall similarities in therapeutic exposures, all patients received a myeloablative conditioning regimen and HCT survivors were grouped into 3 major preparative regimen groups: TBI+CNS radiation (n=31), TBI/no CNS radiation (N=85) and chemotherapy only (n=35). Most survivors had an allogeneic transplant (76.8%) and 76.8% of survivors received TBI and 20.5% of survivors received TBI+CNS.
Table 1:
Demographic and treatment characteristics of HCT survivor and sibling comparison groups. Categorical variables.
| Categorical Variables | Survivor | Sibling | P-value | |||
|---|---|---|---|---|---|---|
| Variable | Categories | N | % | N | % | |
| Age at Study | <18 | 32 | 21.2 | 24 | 26.1 | 0.48 |
| 18-34.9 | 98 | 64.9 | 58 | 63.0 | ||
| 35+ | 21 | 13.9 | 10 | 10.9 | ||
| Sex | Males | 87 | 57.6 | 49 | 53.6 | 0.55 |
| Females | 64 | 42.4 | 43 | 46.4 | ||
| Race/Ethnicity | White non-Hispanic | 137 | 90.7 | 85 | 92.4 | |
| Other | 14 | 9.3 | 7 | 7.6 | ||
| Tanner | 1 | 6 | 4.3 | 2 | 2.3 | 0.12 |
| 2 | 4 | 2.8 | 3 | 3.5 | ||
| 3 | 10 | 7.1 | 1 | 1.2 | ||
| 4 | 9 | 6.4 | 9 | 10.5 | ||
| 5 | 112 | 79.4 | 71 | 82.6 | ||
| BMI | Obese (≥ 30) | 19 | 12.6 | 8 | 8.7 | 0.61 |
| Overweight (25-29.9) | 32 | 21.2 | 21 | 22.8 | ||
| Normal (18.5 to 24.9) | 100 | 66.2 | 63 | 68.5 | ||
| Percent Fat Mass Percentiles | 0-24th | 35 | 23.3 | 42 | 45.7 | <0.001 |
| 25-75th | 68 | 45.3 | 35 | 38.0 | ||
| >75th | 47 | 31.3 | 15 | 16.3 | ||
| Original Cancer Diagnosis | ALL | 47 | 31.1 | · | · | · |
| AML | 67 | 44.3 | · | · | · | |
| Chronic Myeloid Leukemia (CML) | 15 | 9.9 | · | · | · | |
| Hodgkin Lymphoma | 12 | 7.9 | · | · | · | |
| Non-Hodgkin Lymphoma | 10 | 6.6 | · | · | · | |
| Radiation Treatment * | TBI + CNS | 31 | 20.5 | · | · | · |
| TBI/no CNS | 85 | 56.3 | · | · | · | |
| Other RT (not TBI or CNS) | 14 | 9.3 | · | · | · | |
| No RT | 21 | 13.9 | · | · | · | |
| HSCT Type | Allogeneic | 116 | 76.8 | · | · | · |
| +GVHD | 76 | 65.5 | ||||
| −GVHD | 40 | 34.5 | ||||
| Autologous | 35 | 23.2 | · | · | · | |
| Median | Minimum-Maximum | Median | Minimum-Maximum | P-value | ||
| Age at Study | - | 23.3 | 10.9-50.5 | 19.7 | 10.5-47.9 | 0.64 |
| Tanner Stage | - | 5 | 1 - 5 | 5 | 1-5 | 0.033 |
| Age at Diagnosis (years) | - | 7.8 | 0.04 - 20.6 | · | ||
| Years Since Diagnosis | - | 15.3 | 2.9 - 34.8 | · | ||
| Age at Most Recent HCT (years) ** | - | 10.5 | 0.6 - 32.6 | · | ||
| Years since Most Recent HCT | - | 12.8 | 2.6 - 31.5 | · | ||
13 patients received single fraction TBI at a median dose of 750cGy (range 750-850). There were 102 patients who received fractionated TBI at doses between 1200-1575 cGy (median 1320 cGy) divided into 6-11 fractions. One patient received a single fraction TBI dose of 200 cGy.
There were 12 patients who had a prior transplant. The patient who was transplanted at age 32 was diagnosed at age 20.1 and had a first transplant at age 25.2.
After adjusting for age, sex, race, and Tanner stage, insulin sensitivity (lower Mlbm) in survivors was significantly lower than sibling controls (Mlbm least squares [LS] mean, 9.7 [95% CI 8.8,10.6] vs 11.6 [95% CI 10.4,12.7]; p=0.005) and mean fasting insulin was significantly higher (LS mean, 16.5 [95% CI 13.6,19.4] vs 9.9 [95% CI 7.3, 12.4]; p<0.001; Table 2). Compared to siblings, survivors also had significantly higher levels of total and LDL cholesterol, triglycerides, and insulin (p<0.001) and significantly lower levels of HDL (p<0.001). Survivors also had lower height, weight, LBM (p<0.001), higher PFM (p<0.001) and VAT (p=0.014) compared with siblings. SBP, DBP, blood glucose and waist circumference were not significantly different between survivors and siblings.
Table 2:
Adjusted means for continuous outcomes, all ages, comparing survivors and siblings (reference group).
| Survivors | Siblings | ||||
|---|---|---|---|---|---|
| Outcome | Mean | 95% CI | Mean | 95% CI | P-value |
| Mlbm | 9.7 | (8.8, 10.6) | 11.6 | (10.4, 12.7) | 0.005 |
| Systolic Blood Pressure, mmHg | 114.8 | (111.1, 118.5) | 116.1 | (112.0, 120.2) | 0.37 |
| Diastolic Blood Pressure, mmHg | 69.2 | (66.1, 72.3) | 67.8 | (64.8, 70.9) | 0.28 |
| Total Cholesterol, mg/dL | 182.1 | (172.0, 192.2) | 159.6 | (150.3, 168.9) | <.001 |
| LDL-cholesterol, mg/dL | 104.8 | (97.3, 112.3) | 90.2 | (82.5, 97.9) | <.001 |
| HDL-cholesterol, mg/dL | 40.8 | (38.1, 43.5) | 46.5 | (43.3, 49.7) | <.001 |
| Triglycerides, mg/dL | 181 | (147.3, 214.6) | 99.8 | (75.3, 124.2) | <.001 |
| Blood Glucose, mg/dL | 85.7 | (81.9, 89.5) | 81.9 | (78.3, 85.4) | 0.116 |
| Insulin, μU/mL | 16.5 | (13.6, 19.4) | 9.9 | (7.3, 12.4) | <.001 |
| Height, cm | 162 | (159.1, 164.9) | 170 | (167.1, 172.9) | <.001 |
| Weight, kg | 64.2 | (57.9, 70.5) | 72.2 | (64.9, 79.5) | <.001 |
| Waist Circumference, cm | 81 | (76.5, 85.6) | 81.4 | (75.9, 86.9) | 0.81 |
| Lean Body Mass, kg | 38.7 | (36.1, 41.4) | 47.9 | (45.2, 50.6) | <.001 |
| Percent Fat Mass | 34.8 | (32.4, 37.1) | 29.6 | (26.8, 32.5) | <.001 |
| Total Fat Mass, kg | 22.5 | (18.6, 26.4) | 21.2 | (16.4, 25.9) | 0.33 |
| Visceral Adipose Tissue, g | 615.5 | (484.3, 746.6) | 466.9 | (331.0, 602.9) | 0.014 |
Adjusted for age, sex, race/ethnicity, Tanner score
Multivariate regression models examined MDs in continuous outcomes for survivor subgroups defined by radiation treatment exposures compared to sibling controls (Figures 2 and 3, Table 3).
Figure 2:
Adjusted mean differences in body size outcomes of height, weight, body mass index (BMI), waist circumference, lean body mass, total fat mass, visceral adipose tissue (VAT) mass, and percent fat mass (PFM) between all survivors, survivor subgroups who received total body irradiation and central nervous system irradiation (TBI+CNS), TBI/no CNS irradiation (TBI), and no TBI nor CNS irradiation (Chemo Only), and siblings (reference). Comparisons adjusted for age at study, sex, race/ethnicity, and Tanner stage.
Figure 3:
Adjusted mean differences in continuous cardiovascular outcomes for all survivors, survivor subgroups with total body irradiation and central nervous system irradiation (TBI+CNS), TBI but no CNS irradiation (TBI), and no TBI/no CNS irradiation (Chemo Only) relative to those of siblings (reference). Estimates are adjusted for age-at-study (categorized <18, 18-34.9, 35+), sex, race/ethnicity, and Tanner stage (blue symbols), and, these adjustments plus PFM percentiles (categorized <25th, 25th-75th, >75th) (black symbols; +PFM model): (A) Mlbm, fasting blood glucose and fasting insulin. Mlbm: All survivors vs siblings p=0.003, TBI+CNS vs siblings p<0.001, TBI vs siblings p=0.063, Chemo-only vs siblings p=0.29; Mlbm, +PFM model: All survivors vs siblings p=0.012, TBI+CNS vs siblings p<0.001, TBI vs siblings p=0.11, Chemo only vs siblings p=0.38. Fasting blood glucose: All survivors vs siblings p=0.054, TBI+CNS vs siblings p=0.009, TBI vs siblings p=0.093, Chemo-only vs siblings p=0.71. Fasting blood glucose, +PFM model: All survivors vs siblings p=0.16, TBI+CNS vs siblings p=0.12, TBI vs siblings p=0.15, Chemo-only vs siblings p=0.22. Fasting insulin: All survivors vs siblings p<0.001, TBI+CNS vs siblings p<0.001, TBI vs siblings p<0.001, Chemo-only vs siblings p=0.053. Fasting insulin, +PFM model: All survivors vs siblings p<0.001, TBI+CNS vs siblings p<0.001, TBI vs siblings p=0.001, Chemo-only vs siblings p=0.18. (B) Total cholesterol, triglycerides, HDL, and LDL; Total cholesterol: All survivors vs siblings p<0.001, TBI+CNS vs siblings p<0.001, TBI vs siblings p<0.001, Chemo-only vs siblings p=0.09. Total cholesterol, +PFM model: All survivors vs siblings p<0.001, TBI+CNS vs siblings p<0.001, TBI vs siblings p=0.002, Chemo-only vs siblings p=0.18. Triglycerides: All survivors vs siblings p<0.001, TBI+CNS vs siblings p<0.001, TBI vs siblings p<0.001, Chemo-only vs siblings p=0.15. Triglycerides, +PFM model: All survivors vs siblings p<0.001, TBI+CNS vs siblings p<0.001, TBI vs siblings p<0.001, Chemo-only vs siblings p=0.23. HDL: All survivors vs siblings p<0.001, TBI+CNS vs siblings p<0.001, TBI vs siblings p=0.007, Chemo-only vs siblings p=0.007. HDL, +PFM model: All survivors vs siblings p<0.001, TBI+CNS vs siblings p<0.001, TBI vs siblings p=0.027, Chemo-only vs siblings p=0.013. LDL: All survivors vs siblings p<0.001, TBI+CNS vs siblings p<0.001, TBI vs siblings p=0.002, Chemo-only vs siblings p=0.043. LDL, +PFM model: All survivors vs siblings p<0.001, TBI+CNS vs siblings p=0.002, TBI vs siblings p=0.033, Chemo-only vs siblings p=0.067. (C) SBP and DBP. SBP: All survivors vs siblings p=0.43, TBI+CNS vs siblings p=0.34, TBI vs siblings p=41, Chemo-only vs siblings p=0.053. SBP, +PFM model: All survivors vs siblings p=0.15, TBI+CNS vs siblings p=0.50, TBI vs siblings p=0.16, Chemo-only vs siblings p=0.019. DBP: All survivors vs siblings p=0.18, TBI+CNS vs siblings p=0.20, TBI vs siblings p=0.13, Chemo-only vs siblings p=0.53. DBP, +PFM model: All survivors vs siblings p=0.40, TBI+CNS vs siblings p=0.31, TBI vs siblings p=0.26, Chemo-only vs siblings p=0.34.
Table 3:
Estimated mean differences (MD) in body size traits and cardiovascular risk factor measures for all survivors combined and subgroups defined by HCT treatment compared to siblings (reference).
| All Survivors | TBI+CNS | TBI, not CNS | Chemo Only | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Outcome | Model Adjustments* | MD (95% CI)* | P-value | MD (95% CI)* | P-value | MD (95% CI)* | P-value | MD (95% CI)* | P-value |
| Height, cm | Age, sex, race/ethnicity, tanner | −7.9 (−9.9, −5.9) | <0.001 | −11.3 (−14.6, −8) | <0.001 | −9.2 (−11.6, −6.8) | <0.001 | −2.1 (−5, 0.8) | 0.15 |
| Weight, kg | Age, sex, race/ethnicity, tanner | −7.5 (−11.3, −3.6) | <0.001 | −12.3 (−18.4, −6.3) | <0.001 | −9.7 (−13.7, −5.6) | <0.001 | 1.8 (−6, 9.7) | 0.65 |
| BMI, kg/m2 | Age, sex, race/ethnicity, tanner | −0.5 (−1.6, 0.7) | 0.41 | −1.1 (−3.3, 1.0) | 0.30 | −0.9 (−2.1, 0.3) | 0.15 | 1.1 (−1.2, 3.3) | 0.36 |
| Waist Circumference, cm | Age, sex, race/ethnicity, tanner | 0.2 (−2.6, 3.1) | 0.87 | −0.3 (−5.1, 4.6) | 0.92 | −1.1 (−4.3, 2.0) | 0.49 | 3.6 (−1.9, 9.1) | 0.20 |
| Lean Body Mass, kg | Age, sex, race/ethnicity, tanner | −8.8 (−10.9, −6.8) | <0.001 | −12.9 (−15.9, −9.9) | <.001 | −10.3 (−12.3, −8.3) | <0.001 | −2.2 (−6.1, 1.8) | 0.28 |
| Percent Fat Mass | Age, sex, race/ethnicity, tanner | 5.2 (3.0, 7.3) | <0.001 | 5.9 (2.6, 9.2) | <0.001 | 5.0 (2.6, 7.5) | <0.001 | 4.8 (1.2, 8.4) | 0.009 |
| Total Fat Mass, kg | Age, sex, race/ethnicity, tanner | 1.6 (−1.1, 4.3) | 0.25 | 0.6 (−3.5, 4.7) | 0.76 | 0.4 (−2.3, 3.2) | 0.75 | 4.9 (−1.1, 10.9) | 0.11 |
| Visceral Adipose Tissue, g | Age, sex, race/ethnicity, tanner | 193.9 (76.8, 311.0) | 0.001 | 253.2 (81.6, 424.8) | 0.004 | 155.3 (20.7, 289.9) | 0.024 | 221.0 (−22.2, 464.2) | 0.075 |
| Mlbm | Age, sex, race/ethnicity, tanner | −2.0 (−3.3, −0.7) | 0.003 | −4.4 (−6.2, −2.5) | <0.001 | −1.5 (−3.1, 0.1) | 0.063 | −0.9 (−2.6, 0.8) | 0.29 |
| Age, sex, race/ethnicity, tanner, PFM | −1.8 (−3.2, −0.4) | 0.012 | −4.2 (−6.2, −2.3) | <0.001 | −1.4 (−3.1, 0.3) | 0.11 | −0.8 (−2.5, 1.0) | 0.38 | |
| Systolic Blood Pressure, mmHg | Age, sex, race/ethnicity, tanner | −1.2 (−4.1, 1.7) | 0.43 | 2.9 (−3.0, 8.8) | 0.34 | −1.4 (−4.7, 1.9) | 0.41 | −4.6 (−9.2, 0.1) | 0.053 |
| Age, sex, race/ethnicity, tanner, PFM | −2.2 (−5.2, 0.8) | 0.15 | 2.0 (−3.8, 7.8) | 0.50 | −2.4 (−5.8, 0.9) | 0.16 | −5.4 (−9.8, −0.9) | 0.019 | |
| Diastolic Blood Pressure, mmHg | Age, sex, race/ethnicity, tanner | 1.7 (−0.8, 4.1) | 0.18 | 3.1 (−1.7, 7.9) | 0.20 | 2.2 (−0.6, 5.0) | 0.13 | −0.9 (−4.2, 2.3) | 0.58 |
| Age, sex, race/ethnicity, tanner, PFM | 1.0 (−1.3, 3.4) | 0.40 | 2.4 (−2.2, 6.9) | 0.31 | 1.6 (−1.2, 4.4) | 0.26 | −1.6 (−4.8, 1.7) | 0.34 | |
| Total Cholesterol, mg/dL | Age, sex, race/ethnicity, tanner | 23.3 (15.3, 31.2) | <0.001 | 40.9 (24.4, 57.4) | <0.001 | 21.1 (10.9, 31.3) | <0.001 | 11.2 (−1.6, 23.9) | 0.09 |
| Age, sex, race/ethnicity, tanner, PFM | 18.8 (10.7, 26.9) | <0.001 | 36.8 (21.0, 52.5) | <0.001 | 15.9 (5.7, 26.1) | 0.002 | 8.3 (−3.8, 20.3) | 0.18 | |
| LDL-cholesterol, mg/dL | Age, sex, race/ethnicity, tanner | 15.4 (8.2, 22.6) | <0.001 | 23.8 (10.6, 37) | <0.001 | 12.9 (4.6, 21.1) | 0.002 | 13.2 (0.4, 25.9) | 0.043 |
| Age, sex, race/ethnicity, tanner, PFM | 12.3 (5.0, 19.7) | <0.001 | 20.9 (7.9, 33.8) | 0.002 | 9.0 (0.7, 17.2) | 0.033 | 11.3 (−0.8, 23.4) | 0.07 | |
| HDL-cholesterol, mg/dL | Age, sex, race/ethnicity, tanner | −5.6 (−8.2, −3.0) | <0.001 | −8.8 (−12.9, −4.7) | <0.001 | −4.4 (−7.5, −1.2) | 0.007 | −5.4 (−9.3, −1.5) | 0.007 |
| Age, sex, race/ethnicity, tanner, PFM | −5.1 (−7.8, −2.3) | <0.001 | −8.4 (−12.7, −4.1) | <0.001 | −3.8 (−7.1, −0.4) | 0.027 | −5.0 (−9.0, −1.0) | 0.013 | |
| Triglycerides, mg/dL | Age, sex, race/ethnicity, tanner | 80.9 (53.2, 108.6) | <0.001 | 145.1 (76.4, 213.9) | <0.001 | 78.1 (36.9, 119.2) | <0.001 | 27.7 (−9.9, 65.3) | 0.15 |
| Age, sex, race/ethnicity, tanner, PFM | 70 (43.1, 97) | <0.001 | 134.6 (63.1, 206.1) | <0.001 | 66.4 (27.7, 105.2) | <0.001 | 21.2 (−13.1, 55.4) | 0.23 | |
| Blood Glucose, mg/dL | Age, sex, race/ethnicity, tanner | 4.6 (−0.1, 9.3) | 0.054 | 6.8 (1.7, 11.9) | 0.009 | 6.1 (−1.0, 13.3) | 0.093 | −0.9 (−5.7, 3.8) | 0.71 |
| Age, sex, race/ethnicity, tanner, PFM | 2.7 (−1.1, 6.6) | 0.16 | 4.4 (−1.2, 10.0) | 0.12 | 4.5 (−1.6, 10.7) | 0.15 | −2.8 (−7.4, 1.7) | 0.22 | |
| Insulin, μU/mL | Age, sex, race/ethnicity, tanner | 7.0 (4.5, 9.5) | <0.001 | 10.8 (6.4, 15.1) | <0.001 | 6.8 (3.3, 10.3) | <0.001 | 4.1 (−0.1, 8.3) | 0.053 |
| Age, sex, race/ethnicity, tanner, PFM | 5.4 (3.0, 7.7) | <0.001 | 8.9 (4.3, 13.5) | <0.001 | 5.3 (2.0, 8.5) | 0.001 | 2.5 (−1.1, 6.1) | 0.18 | |
Compared to siblings; Adjusted for age-at-study (age), sex, race/ethnicity, and Tanner score (tanner). Age-at-study is categorized <18, 18-34.8, 35+, and percent fat mass (PFM) is categorized <25th, 25th-75th, and >75th percentiles.
Body Composition:
Compared to sibling controls, survivors exposed to radiation had a lower height (TBI+CNS: MD, −11.3 [95% CI −14.6, −8.0]; p<0.001; TBI/no CNS: MD, −9.2 [95% CI −11.6, −6.8]; p<0.001) and weight (TBI+CNS: MD, −12.3 [95% CI −18.4, −6.3]; p<0.001; TBI/no CNS: MD, −9.7 [95% CI −13.7, −5.6]; p<0.001), after adjusting for age-at study, sex, race, and Tanner stage (Table 3). BMI and waist circumference were not different between survivors and siblings. However, LBM was significantly lower in those exposed to TBI, particularly TBI+CNS (TBI+CNS: MD, −12.9 [95% CI −15.9, −9.9]; p<0.001; TBI/no CNS: MD, −10.3 [95% CI −12.3, −8.3]; p<0.001). Additionally, PFM was significantly higher than sibling controls for all HCT survivors including those with only chemotherapy exposure (TBI+CNS: MD, 5.9 [95% CI 2.6, 9.2]; p<0.001; TBI/no CNS: MD, 5.0 [95% CI 2.6, 7.5]; p<0.001; chemotherapy only: MD, 4.8 [95% CI 1.2, 8.4]; p=0.009). Compared to siblings, visceral adipose tissue was significantly higher in survivors who were exposed to TBI (TBI+CNS: MD, 253.2 [95% CI 81.6, 424.8]; p=0.004; TBI/no CNS: MD, 155.3 [95% CI 20.7, 289.9]; p=0.024) whereas there was no significant difference in total fat mass (TFM).
Insulin Sensitivity:
Fasting insulin levels were significantly higher in survivors than sibling controls with the greatest impact seen in those who received TBI+CNS (PFM adjusted MD, 8.9 [95% CI 4.3, 13.5]; p<0.001. Table 3). While the overall cohort of survivors was less insulin sensitive, the most significant impact on insulin sensitivity (Mlbm) was seen in those who were exposed to TBI+CNS compared to siblings (PFM adjusted MD, −4.2 [95% CI −6.2, −2.3]; p<0.001).
Dyslipidemia:
Compared with sibling controls, total cholesterol levels and fasting triglyceride levels were higher in TBI exposed survivors, with the greatest increase in the TBI+CNS group (PFM adjusted total cholesterol MD, 36.8 [95% CI 21.0, 52.5]; p<0.001. Table 3) (PFM adjusted fasting triglyceride MD, 134.6 [95% CI 63.1, 206.1]; p<0.001). HDL cholesterol levels were significantly lower than sibling controls regardless of radiation exposure with the greatest impact was seen in those who received TBI+CNS (PFM adjusted MD, −8.4 [95% CI −12.7, −4.1]; p<0.001). Additionally, LDL cholesterol levels were found to be significantly higher except in the chemotherapy only group in the PFM adjusted analysis.
Blood Pressure:
Just the chemo-only survivors were significantly different compared to siblings in SBP (adjusted for PFM MD, −5.4 [95% CI −9.8, −0.9]; p=0.019). There was no significant difference found in DBP between any of the survivor treatment groups and controls.
Cardiovascular risk factors comparisons by treatment exposure among survivors
In pairwise comparisons of mean differences between subgroups of survivors defined by treatment group, those who received TBI+CNS radiation had lower Mlbm compared with those who received TBI/no CNS (PFM adjusted MD, −3.1 [95% CI −5.1, −1.1]; p=0.002) and chemotherapy only (PFM adjusted MD, −3.5 [95% CI −5.8, −1.2]; p=0.003; Table 4) after adjusting for age, sex, race, Tanner stage and PFM. Survivors who received TBI+CNS radiation had a significantly decreased LBM compared with those who received chemotherapy only (MD − 10.3 [95% CI −14.0, −6.1]; p<0.001) while no significant difference was observed compared to those who received TBI/no CNS. Total cholesterol and LDL cholesterol were significantly higher, and HDL-cholesterol was significantly lower in the TBI+CNS group compared with survivors who received TBI/no CNS, after adjusting for age, sex, race, Tanner stage and PFM. Within the subgroups of graft versus host disease (GVHD)+ and GVHD−, the association between cardiovascular risk factors and treatments did not differ compared to autologous HCT survivors (data not shown).
Table 4:
Pairwise comparisons of estimated mean differences (MD) between treatment groups.
| TBI+CNS vs TBI/no CNS | TBI+CNS vs. Chemo only | TBI/no CNS vs. Chemo Only | |||||
|---|---|---|---|---|---|---|---|
| Outcome | model adjustments | MD (95% CI) | P-value | MD (95% CI) | P-value | MD (95% CI) | P-value |
| Mlbm | Age, sex, race/ethnicity, tanner | −3.1 (−5.1, −1.1) | 0.002 | −3.5 (−5.8, −1.2) | 0.003 | −0.4 (−2.3, 1.6) | 0.70 |
| Age, sex, race/ethnicity, tanner, PFM | −3.1 (−5.1, −1.1) | 0.002 | −3.5 (−5.8, −1.2) | 0.003 | −0.4 (−2.4, 1.5) | 0.68 | |
| Systolic Blood Pressure mmHg | Age, sex, race/ethnicity, tanner | 4.3 (−1, 9.6) | 0.11 | 8 (1.7, 14.2) | 0.013 | 3.6 (−1.7, 8.9) | 0.18 |
| Age, sex, race/ethnicity, tanner, PFM | 4.5 (−0.6, 9.7) | 0.09 | 7.8 (1.8, 13.9) | 0.012 | 3.3 (−1.9, 8.5) | 0.21 | |
| Diastolic Blood Pressure, mmHg | Age, sex, race/ethnicity, tanner | 0.8 (−3.3, 5) | 0.70 | 4.2 (−0.6, 9.1) | 0.089 | 3.4 (−0.7, 7.6) | 0.11 |
| Age, sex, race/ethnicity, tanner, PFM | 0.7 (−3.4, 4.7) | 0.74 | 4.1 (−0.7, 8.9) | 0.091 | 3.4 (−0.6, 7.5) | 0.10 | |
| Total Cholesterol, mg/dL | Age, sex, race/ethnicity, tanner | 21 (3.4, 38.6) | 0.019 | 35 (14.3, 55.6) | <.001 | 14 (−3.6, 31.6) | 0.12 |
| Age, sex, race/ethnicity, tanner, PFM | 20.7 (3.9, 37.5) | 0.016 | 32.7 (12.9, 52.4) | 0.001 | 12 (−4.9, 28.8) | 0.16 | |
| LDL-cholesterol, mg/dL | Age, sex, race/ethnicity, tanner | 15.5 (1.5, 29.4) | 0.029 | 18.4 (1.9, 34.8) | 0.029 | 2.9 (−10.6, 16.4) | 0.68 |
| Age, sex, race/ethnicity, tanner, PFM | 14.2 (0.8, 27.6) | 0.038 | 15.2 (−0.6, 31.1) | 0.059 | 1.1 (−11.9, 14.1) | 0.87 | |
| HDL-cholesterol, mg/dL | Age, sex, race/ethnicity, tanner | −4.7 (−9, −0.5) | 0.029 | −4 (−9, 1) | 0.113 | 0.7 (−3.6, 4.9) | 0.75 |
| Age, sex, race/ethnicity, tanner, PFM | −4.8 (−9, −0.7) | 0.021 | −3.6 (−8.5, 1.2) | 0.14 | 1.2 (−2.9, 5.3) | 0.57 | |
| Triglycerides, mg/dL | Age, sex, race/ethnicity, tanner | 68 (−5.2, 141.1) | 0.07 | 121 (34.9, 207) | 0.006 | 53 (−20.3, 126.2) | 0.16 |
| Age, sex, race/ethnicity, tanner, PFM | 67.7 (−4.7, 140) | 0.07 | 114.8 (29.6, 199.9) | 0.008 | 47.1 (−25.5, 119.7) | 0.20 | |
| Blood Glucose, mg/dL | Age, sex, race/ethnicity, tanner | 1.2 (−10.1, 12.5) | 0.83 | 7 (−6.4, 20.4) | 0.307 | 5.8 (−5.7, 17.2) | 0.32 |
| Age, sex, race/ethnicity, tanner, PFM | 0.6 (−10.4, 11.5) | 0.92 | 6.3 (−6.7, 19.2) | 0.344 | 5.7 (−5.3, 16.7) | 0.31 | |
| Insulin, μU/dL | Age, sex, race/ethnicity, tanner | 4 (−1.9, 9.9) | 0.18 | 6.9 (0, 13.7) | 0.048 | 2.9 (−3, 8.8) | 0.33 |
| Age, sex, race/ethnicity, tanner, PFM | 3.7 (−1.7, 9.1) | 0.18 | 6.5 (0.1, 12.8) | 0.045 | 2.8 (−2.7, 8.2) | 0.32 | |
| Height, cm | Age, sex, race/ethnicity, tanner | −1.6 (−5.3, 2.1) | 0.39 | −8.6 (−12.9, −4.3) | <.001 | −7 (−10.7, −3.3) | <.001 |
| Weight, kg | Age, sex, race/ethnicity, tanner | −2.1 (−9, 4.8) | 0.56 | −13.4 (−21.6, −5.3) | 0.001 | −11.4 (−18.3, −4.5) | 0.001 |
| BMI, kg/m2 | Age, sex, race/ethnicity, tanner | −0.1 (−2.3, 2) | 0.90 | −2 (−4.6, 0.5) | 0.114 | −1.9 (−4.1, 0.2) | 0.08 |
| Waist Circumference, cm | Age, sex, race/ethnicity, tanner | 1.1 (−4, 6.2) | 0.67 | −3.4 (−9.4, 2.6) | 0.273 | −4.5 (−9.6, 0.7) | 0.09 |
| Lean Body Mass, kg | Age, sex, race/ethnicity, tanner | −2.6 (−6.1, 1) | 0.15 | −10.3 (−14.4, −6.1) | <.001 | −7.7 (−11.2, −4.2) | <.001 |
| Percent Fat Mass | Age, sex, race/ethnicity, tanner | 1.2 (−2.4, 4.8) | 0.52 | 1.1 (−3.1, 5.3) | 0.61 | −0.1 (−3.7, 3.5) | 0.97 |
| Visceral Adipose Tissue, g | Age, sex, race/ethnicity, tanner | 99.3 (−116.7, 315.4) | 0.37 | 48.7 (−201.5, 298.9) | 0.703 | −50.6 (−263.8, 162.6 | 0.64 |
Adjusted for age-at-study (age), sex, race/ethnicity, Tanner score (tanner), and/or percent Fat Mass (PFM).
DISCUSSION
We show that HCT survivors are less insulin sensitive and more likely to have adverse CVD risk factors in comparison to their healthy siblings. In particular, significantly higher PFM and VAT, and significantly lower LBM were also noted in HCT survivors than sibling controls despite having a similar BMI between the two groups. Adiposity, usually expressed as an increased BMI, is associated with adverse levels of CVD risk factors and IR.17–20 However, in this population of HCT survivors, BMI provided a less accurate representation of adiposity, which was defined only after DXA scanning for body composition and determination of lean and fat masses. We confirm that one of the strongest factors associated with abnormal body composition leading to sarcopenic obesity (decreased LBM and increased PFM) was the use of TBI in the conditioning regimen. While waist circumference was not significantly different, body composition data showed that survivors exposed to TBI had a higher VAT compared to sibling controls. Additionally, we describe that HCT survivors were more likely to have dyslipidemias including higher total cholesterol, LDL cholesterol and triglyceride level and a lower HDL level compared to sibling controls, all indicative of an adverse CVD risk profile.
In general, late effects after single fraction TBI have been more significant than those seen after fractionated TBI. However, the number of patients who have received single fraction TBI is this cohort is relatively small which precludes us from performing a formal analysis. In addition, the practice of delivering high dose (750-1000 cGy) of single fraction TBI has been abandoned. Given the fact that 88% of patients in this cohort received fractionated TBI (the vast majority at doses of 1200-1320 cGy), the findings reported in this manuscript are primarily driven by that group of patients.
A study by Bizzarri et al. showed that HCT survivors, while not overtly obese by WHO BMI criteria (BMI >30), may develop IR as measured by indirect approximates of insulin resistance (homeostatic model assessment for insulin resistance [HOMA-IR]) and oral glucose tolerance testing.21 Similar findings with decreased insulin sensitivity (or insulin resistance), and abnormal body composition reflected in reduced subcutaneous and increased visceral fat distribution, increased TFM and reduced LBM have also been described in a smaller cohort of long-term childhood survivors of HCT however we have described differences between sibling controls and use gold standard insulin clamp testing to measure insulin sensitivity.7 A study by Taskinen et. al. of HCT survivors 3-18 years after transplant showed that a history of GVHD was associated with hyperinsulinemia and impaired glucose tolerance though we did find that association in this study.5 Other studies by our group have also shown that childhood cancer survivors have greater adiposity, lower LBM, higher total cholesterol, and were less insulin sensitive than sibling controls.22 By using a direct measure of insulin sensitivity (i.e., hyperinsulinemic euglycemic clamp), we were able to demonstrate decreased insulin sensitivity in HCT survivors compared to sibling controls, even after adjustment for adiposity, suggesting that insulin sensitivity in HCT may be related to cancer and/or conditioning chemotherapy, with the strongest association found with TBI exposure. Decreased insulin sensitivity has been shown to be related to obesity and elevated CV risk factors and therefore may be valuable in identifying individuals at greatest risk for future CV disease.18
This study has some potential limitations. With an overall participation rate of 45%, selection bias cannot be excluded. As noted above this was a randomly selected cohort from all eligible cases but did not collect any data on cases who were lost to follow-up or who were passive refusals and thus are not able to make any comparisons between those and the enrolled cases. The population was predominantly white non-Hispanic; therefore, the findings may not be generalizable to other racial/ethnic groups. Modern cancer therapy relies on multi-modal treatments including radiation therapy and/or multi-agent chemotherapy. The authors did not have access to pre-transplant therapy in these patients and therefore cannot account for this in our analyses. We also did not collect total radiation exposure data from participants.
Determining the impact of any individual therapy becomes very complex and requires very large numbers of subjects. Therefore, the current analysis incorporates the combined impact of the therapeutic exposures on HCT survivors. Although measures of fitness were not obtained, it is conceivable that similar to other populations, promotion of physical activity focused on improving sarcopenia and reducing fat mass may reduce the magnitude of abnormal cardiometabolic risk factors in HCT survivors.
The results from this study have important implications for the long-term survivorship care of pediatric and young adult HCT survivors. We have demonstrated that HCT survivors have a higher than expected prevalence of multiple CVD risk factors, and it is known that early mortality from CVD is one of their leading causes of non-relapse mortality.9,23 We demonstrate that TBI can have long-term impact on body composition including LBM and VAT. It has been shown that CV risk factors present in children often continue into adulthood on a worsening trajectory. Our findings support that HCT survivors should be monitored for adverse lipid profiles, as recommended by Children’s Oncology Group Long Term Follow-Up Guidelines version 5.0, and these abnormalities are potential targets for lifestyle and pharmacologic interventions. Thus, the presence of CVD risk factors present at such a relatively young age in HCT survivors raises concern for an escalating trajectory of CVD risk and subsequently adverse CVD related events at a younger than expected age. Screening HCT survivors for cardiometabolic risk factors and identification of patients at risk will be crucial for early intervention and prevention of CVD related complications.
Highlights.
HCT usage for treating malignant conditions in children has risen over 5 decades with increased long-term survival rates.
Childhood HCT survivors exhibit higher prevalence of metabolic syndrome compared to the general population.
HCT survivors are significantly less insulin sensitive and have adverse CVD risk profiles when compared to sibling controls.
Body Mass Index (BMI) provides a less accurate depiction of adiposity in HCT survivors, with more accurate insights from DXA scans.
Total Body Irradiation (TBI) in the conditioning regimen leads to notable body composition changes in HCT survivors, like decreased Lean Body Mass (LBM) and increased Percent Fat Mass (PFM).
Financial Support
The study was supported by the National Institutes of Health: Ruth L. Kirschstein National Research Service Award T32CA009351, NCI grant R01CA112530 to K.S.B., and the National Center for Research Resources (NCRR) Grants 1UL1RR033183 to the University of Minnesota Clinical and Translational Science Institute, and the General Clinical Research Center Program M01-RR00400, and to the University of Washington Clinical and Translational Science Institute, NCRR 1 ULI TR000423. The contents of this study are solely the responsibility of the authors and do not necessarily represent the official views of the CTSI or the NIH.
Glossary
- BMI
Body mass index
- CNS
Central nervous system
- CVD
Cardiovascular disease
- DBP
Diastolic blood pressure
- DXA
Dual x-ray absorptiometry
- GVHD
Graft versus host disease
- HCT
Hematopoietic cell transplant
- HDL
High-density lipoprotein cholesterol
- IR
Insulin resistance
- LDL
Low-density lipoprotein cholesterol
- MD
Mean Difference
- PFM
Percent fat mass
- SBP
Systolic blood pressure
- TBI
Total body irradiation
- TFM
Total fat mass
- VAT
Visceral adipose tissue
Footnotes
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Conflict of Interest
The authors of this Manuscript have no conflict of interest to report relevant to this research.
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