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.

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.

An in vitro paradigm for diabetic cerebral oedema and its therapy: a critical role for taurine and water channels.

The pathophysiology of cerebral oedema (CE) in diabetic ketoacidosis (DKA) remains enigmatic. We investigated the role of the idiogenic osmol taurine and aquaporin channels in an in vitro model, the SH-SY5Y neuroblastoma cell line, by sequentially mimicking DKA-like hyperglycemia/hypertonicity and hypotonic fluid therapy. Exposure to DKA-like hyperosmolarity led to shrinkage, while hypotonic fluid exposure led to cell swelling and impaired viability. Low sodium compensated in part for elevated glucose, pointing to a critical role for overall osmolality. Taurine, was synthesized and retained intracellularly during DKA-like hypertonicity, and released during hypotonicity, in part mitigating neuronal swelling. Metabolic labeling showed that the rate of taurine release was inadequate to fully prevent neuronal swelling during hypotonic fluid therapy following DKA-like hypertonicity. Under these conditions, Aquaporin4 & 9 channels were respectively down and up-regulated. Our study provides further novel insights into molecular mechanisms contributing to CE in DKA and its therapy.

Virginal breast hypertrophy of an 11-year-old girl.

We report a case of an 11-year-old girl with virginal breast hypertrophy; a rare condition characterised by rapid breast enlargement in the peripubertal period. In this paper we highlight complexities of management in this age group.