No abstract

Long-term childhood cancer survivors treated with TBI during early childhood display significant signs of premature arterial aging during young adulthood.

Objective: The aim of the study was to evaluate long-term ovarian function after allogeneic hematopoietic stem cell transplantation (HSCT) in childhood and adolescence. Subjects and methods: Predictive factors for ovarian function were evaluated among 92 adult or pubertal female survivors transplanted at Huddinge and Helsinki University Hospital during 1978-2000, at a mean age of 9G4.3 years (range 1-19). At the time of the study a meanGS.D. of 13G5.5 years (range 6-27) had elapsed since the HSCT and the mean age of the participants was 22G6.3 years (range 9-41). Results: Spontaneous puberty based on breast development occurred in 40 and menarche in 30 of the 70 girls who were prepubertal at transplantation. Six out of 20 girls who received HSCT after initiation of pubertal development recovered their ovarian function. Younger age at HSCT, conditioning without total body irradiation (TBI), and a non-leukemia diagnosis predicted the spontaneous menarche. The incidence of menarche was higher after fractioned vs single fraction TBI (P!0.05), cyclophosphamide (Cy) vs busulfan (Bu)-based conditioning (P!0.05), and among leukemia patients transplanted at first remission vs later remissions (P!0.01) and with no cranial irradiation (cranial radiotherapy, CRT) vs given CRT (14-24 Gy) (P!0.01). The majority of recipients conditioned with only Cy vs TBI (P!0.001) or vs Bu-based regimens (P!0.01) showed preserved ovarian function and required no estrogen replacement at their latest follow-up visit at a mean age of 23G6.3 years (range 15-41). Ten women became pregnant. Conclusions: Patients conditioned with TBI or Bu-based regimes are at high risk of ovarian failure. Intensive antileukemia therapy before HSCT including CRT especially among relapsed patients may further decrease the possibility of spontaneous menarche.

The aim of this study was to analyze the prevalence of frailty and physical health limitations among long-term survivors of high-risk neuroblastoma (HR NBL) and to investigate whether frail health is associated with variables of cardiovascular function, markers of inflammation and telomere length. A national study cohort of 19 (median age 22, range 16-30 years) long-term (>10 years) HR NBL survivors was studied and the findings were compared with 20 age- and sex-matched controls. Frailty was defined as ⩾3 of the following conditions: low muscle mass, low energy expenditure, slow running and weakness. The prevalence of frailty was significantly higher among the HR NBL survivors 9/19 (47%) than among the controls (0%). Thirteen (68%) of the survivors reported significant physical health limitations in vigorous activities, as opposed to none of the controls. The HR NBL survivors had significantly shorter telomere length and higher serum levels of high sensitivity C-reactive protein than did the controls. Frail health and poor physical functioning are prevalent among HR NBL survivors and suggest premature aging. Survivors with gonadal damage, very low fat mass percentage, low glycosylated hemoglobin A1c and increased common carotid artery intima-media thickness may be more prone to early aging after high dose therapy.

A larger adult testicular volume, normal serum levels of FSH and spermatozoa detected in a majority of seminal fluids after busulfan-based or cyclophosphamide conditionings suggest very long-term recovery of spermatogenesis after chemotherapy-based regimens. A simple measurement of adult testicular volume may help predict spermatogenetic potential among pediatric HSCT survivors.

Treatment-related late toxicities after pediatric allogeneic hematopoietic SCT (allo-HSCT) are increasingly important as long-term survival has become an expected outcome for many transplanted children and adolescents. In a retrospective cohort study, we assessed long-term health outcomes in 204 allo-HSCT survivors transplanted in childhood or adolescence (o 20 years) between 1978 through 2000 after a median follow-up time of 12 (range 4-28) years. Data on conditioning regimen, adverse health events (AE) and growth and hormonal substitutions (hormone replacement therapies (HRTs)) were obtained from medical records. AEs were graded retrospectively according to Common Terminology Criteria for Adverse Events v3.0. Late deaths (⩾48 months after allo-HSCT) were evaluated separately. Multivariate analysis demonstrated that chronic GVHD (P o0.000) and longer follow-up time (P o0.05) correlated with AEs, whereas CY-based conditioning was inversely correlated (P o 0.002). TBI and longer follow-up duration predicted more severe AEs (P o 0.001 and P o 0.001, respectively). HRTs were more frequent after TBI. Diabetes type II, dyslipidemia and hypertension were detected in 9, 7 and 7% of the survivors, respectively. Late deaths (n = 22) were most frequently due to pulmonary failure (n = 7), followed by secondary malignancy (n = 5). The occurrence of AEs after pediatric allo-HSCT is high and likely to increase during extended follow-up, particularly in patients who have received TBI.

High-dose therapy and hematopoietic stem cell transplantation (HSCT) have been shown to improve survival rates in high-risk neuroblastoma (HR-NBL), but may cause adverse effects on the growing skeleton. We studied skeletal health in a national cohort of long-term survivors of HR-NBL (n=21; age 16-30 years, median 22 years) and in 20 healthy age- and sex-matched controls. In addition to clinical evaluation and measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry, we performed spinal magnetic resonance imaging. Skeletal complications were categorized according to Common Terminology Criteria for Adverse Events (CTCAE). Altogether, 18/21 survivors presented with at least one skeletal adverse event according to CTCAE, the most common skeletal complications being short stature (n=14) and osteopenia (n=13). Altogether, 38% of the subjects had a severe complication (CTCAE score ⩾3) including bilateral slipped capital femoral epiphyseolysis in 3/21. Fracture rate was not increased. In spinal MRI, no vertebral fractures were found and degenerative intervertebral disc changes were equally prevalent in survivors and controls. BMD was lower in survivors than controls, but differences became non-significant when adjusted for bone size. In conclusion, skeletal late complications are common and can significantly impair the quality of life in young adult survivors of HR-NBL treated with high-dose protocols and HSCT.

Abbreviations: BMI = body mass index; BSA = body surface area; DOXO = cumulative doxorubicin dose; F = female; HSCT = hematopoietic stem cell transplantation; hs-CRP = high-sensitivity C-reactive protein; M = male; proBNP = N-terminal pro-B-type natriuretic peptide; 24hHR = 24-hr mean heart rate; 24hSYS/DIA% = 24-hr mean systolic or diastolic blood pressure. Results are reported as mean ± s.d.