Physical Fitness and Frailty in Males after Allogeneic Hematopoietic Stem Cell Transplantation in Childhood: A Long-Term Follow-Up Study.

PURPOSE AND METHODS: To analyze physical fitness, physical activity and the prevalence of frailty in male long-term survivors of pediatric allogeneic hematopoietic stem cell transplantation (HSCT). We performed a Nordic two-center study of 98 male survivors (mean age 28.7 years, range 18.5-47.0) treated with pediatric allogeneic hematopoietic stem cell transplantation (HSCT) 1980-2010 in denmark or finland. physical fitness was evaluated by the dominant hand grip-strength, timed up-and-go, sit-to-stand, gait speed and two-minute walk tests. RESULTS: Survivors presented significantly lower muscle strength and muscle endurance in the dominant hand-grip strength (median Z-score -0.7, range -4.3-3.9) and sit-to-stand tests (median Z-score -1.5, range -3.5-2.5) compared to age and sex matched normative values of the tests. However, mobility and gait speed were not affected on a group level. The prevalence of frailty (pre-frail 20% or frail 10%) was high among the survivors. In multiple regression analysis, chronic graft-versus-host disease, shorter stature, higher body fat mass and hazardous drinking predicted prefrail/frail status. Common cardiovascular risk factors, such as increased levels of serum triglycerides, higher resting heart rate and diastolic blood pressure, were associated with lower physical fitness. CONCLUSION: Low muscle strength and a high incidence of frailty were observed in survivors of pediatric HSCT. There is a predominant risk of cardiovascular and metabolic diseases in the long-term.

Cardiac Function After Cardiotoxic Treatments for Childhood Cancer-Left Ventricular Longitudinal Strain in Screening.

Background: The majority of childhood cancer survivors (CCSs) have been exposed to cardiotoxic treatments and often present with modifiable cardiovascular risk factors. Our aim was to evaluate the value of left ventricular (LV) longitudinal strain for increasing the sensitivity of cardiac dysfunction detection among CCSs. Methods: We combined two national cohorts: neuroblastoma and other childhood cancer survivors treated with anthracyclines. The final data consisted of 90 long-term CCSs exposed to anthracyclines and/or high-dose chemotherapy with autologous stem cell rescue and followed up for > 5 years and their controls (n = 86). LV longitudinal strain was assessed with speckle tracking (Qlab) and LV ejection fraction (EF) by three-dimensional echocardiography (3DE). Results: Of the CCSs, 11% (10/90) had abnormal LV longitudinal strain (i.e., < -17.5%); of those, 70% (7/10) had normal 3DE LV EF. Multivariable linear model analysis demonstrated that follow-up time (p = 0.027), sex (p = 0.020), and BMI (p = 0.002) were significantly associated with LV longitudinal strain. Conversely, cardiac risk group, hypertension, age, cumulative anthracycline dose or exposure to chest radiation were not. Conclusion: LV longitudinal strain is a more sensitive method than LV EF for the detection of cardiac dysfunction among CCSs. Therefore, LV longitudinal strain should be added to the screening panel, especially for those with modifiable cardiovascular risk factors.

Metabolic Syndrome in Male Survivors of Pediatric Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Total Body Irradiation, Low-Grade Inflammation, and Hypogonadism.

Metabolic syndrome (MetS) is a growing concern in survivors of pediatric hematopoietic stem cell transplantation (HSCT), but little is known about the underlying mechanisms. This study aimed to determine the prevalence and clinical presentation of MetS in male long-term survivors of pediatric HSCT and to investigate predisposing factors, including low-grade inflammation, altered fat distribution, and low testosterone levels. We included 98 survivors age 19 to 47 years at a median follow-up of 18 years (range, 8 to 35 years) after pediatric HSCT. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. The prevalence and clinical manifestations of MetS were compared between our cohort and a control group of males from the background population (n = 4767). Fat distribution was assessed by android/gynoid ratio from a whole-body dual-energy X-ray absorptiometry scan. Systemic inflammation was evaluated by IL-6 and high-sensitivity C-reactive protein (hsCRP). Serum testosterone levels were measured in morning samples. The prevalence of MetS was 30%, corresponding to the prevalence in the 50- to 80-year-old males from the background population. In individuals with MetS, hyperglycemia was more frequent in the HSCT survivors compared with age-matched controls with MetS (76% versus 20%; P < .001), whereas hypertension was more dominant in the control group with MetS (69% versus 93%; P = .01). In addition, normal or low body mass index was more commonly observed among HSCT survivors with MetS compared with age-matched controls with MetS (41% versus 11%; P = .002). MetS was more often associated with total body irradiation (TBI) compared with chemotherapy regimens (odds ratio [OR], 4.3; 95% confidence interval [CI], 1.2 to 24.4; P = .02), lower testosterone levels (OR, 5.4; 95% CI, 1.3 to 23.6; P = .02), higher IL-6 levels (OR, 1.8; 95% CI, 1.2 to 2.8; P = .004), and higher hsCRP levels (OR, 1.8; 95% CI, 1.3 to 2.6; P < .001) (estimates per 2-fold increase). In addition, an increased android/gynoid (AG) fat ratio was strongly associated with MetS (OR, 2.1; 95% CI, 1.5 to 2.9; P < .001), even though only 7% of patients met the criteria for increased abdominal circumference. Our results indicate an increased risk of MetS in early adulthood after pediatric HSCT. The clinical manifestations differed from those seen in age-matched controls with MetS, indicating different pathophysiology driven by hyperglycemia, altered fat distribution (despite no clinical abdominal obesity), and low-grade inflammation. Risk factors included TBI-based conditioning and low testosterone levels. These results underline the importance of continuous clinical assessment of the cardiometabolic risk profile and stress the presence of important dissimilarities in the pathophysiology of MetS in HSCT survivors compared with the background population.

Altered body composition in male long-term survivors of paediatric allogeneic haematopoietic stem cell transplantation: impact of conditioning regimen, chronic graft-versus-host disease and hypogonadism.

Changes in body composition related to metabolic syndrome are frequent among survivors of haematopoietic stem cell transplantation (HSCT), but insights into predisposing factors are incomplete, and it is unknown to what degree these changes persist at long term. We cross-sectionally investigated body composition by dual-energy X-ray absorptiometry in 98 male survivors of paediatric allogeneic HSCT. Median (range) age at follow-up was 28.1 (18.5-47.0) years and median (range) time from transplant was 18.3 (7.7-34.6) years. Lean Body Mass Index and Skeletal Muscle Mass Index were lower in patients compared to the reference population (mean (SD) standard deviation score (SDS) -1.29 (0.99), p < 0.001 and -1.20 (1.03), p < 0.001). Fat Mass Index was comparable to the reference population, but android/gynoid (AG) fat ratio SDS was higher (mean (SD) 0.46 (1.28), p < 0.001). These changes were found in patients treated with total body irradiation (TBI) as well as non-TBI regimens, although most pronounced in the former. Further, low lean mass was associated with chronic graft-versus-host disease, while high AG ratio was associated with lower testosterone levels. Since the combination of low lean mass and high AG ratio increases the risk of cardio-metabolic disease, these health issues should be monitored at long-term clinical follow-up after paediatric HSCT.

Male Sexual Function after Allogeneic Hematopoietic Stem Cell Transplantation in Childhood: A Multicenter Study.

There are many known endocrine complications after allogeneic hematopoietic stem cell transplantation (HSCT) in childhood including increased risk of biochemical hypogonadism. However, little is known about sexuality in adulthood following childhood HSCT. In this multicenter study, sexual functions and possible risk factors were assessed comprehensively in two national cohorts (Finland and Denmark) of male adult survivors of childhood HSCT. Compared to a healthy control group (n = 56), HSCT survivors (n = 97) reported less sexual fantasies, poorer orgasms, lower sexual activity with a partner and reduced satisfaction with their sex life, even in the presence of normal erectile functions and a similar frequency of autoerotic acts. Of the HSCT survivors, 35% were cohabitating/married and 66% were sexually active. Risk factors for poorer self-reported sexual functions were partner status (not cohabitating with a partner), depressive symptoms, CNS and testicular irradiation. Sexual dysfunction increased by age in the HSCT group with a pace comparable to that of the control group. However, because of the lower baseline level of sexual functions in the HSCT group, they will reach the level of clinically significant dysfunction at a younger age. Hence, male survivors of childhood HSCT should be interviewed in detail about their sexual health beyond erectile functions.

Early Arterial Intimal Thickening and Plaque Is Related with Treatment Regime and Cardiovascular Disease Risk Factors in Young Adults Following Childhood Hematopoietic Stem Cell Transplantation.

The long-term vascular effects following childhood hematopoietic stem cell transplantation (HSCT) are not well characterized. We compared arterial wall morphology and function using very-high resolution ultrasound (25-55 MHz) in 62 patients following autologous (n = 19) or allogenic (n = 43) HSCT for childhood malignancies and hematological disease (median age 25.9 years, IQR 21.1-30.1; median follow-up time 17.5 years IQR 14.1-23.0) with an age matched healthy control group (n = 44). Intima-media thickness of carotid (CIMT 0.49 ± 0.11 vs. 0.42 ± 0.06 mm, p < 0.001), brachial, femoral, radial arteries, and local carotid stiffness, but not adventitial thickness, were increased (p < 0.001). Diffuse intimal thickening (>0.06 mm) of femoral or radial arteries (n = 17) and subclinical carotid or femoral plaques (n = 18) were more common (p < 0.001). Radiation predicted plaques (p < 0.001) and local carotid stiffness (p < 0.001), but not intimal thickening. CIMT was predicted by age, BMI >30 kg/m2, hsCRP >2.5 mg/L, hypertension, HbA1c > 42 mmol/L, and cumulative anthracycline >150 mg/m2. Cumulative metabolic syndrome criteria and cardiovascular disease (CVD) risk factors were more common among HSCT and related with CIMT (p < 0.001), but CIMT was similar among controls and HSCT without CVD risk factors. Long-term childhood HSCT survivors show early arterial aging related with radiation, metabolic, and CVD risk factors. Prevention of risk factors could potentially decelerate early arterial wall thickening.

Male Gonadal Function after Allogeneic Hematopoietic Stem Cell Transplantation in Childhood: A Cross-Sectional, Population-Based Study.

Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT), but detailed insight into patterns of male gonadal function at long-term is limited by retrospective studies without semen sample data. In this study, we investigated the risk of azoospermia and testosterone deficiency, the diagnostic value of markers of spermatogenesis, and paternity at long-term follow-up after pediatric allogeneic HSCT. All male HSCT survivors age ≥18 years, transplanted in Denmark or Finland between 1980 and 2010, were invited to participate in this cross-sectional study. Examinations included a semen sample, measurements of reproductive hormones and testicular volume, and screening for chronic graft-versus-host disease (GVHD). Cumulative (pre-HSCT plus HSCT) treatment doses were calculated. Of 181 eligible patients, 98 participated, at a median 18 years (range, 8 to 35 years) after undergoing HSCT. Sperm was found in 30 patients, azoospermia in 42, and azoospermia during testosterone substitution in 24. A higher cumulative testicular irradiation dose was associated with increased risk of azoospermia and testosterone substitution (odds ratio [OR] per +1 Gy, 1.27; 95% confidence interval [CI], 1.14 to 1.46 [P < .001] and 1.21; 95% CI, 1.11 to 1.38 [P < .001], respectively). All patients treated with >12 Gy had azoospermia, and all but 1 patient treated with >16 Gy needed testosterone substitution. In patients treated with chemotherapy only (n = 23), a higher cumulative cyclophosphamide equivalent dose was associated with an increased risk of azoospermia (OR per +1 g/m2, 1.34; 95% CI, 1.01 to 2.15; P = .037). Prepubertal stage at HSCT was a risk factor for testosterone substitution (OR, 15.31; 95% CI, 2.39 to 315; P = .017), whereas chronic GVHD was unrelated to gonadal dysfunction. Inhibin B was the best surrogate marker of azoospermia (area under the curve, .91; 95% CI, .85 to .98; 90% sensitivity and 83% specificity) compared with follicle-stimulating hormone and testicular volume. Of 24 males who had attempted to conceive, 6 had fathered children. In conclusion, the risk of male gonadal dysfunction after pediatric HSCT is high and depends primarily on the cumulative testicular irradiation dose and pubertal stage at transplantation. Our findings support the need for fertility preservation before HSCT, as well as for prolonged follow-up of pediatric HSCT recipients into adulthood.

Long-term renal prognosis and risk for hypertension after myeloablative therapies in survivors of childhood high-risk neuroblastoma: A nationwide study.

BACKGROUND: Patients with high-risk neuroblastoma (HR NBL) treated with myeloablative regimens are reported to be at risk for cardiovascular morbidity, and this risk may be increased by impaired renal function. PROCEDURE: Long-term renal function was assessed in a national cohort of 18 (age 22.4 ± 4.9 years) HR NBL survivors by plasma creatinine (P-Cr), urea, and cystatin C (P-Cys C) concentrations, urine albumin/creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR). Ambulatory blood pressure was monitored, and common carotid intima-media thickness (CIMT) and left ventricular mass index (LVMI) were evaluated. RESULTS: No significant difference in P-Cr, P-Cys C, or eGFR was found between the NBL survivors and the age- and sex-matched 20 controls. P-Cys C-based eGFR (eGFRcysc) was significantly lower than the P-Cr-based eGFRcr (97 ± 17 mL/min/1.73 m2 vs 111 ± 19 mL/min/1.73 m2 , P < 0.001) among the NBL survivors. The eGFRcysc was below normal in 28%, and ACR was above normal in 22% of the NBL survivors. Abnormal blood pressure was found in 56% of the survivors, and an additional 17% were normotensive at daytime but had significant nocturnal hypertension. Both ACR and P-Cys C were associated with nighttime diastolic hypertension. CONCLUSIONS: Long-term survivors of childhood HR NBL showed signs of only mild renal dysfunction associated with diastolic hypertension. Elevated ACR and P-Cys C were the most sensitive indicators of glomerular renal dysfunction and hypertension in this patient cohort.

Gonadal Failure Is Common in Long-Term Survivors of Childhood High-Risk Neuroblastoma Treated With High-Dose Chemotherapy and Autologous Stem Cell Rescue.

Background: Neuroblastoma is the most common extra-cranial solid tumor in children. Intensive therapy including autologous stem-cell transplantation (HSCT) has improved the poor prognosis of high-risk neuroblastoma (HR-NBL) but may impair gonadal function. Objectives: To investigate the gonadal function and fertility in long-term survivors of childhood HR-NBL. Design: A cohort including all Finnish (n = 20; 11 females) long-term (>10 years) survivors of HR-NBL and an age- and sex-matched control group (n = 20) was examined at a median age of 22 (16-30) years. Oncologic treatments, pubertal timing, hormonal therapies and the number of off-spring were recorded, and pituitary and gonadal hormones were measured. Results: Altogether 16/20 of the long-term survivors of HR-NBL entered puberty spontaneously; puberty was hormonally induced in four survivors (three females). Among the 8/11 female survivors with spontaneous puberty, seven had spontaneous menarche, but 5/8 developed ovarian failure soon after puberty. Nine females currently needed estrogen substitution. AMH, a marker of ovarian reserve, was lower in the female survivors than controls (median 0.02 vs. 1.7 µg/l, p < 0.001). As a group, male survivors had smaller testicular size (8.5 vs. 39 ml, p < 0.001) and lower inhibin B (<10 vs. 170 ng/l, p < 0.001) compared with control males, with altogether 6/9 survivor males fulfilling the criteria of gonadal failure (absent puberty, small testicle size or increased FSH with need of testosterone substitution). Gonadal failure was more common in female and male survivors treated with total-body irradiation. Three survivors (one male) had offspring, all treated without total-body irradiation and moderate dose of alkylating chemotherapy. Growth velocity was compromised in all survivors after HR-NBL diagnosis, with absent pubertal growth spurt in 7/17 survivors with complete growth data. Conclusion: Gonadal failure is common in long-term survivors of HR-NBL treated with HSCT. Fertility may be preserved in some survivors treated without total-body irradiation.

Telomere length regulators are activated in young men after pediatric kidney transplantation compared to healthy controls and survivors of childhood cancer-A cross-sectional study.

Chronic diseases are known to cause premature aging and frailty. Data about telomere length and telomere length-regulating proteins after pediatric KTx are scarce. Leukocyte telomere length and gene expression level of eight telomere-binding proteins were analyzed in 20 KTx recipients, eight childhood NBL survivors, and nine healthy controls. The influence of key clinical parameters on telomere length and on regulators of telomere length was evaluated. The telomere length in the KTx recipients tended to be shorter (0.53 AU) than in the healthy controls (0.64 AU) but longer than in the NBL survivors (0.38 AU). There was no significant difference in telomere length between the NBL survivors and the KTx recipients (P = .110). The gene expression level of telomere length-preserving protein RPA1 was significantly higher in the KTx recipients than among the NBL survivors or healthy controls, while the expression of TRF2 and the tumor suppressor gene p16 was significantly higher in the KTX recipients when compared to the controls. TRF2 and TIN2 correlated significantly with hsCRP; additionally, TRF2 showed significant correlation with plasma creatinine and eGFR. KTx recipients have near to normal telomere length, but they have significantly higher gene expression levels of telomere regulatory proteins compared with healthy controls, suggesting activation of mechanisms preserving telomere length among KTx recipients. Our results suggest that declined graft function and consequent inflammatory response may have influence on telomerase activity.