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1.
Metabolic syndrome as a late effect of childhood hematopoietic stem cell transplantation - A thorough statistical evaluation of putative risk factors
Gerbek, T., Thomsen, B. L., Muhic, E., Christiansen, T., Sørensen, K., Ifversen, M., Kofoed, K., Müller, K.
Pediatric transplantation. 2023;:e14530
Abstract
BACKGROUND Metabolic syndrome (MetS) is frequent among survivors of childhood hematopoietic stem-cell transplantation (HSCT), but assessment of risk factors is challenged by survivor and participation bias in long-term follow-up studies. METHODS A cohort of 395 pediatric patients transplanted between 1980 and 2018 was investigated. MetS was assessed at follow-up between December 2018 and March 2020. Two composite outcomes ((a) combining MetS and death, (b) combining MetS, death, and nonparticipation) were considered to address the risk of selection bias. RESULTS Among 234 survivors invited to the follow-up, 96 individuals (median age 27 years) participated. MetS prevalence was 30% among participants. The only significant HSCT risk factor was a variable combining HSCT indication and conditioning with total-body irradiation (TBI) (p = .0011). Compared to acute leukemias (AL) treated with high-grade TBI (8-12 Gy), a lower MetS prevalence was seen for nonmalignant diseases treated with no/low-grade TBI (0-4.5 Gy) (OR = 0.04, 95% confidence interval (CI): 0.00-0.23). Analyses of the composite outcomes indicated overestimation of the effect of high-grade TBI due to selection bias. Scrutiny showed strong residual confounding between HSCT indication and high-grade TBI within AL-patients. The HSCT effect on MetS reflected HSCT effects on high-density-lipoprotein (HDL) and triglycerides. Compared to AL treated with high-grade TBI, nonmalignant diagnoses treated with no/low-grade TBI had higher HDL (+40%, 95% CI: +21% to +62%) and lower triglyceride (-59%, 95% CI: -71% to -42%). CONCLUSION The TBI effect on MetS may be overestimated in follow-up studies due to selection bias and confounding. The TBI effect was confined to the potentially modifiable MetS criteria HDL and triglyceride.
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2.
Physical Fitness and Frailty in Males after Allogeneic Hematopoietic Stem Cell Transplantation in Childhood: A Long-Term Follow-Up Study
Suominen, A., Haavisto, A., Mathiesen, S., Mejdahl Nielsen, M., Lähteenmäki, P. M., Sørensen, K., Ifversen, M., Mølgaard, C., Juul, A., Müller, K., et al
Cancers. 2022;14(14)
Abstract
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.
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3.
Male gonadal function after pediatric hematopoietic stem cell transplantation: a systematic review
Mathiesen, S., Andrés-Jensen, L., Nielsen, M. M., Sørensen, K., Ifversen, M., Jahnukainen, K., Juul, A., Müller, K.
Transplantation and cellular therapy. 2022
Abstract
CONTEXT Male gonadal dysfunction is a frequent late effect following pediatric hematopoietic stem cell transplantation (HSCT) that can lead to disturbances in pubertal development, sexual dysfunction, and infertility. However, no systematic review exists regarding prevalence and risk factors in relation to different treatment regimens. AIM: To systematically evaluate the current evidence regarding the prevalence of male gonadal dysfunction after pediatric HSCT, related risk factors, and the diagnostic value of surrogate markers of spermatogenesis in this patient group. METHODS We searched PubMed and Embase using a combination of text words and subject terms. The eligibility screening was conducted using predefined criteria. Data were extracted corresponding to the Leydig cell compartment involved in testosterone production and the germ cell compartment involved in spermatogenesis, respectively. Subsequently, data synthesis was performed. RESULTS Of 2369 identified records, 25 studies were eligible. The studies were heterogeneous in terms of included diagnoses, gonadotoxic therapy, follow-up time, and definitions of gonadal dysfunction. The data synthesis revealed a preserved Leydig cell function in patients treated with non-total body irradiation (TBI) regimens, whereas the evidence regarding the impact of TBI conditioning on Leydig cell function was conflicting. Based on surrogate markers of spermatogenesis and only limited data on semen quality, the germ cell compartment was affected in half of the patients treated with non-TBI regimens and in nearly all patients treated with TBI conditioning. Testicular irradiation as part of front-line therapy prior to referral to HSCT led to complete Leydig cell failure and germ cell failure. Evidence regarding the impact of diagnosis, pubertal stage at HSCT, and chronic graft-versus-host disease is limited, as is the evidence of the diagnostic value of surrogate markers of spermatogenesis. CONCLUSIONS Testicular irradiation as part of front-line therapy and TBI conditioning are the main risk factors associated with male gonadal dysfunction after pediatric HSCT; however, impaired spermatogenesis is also observed in half of the patients treated with non-TBI regimens. Methodological shortcomings limit existing evidence, and future studies should include semen quality analyses, follow-up into late adulthood, and evaluation of the cumulative exposure to gonadotoxic therapy.
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4.
Childhood reproductive hormone levels after pediatric hematopoietic stem cell transplantation in relation to adult testicular function
Mathiesen, S., Sørensen, K., Ifversen, M., Hagen, C. P., Holm Petersen, J., Juul, A., Müller, K.
Endocrine connections. 2021;10(10):1352-1365
Abstract
OBJECTIVES Longitudinal assessment of testicular function after pediatric hematopoietic stem cell transplantation (HSCT) is needed to guide clinical follow-up. We investigated dynamics in male reproductive hormones after pediatric HSCT, focusing on pubertal timing and associations with testosterone deficiency and azoospermia in adulthood. METHODS This retrospective, longitudinal study included 39 survivors median 19 years after pediatric HSCT. Serum concentrations of LH, testosterone, FSH, and inhibin B from the time of HSCT, during puberty, and into adulthood were analyzed. Pubertal timing (rise in LH and testosterone) was compared to a reference cohort of 112 healthy boys. Associations between reproductive hormone levels during puberty and adult testicular function (including semen quality) were investigated. RESULTS Pubertal induction with testosterone was needed in 6/26 patients who were prepubertal at HSCT. In the remaining patients, pubertal timing was comparable to the reference cohort. However, 9/33 patients (without pubertal induction) developed testosterone deficiency in early adulthood, which was associated with higher LH levels from age 14 to 16 years. Azoospermia in adulthood was found in 18/26 patients without testosterone substitution. Higher FSH and lower inhibin B levels from mid-pubertal age were associated with azoospermia in adulthood, in patients being prepubertal at HSCT. CONCLUSION Our results indicate a substantial risk of deterioration in testicular function after pediatric HSCT, despite normal pubertal timing. Although reproductive hormone levels from mid-puberty indicated adult testicular function, prolonged follow-up into adulthood is needed in these patients, including clinical examination, reproductive hormone analysis, and semen sample for patients interested in their fertility potential.
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5.
Metabolic syndrome in male survivors of pediatric allogeneic hematopoietic stem cell transplantation: impact of total body irradiation, low-grade inflammation, and hypogonadism
Muhic, E., Mathiesen, S., Nielsen, M. M., Suominen, A., Sørensen, K., Ifversen, M., Nolsöe, R. L., Pedersen, K. M., Lähteenmäki, P., Nordestgaard, B. G., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Metabolic syndrome (MetS) is a growing concern in survivors of pediatric hematopoietic stem cell transplantation (HSCT), but little is known about the underlying mechanisms. OBJECTIVES To determine the prevalence and clinical presentation of MetS in male long-term survivors of pediatric HSCT and investigate predisposing factors including low-grade inflammation, altered fat distribution, and low testosterone levels. STUDY DESIGN We included 98 survivors aged 19-47 years at follow-up, median 18 (range 8-35) years after pediatric HSCT. MetS was defined according to the NCEP ATP III criteria. The prevalence and clinical manifestations of MetS were compared to a control group of males from the background population (n=4767). Fat distribution was assessed by android/gynoid (AG) ratio from a whole-body DXA scan. Systemic inflammation was evaluated by interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP). Serum testosterone levels were measured in morning samples. RESULTS The prevalence of MetS was 30%, corresponding to the prevalence in the 50-80-year-old males from the background population. In individuals with MetS, hyperglycemia was more frequent in the HSCT survivors compared to age-matched controls (76% vs. 20%, p<0.001), whereas hypertension was more dominant in the control group (69% vs. 93%, p=0.01). In addition, normal or reduced BMI was more commonly observed among HSCT survivors with MetS compared with age-matched controls (41% vs. 11%, p=0.002). MetS was associated with total body irradiation (TBI) compared to chemotherapy regimens (OR=4.3 95% CI [1.2-24.4], p=0.02); lower testosterone levels (OR=5.4 95% CI [1.3-23.6], p=0.02); higher levels of IL-6 (OR=1.8 95% CI [1.2-2.8], p=0.004) and hsCRP (OR=1.8 95% CI [1.3-2.6], p<0.001) (estimates per two-fold increase). In addition, an increased AG ratio was strongly associated with MetS (OR=2.1 95% CI [1.5-2.9], p<0.001), despite only 7% of patients fulfilled the criteria for increased abdominal circumference. CONCLUSION Our results indicate an increased risk of MetS in early adulthood after pediatric HSCT. The clinical manifestation differed from age-matched controls 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 cardio-metabolic risk-profile and stress the presence of important dissimilarities in the pathophysiology of MetS in HSCT survivors compared to the background population.
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6.
Male Sexual Function after Allogeneic Hematopoietic Stem Cell Transplantation in Childhood: A Multicenter Study
Haavisto, A., Mathiesen, S., Suominen, A., Lahteenmaki, P., Sorensen, K., Ifversen, M., Juul, A., Mejdahl Nielsen, M., Muller, K., Jahnukainen, K.
Cancers. 2020;12(7)
Abstract
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.
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7.
Male gonadal function after allogeneic hematopoietic stem cell transplantation in childhood: a cross-sectional, population-based study
Mathiesen, S., Sorensen, K., Nielsen, M. M., Suominen, A., Ifversen, M., Grell, K., Lahteenmaki, P., Frederiksen, H., Juul, A., Muller, K., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT), but detailed insights into patterns of male gonadal function at long-term is limited since studies have been retrospective without semen sample data. We investigated 1) the risk of azoospermia and testosterone deficiency, 2) the diagnostic value of markers of spermatogenesis, and 3) paternity at long-term follow-up after pediatric allogeneic HSCT. All surviving men ≥18 years of age transplanted in Denmark or Finland between 1980-2010 were invited to this cross-sectional study. Examinations included a semen sample, reproductive hormones, testicular volumes and screening for chronic graft-versus-host-disease (GvHD). Cumulative (pre-HSCT plus HSCT) treatment doses were calculated. Of 181 eligible patients, 98 participated median (range) 18 (8-35) years after HSCT. Sperm was found in 30 patients, azoospermia in 42, and azoospermia during testosterone substitution in 24 patients. 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%CI 1.14-1.46); p<0.001 and 1.21, 95%CI 1.11-1.38; p<0.001, respectively). All patients treated with >12 Gy had azoospermia and all but one treated with >16 Gy needed testosterone substitution. In patients treated with chemotherapy only (n=23), a higher cumulative cyclophosphamide equivalent dose was associated with increased the risk of azoospermia (OR per +1 g/m(2) 1.34, 95%CI 1.01-2.15; p=0.037). Pre-pubertal stage at HSCT was a risk factor for testosterone substitution (OR 15.31, 95%CI 2.39-315; p=0.017), while chronic GvHD was unrelated to gonadal dysfunction. Inhibin B was the best surrogate marker of azoospermia (area under the curve 0.91, 95%CI 0.85-0.98, 90% sensitivity and 83% specificity) compared to follicle-stimulating hormone and testicular volume. Of 24 males who had attempted to conceive, six 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 transplant. Our findings pinpoint the need of fertility preservation before HSCT as well as prolonged follow-up of pediatric HSCT patients into adulthood.
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8.
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
Mejdahl Nielsen, M., Mathiesen, S., Suominen, A., Sørensen, K., Ifversen, M., Mølgaard, C., Lähteenmäki, P. M., Juul, A., Jahnukainen, K., Müller, K.
Bone marrow transplantation. 2020
Abstract
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.
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9.
Lung clearance index for early detection of pulmonary complications after allo-HSCT in children
Uhlving, H. H., Skov, L., Buchvald, F., Heilmann, C., Grell, K., Ifversen, M., Green, K., Muller, K., Nielsen, K. G.
Pediatric pulmonology. 2019
Abstract
BACKGROUND Pulmonary chronic graft-vs-host disease (cGvHD) after hematopoietic stem cell transplantation (HSCT) is characterized by impairment of the small airways. Assessment of lung clearance index (LCI) gained from multiple breath washout (MBW) is more sensitive than spirometry in detection of small airways disease. The aim of this study was to describe the development of LCI during the first year after pediatric HSCT and how LCI relates to other pulmonary function parameters and cGvHD. METHODS This prospective, longitudinal study included 28 pediatric HSCT-recipients. Spirometry, Sulfur hexafluoride MBW and diffusion capacity of the lungs were performed before and at 3, 6, 9, and 12 months after HSCT. Respiratory symptoms and signs of cGvHD were recorded at each visit. RESULTS Before HSCT, 47.8% had abnormal LCI and 12.5% had abnormal forced expiratory volume in 1 second (FEV1 ). Patients with persisting respiratory symptoms 12 months post-HSCT had higher median LCI (factor 5.7, P = 0.0018) and lower FEV1 z-scores (-1.5, P = 0.033) post-HSCT compared to patients free of respiratory symptoms. Overall, post-HSCT LCI values were 3.49 times higher and FEV1 was 2.31 z-scores lower in eight patients with cGvHD in any organ system compared with patients without cGvHD (P = 0.0089 and P < 0.0001). LCI values during the first 3 months were not predictive of pulmonary cGvHD. CONCLUSION LCI is a sensitive marker for cGvHD and high LCI values were associated with persisting respiratory symptoms after 1 year. Further evaluation of MBW in early detection of HSCT-related pulmonary complications require larger patient cohorts and closer follow-up during the first months after HSCT.
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10.
Solid organ transplantation after haematopoietic stem cell transplantation in childhood: a multicentric retrospective survey
Faraci, M., Bertaina, A., Dalissier, A., Ifversen, M., Schulz, A., Gennery, A., Burkhardt, B., Badell Serra, I., Diaz-de-Heredia, C., Lanino, E., et al
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2018
Abstract
We report data obtained from a retrospective multicenter pediatric survey on behalf of the European Society for Blood and Marrow Transplantation (EBMT). Information on Solid Organ Transplantation (SOT) performed in pediatric recipients of either autologous or allogeneic hematopoietic stem cell transplantation (HSCT) between 1984 and 2016 were collected in 20 pediatric EBMT Centers (25.6%). Overall, we evaluated data on 44 SOTs following HSCT including 20 liver (LTx), 12 lung (LuTx), 6 heart (HTx), and 6 kidney (KTx) transplantations. The indication for SOT was organ failure related to intractable Graft-versus-Host Disease in 16 children (36.3%), acute or chronic HSCT-related toxicity in 18 (40.9%) and organ dysfunction related to the underlying disease in 10 (22.8%). The median follow-up was 10.9 years (95% CI: 1.7-29.5). The overall survival (OS) rate at 1 and 5 years after SOT was 85.7% and 80.4%, respectively: it was 74% and 63.2% after LTx, 83.2% after HTx, and 100% equally after LuTx and KTx. This multicenter survey confirms that SOT represents a promising option in children with severe organ failure occurred after HSCT. Additional studies are needed to further establish the effectiveness of SOT after HSCT and to better understand the mechanism underlying this encouraging success. This article is protected by copyright. All rights reserved.