Abstract 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.
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.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.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.
Abstract Background Central nervous system (CNS) tumors are the most common pediatric solid cancer type. Tissue biopsy is not always feasible for CNS tumors due to difficult location and high complication risk. Tissue biopsies also do not represent fully the heterogeneity of the tumor, which may lead to false negative or incomplete diagnosis. Platelets have been shown to interact with tumors by various mechanisms, including taking up nucleic acids. These interactions educate platelets causing changes in their gene expression leading to development of tumor educated platelets (TEPs). Consequently, these TEPs exhibit altered function and can promote tumor cell survival and metastasis. Previous studies have demonstrated that transcriptomic analysis of TEPs allows discrimination of false positive progression from actual progression in adult glioblastoma patients. In pediatric CNS tumors, TEPs have not been widely studied earlier. The aim of this study is to evaluate the potential of TEP transcriptomic analyses to distinguish the patients with CNS tumor from asymptomatic controls, and to predict tumor progression. Methods We studied eight pediatric CNS tumor patients (aged 0-18 years) including two high grade gliomas, five low grade gliomas, and one atypical teratoid rhabdoid tumor. Blood was drawn into EDTA tubes from pediatric tumor patients before the treatment initiation, and from pediatric controls without any history of tumors (n=8). Platelets were isolated from blood using double centrifugation and CD45+ leukocyte depletion. RNA was extracted from platelets and the RNA integrity and quantity was determined using Agilent 2100 Bioanalyzer. RNA sequencing (RNA-seq) libraries were constructed from 1ng of total RNA. Rsubread was used to assign RNA-seq reads to human reference genome EnsEMBL release 111 and NCBI nuclear rRNA gene models and to determine read counts per genes. Differential expression analysis was made using DESeq2 and pathway analysis was made using Enrichr. Results We observed differential expression of 42 genes (FDR<0.1), of which 27 were protein coding, in platelets from pediatric CNS tumor patients compared to controls. Out of the protein coding genes, 5 genes were down regulated, and 22 were upregulated. Pathway enrichment analysis demonstrated that various pathways were altered, such as pathways related to immune system and interleukin signaling (p<0.001) in TEPs collected from pediatric CNS tumor patients. Furthermore, our results suggested that gene expression signature of TEPs discriminated aggressive pediatric CNS malignancies from low grade tumors. Conclusions In this pilot study we demonstrated that pediatric CNS tumor patients have alterations in TEP transcriptome compared to pediatric controls. Our preliminary results are in line with previous studies of TEPs suggesting that the presence of tumor alters platelets´ gene expression. Moreover, gene expression analysis of TEPs may be utilized as a diagnostic approach for pediatric CNS malignancies, but more validation and larger cohorts are needed before clinical use. Citation Format: Markus Talka, Amanda Holmström, Satu Långström, Matti Kankainen, Mia Westerholm-Ormio, Anu M. Suominen, Pirjo Isohanni, Pia Valle, Atte Karppinen, Päivi Koroknay-Pal, Anna Piippo-Karjalainen, Nuutti Vartiainen, Olli Tynninen, Soili Kytölä, Anna-Kaisa Anttonen, Virve Penteikäinen, Katja Eloranta. Tumor educated platelets in detecting pediatric central nervous system tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A040.
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.
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.
Abstract 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 m 2 vs 111 ± 19 mL/min/1.73 m 2 , 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.
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.
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 yrs) 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 4 survivors (3 females). Among the 8/11 female survivors with spontaneous puberty, 7 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 (1 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.
