Disease of the liver following bone marrow transplantation in children: incidence, clinical course and outcome in a long-term perspective

Sixty-four consecutive cases of allogeneic ( n = 16), autologous ( n = 47) or syngeneic ( n = 1) bone marrow transplantation (BMT) in children with haematological or lymphoid malignancy, aplasia or metabolic disease were reviewed to assess the incidence, clinical presentation and outcome of liver disease. Median follow-up time was 5 y (1.0-10). No liver diagnosis was established at the pre-transplant check-up. During the first 100d post-transplant, 81% of the patients had impaired liver function as documented by various biochemical parameters. Three of 64 patients (5%) met diagnostic criteria for veno-occlusive disease. Four (25%) of the 16 receiving allografts were diagnosed as having acute graft vs host disease (GVHD) with liver involvement (grades II-III). No patient died of liver disease. During the late post-transplant follow-up, one patient developed HCV hepatitis after packed erythrocyte transfusion. Four patients were diagnosed as having chronic GVHD with liver involvement; three of them also had an episode of CMV hepatitis. At their latest follow-up, the patients with chronic GVHD had aminotransferase values 1.5–3 times the normal, whereas all other long-term survivors had normal or near-normal liver function tests. We conclude that the incidence of serious liver disease was low in this paediatric population of bone marrow recipients.     

Unrelated umbilical cord blood transplantation and unrelated bone marrow transplantation in children with hematological disease: A meta-analysis

Abstract:  UCB has been used as an alternative source of HSC. Both unrelated donor BM and UCB are available as potential options for transplantation. However, there have been limited comparisons of the outcomes of unrelated donor UCBT vs. UBMT in the unrelated setting. Our aim is to observe the therapeutic efficacy of UCBT and UBMT for treatment of pediatric hematological diseases. We electronically searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and critically appraised all relevant articles (1989.1–2008.5). Comparative studies were carried out on clinical therapeutic effect of UCBT and UBMT with research on stem cells engraftment, complications, earlier mortality, and survival rate. We performed a meta-analysis using review manager 5.0 software (RevMan, The Nordic Cochrane Center, The Cochrane Collaboration) and adopted funnel plot regression to assess the publication bias. We obtained 324 records. Seven trials totaling 1453 patients have been assessed. Pooled comparisons of studies of UCBT and UBMT in children found that the incidence of engraftment failure and earlier transplantation-related mortality were higher with UCBT because of its delay of hematological recovery [OR = 4.96, 95% CI (3.25, 7.59), p < 0.00001 and OR = 2.36, 95% CI (1.79, 3.11), p < 0.00001 respectively], but CMV infection didn't increase obviously. There was no difference in long disease-free survival rate [OR = 0.85, 95% CI (0.65, 1.01), p = 0.06] between UCBT and UBMT due to the decrease of GVHD in UCBT [OR = 0.45, 95% CI (0.34, 0.60), p < 0.0001]. Our meta-analysis confirmed that UCBT in children is also an effective way to treat children with hematological disease and has equivalent survival outcomes compared with UBMT.     

Risk factors for low bone mineral density in children and young adults with Crohn's disease.

OBJECTIVE: Low bone mineral density (BMD) is a recognized complication of Crohn's disease (CD). The aim of this study was to identify the risk factors for low BMD in pediatric patients with CD. STUDY DESIGN: One hundred nineteen subjects with CD ranging in age from 5 to 25 years were enrolled. BMD of the lumbar spine was measured by dual-energy x-ray absorptiometry. Growth parameters were assessed by examination. Disease-specific variables and use of selected medications were determined by chart review. RESULTS: Powerful risk factors for low BMD z-score included hypoalbuminemia, exposure to nasogastric tube feeds, total parenteral nutrition, 6-mercaptopurine, and corticosteroids. Corticosteroid dosing at a level >7.5 mg/d, 5000 mg lifetime cumulative dose, or >12 months of lifetime exposure were significant risk factors for low BMD z-score. Weaker but significant associations with low BMD z-scores included measures of disease severity such as pediatric Crohn's disease activity index, hospital admissions, and length of hospital stay. Site and duration of disease were not predictive. CONCLUSIONS: The presence of several clinically available factors was predictive of poor bone mineral status in this sample of subjects with CD. Hypoalbuminemia, corticosteroid exposure, nasogastric tube feeds, total parenteral nutrition, and 6-mercaptopurine were the most powerful risk factors for low bone mineral status.     

MR appearances of bone marrow in children following bone marrow transplantation

Two cases are presented of children who demonstrated complete absence of bone marrow signal on MR imaging of the spine following bone marrow transplantation. The possible causes for these appearances are discussed.     

Risk factors for coronary heart disease in children and young adults

This review covers two ongoing studies in Finland: the Cardiovascular Risk in Young Finns study, which started in 1978, and the Special Turku Coronary Risk Factor Intervention Project for Children (STRIP), which started in 1989. In the cross-sectional Cardiovascular Risk in Young Finns study, cardiovascular risk factors were first assessed in 1980 in 3596 children and adolescents covering ages between 3 and 18 y at 3-y intervals. The latest follow-up examination was performed in 2001, when risk factors and early markers of atherosclerosis in carotid and brachial arteries were examined in 2264 subjects from the original cohorts, now covering ages from 24 to 39 y. The results clearly show that an individual's coronary heart disease (CHD) risk factor profile is regulated by early lifestyle-related factors and that exposure to risk factors in childhood induces changes in arteries that contribute to the development of atherosclerosis in adulthood. In the STRIP study, 1062 infants were randomized into an intervention group (n = 540; low-saturated-fat, low-cholesterol diet) or a control group (n = 522) at 7 mo of age. Fat, saturated fat and cholesterol intakes have been lower, while the polyunsaturated to saturated fat ratio has been higher in the intervention children than in the control children throughout the ongoing trial. During the first 7 y of life, serum cholesterol concentration was 0.2-0.3 mmol/l lower in the intervention boys than in the control boys, but the difference was negligible in girls. Neurological development of the intervention children at age 5 y was at least as good as that of the control children. Counselling had no effect on children's growth.     

Plasma pharmacokinetics of high-dose oral busulfan in children and adults undergoing bone marrow transplantation

Abstract: We have analyzed the plasma pharmacokinetics of busulfan in 272 patients receiving high-dose oral busulfan and intravenous cyclophosphamide in conjunction with allogeneic or autologous bone marrow transplantation. The patients ranged in age from 2 months to 59 yr (mean 10, median 12 yr) and had the following diagnoses: thalassemia or sickle cell anemia (n = 74); leukemia or myelodysplasia (n = 112); inborn errors of metabolism (n = 41) or immunodeficiency (n = 45). Plasma specimens were collected following the first dose for each patient which ranged from 1 to 4 mg/kg (mean ± SD, 1.21 ± 0.41, median 1.15). Busulfan was quantitated using ultraviolet absorbance detection after derivatization and HPLC separation. Pharmacokinetic parameters were derived by modeling the raw data to fit first-order single compartment kinetics. The kinetic parameters showed wide interpatient variability independent of age and diagnosis. There was a statistically significant correlation of age with the following parameters: area under the curve (AUC); maximal concentration; minimum concentration; clearance; volume of distribution and absorption half-time. The coefficients of determination (i.e. correlation coefficient squared) were low ranging from 0.04 to 0.12 implying only a small part (i.e. 4–12%) of the variance was explained by age. Although busulfan pharmacokinetics are age-related most of the variability is not explained by age or diagnosis.     

Risk factors for coronary heart disease in children and young adults

This review covers two ongoing studies in Finland: the Cardiovascular Risk in Young Finns study, which started in 1978, and the Special Turku Coronary Risk Factor Intervention Project for Children (STRIP), which started in 1989. In the cross-sectional Cardiovascular Risk in Young Finns study, cardiovascular risk factors were first assessed in 1980 in 3596 children and adolescents covering ages between 3 and 18 y at 3-y intervals. The latest follow-up examination was performed in 2001, when risk factors and early markers of atherosclerosis in carotid and brachial arteries were examined in 2264 subjects from the original cohorts, now covering ages from 24 to 39 y. The results clearly show that an individual's coronary heart disease (CHD) risk factor profile is regulated by early lifestyle-related factors and that exposure to risk factors in childhood induces changes in arteries that contribute to the development of atherosclerosis in adulthood. In the STRIP study, 1062 infants were randomized into an intervention group ( n = 540; low-saturated-fat, low-cholesterol diet) or a control group ( n = 522) at 7 mo of age. Fat, saturated fat and cholesterol intakes have been lower, while the polyunsaturated to saturated fat ratio has been higher in the intervention children than in the control children throughout the ongoing trial. During the first 7 y of life, serum cholesterol concentration was 0.2–0.3 mmol/l lower in the intervention boys than in the control boys, but the difference was negligible in girls. Neurological development of the intervention children at age 5 y was at least as good as that of the control children. Counselling had no effect on children's growth.     

非血缘脐血及骨髓移植治疗儿童血液病的meta分析

目的 观察非血缘脐血移植(UCBT)和非血缘骨髓移植(UBMT)对儿童血液病的治疗效果.方法 计算机检索Cochrane、Medline、CNKI、CBM在1999-2007年期间发表的关于儿童脐血移植和非血缘骨髓移植的研究文献.从干细胞植入、移植并发症、早期死亡、生存率等方面对比分析了UCBT和UBMT的临床疗效.采用Review Manager 4.2软件进行meta分析,发表性偏倚采用倒漏斗图(funnel plot)显示.结果 检索出292篇文献,最终纳入6个试验共668例患儿.UCBT与UBMT相比,因植入延迟使植入失败率增高、早期移植相关死亡率增加,但巨细胞病毒(CMV)感染并未明显增加,而慢性移植物抗宿主病(GVHD)减少使两者的长期生存率相似.结论 儿童UCBT和UBMT移植后的长期生存率无明显区别,目前文献表明,UCBT也是儿童血液病的有效治疗方法.     

Gonadal function of young patients with beta-thalassemia following bone marrow transplantation

Bone marrow transplantation (BMT) can induce short- and long-term impairment of gonadal function. Patients with beta-thalassemia represent a special group, as their primary diagnosis and its treatment modalities are responsible for gonadal dysfunction. To address the effect of BMT on puberty and gonadal function, we investigated 25 patients (12 males) with thalassemia who received allogenic BMT during childhood or adolescence and at the post-transplant evaluation were at an age that the pubertal process should have started. Pubertal stage by Tanner of breast and pubic hair, as well as testicular volume were assessed pre-BMT once and post-BMT at least twice. Menstrual history was recorded. FSH, LH, testosterone and estradiol levels were also determined. The impact of BMT appears to be different in the two sexes. Males seem to have higher tolerance, as all males who were pubertal at the time of BMT had normal testosterone, and all but one normal gonadotropin levels. From those who were prepubertal at BMT, 62% proceeded to normal pubertal development. Post-menarcheal females seem to be an extremely sensitive group to the deleterious effect of the transplantation process, as 100% of the post-menarcheal females exhibited amenorrhea and elevated gonadotropin levels. These findings are important for pre- and post-BMT counseling.     

Bone marrow transplantation and cord blood transplantation in children

OBJECTIVE: To review the indications, main steps and complications of bone marrow transplantation in children. SOURCES: Medline-based literature review. SUMMARY OF THE FINDINGS: We comment about the indications of autologous, allogeneic and syngeneic bone marrow transplantation, donor selections, harvest and infusion of the hematopoietic progenitor cells that will reconstitute the hematopoietic and immune systems. We describe the different conditioning regimens and the new sources of cells, such as cord blood. We also describe the most common events after the procedure, including infections, graft versus host disease, and cardiovascular, pulmonary, hepatic, genitourinary, and gastrointestinal complications. The late effects and their impact on quality of life are also discussed. CONCLUSIONS: Bone marrow transplantation does not confer an absolutely normal life span to all the patients; however, it represents the only chance of cure for children with certain neoplastic or immunological diseases. By knowing the steps of the procedure, pediatricians can be a source of information on bone marrow transplantation to the patients and their families.     

Endocrine complications of bone marrow transplantation in children

Eighty-seven patients had a bone marrow transplantation (BMT) at our institution between 1980 and 1992. We wished to study the endocrine complications that accompany this procedure as long-term survival is now much more common. Forty-three patients were retrospectively available for review and their records were examined for evidence of thyroid, pubertal, and growth complications. Fifteen per cent of the patients showed evidence of thyroid involvement. Pubertal delay or gonadal damage was almost universal in pubertal-aged girls treated with busulfan/cyclophosphamide. Gonadal involvement was more frequent in girls than in boys (70% vs. 47%). Sixty per cent of children were shorter or grew at a slower rate. Sixty-five per cent of the children presented with one or more endocrine complications. These are the combined effects of different treatment regimens (chemotherapy, radiotherapy, combined therapy). It is essential to know the natural history of these patients in order to offer proper guidance and treatment as survival rates are increasing.     

Epidemiology of bone tumours in children and young adults

Although the epidemiology of malignant bone tumours in children and young adults has been explored, no definitive causation of any specific tumour has yet been identified. We performed a literature review (1970–2008) to find all papers covering possible aetiological factors involved in the development of bone tumours in children and young adults. Several associations have been reported with some consistency: the presence of hernias and Ewing sarcoma; high fluoride exposure and osteosarcoma; and parental farming and residence on a farm, younger age at puberty and family history of cancer for all bone tumours, especially osteosarcoma. Clearly further research is needed to confirm or refute these putative risk factors. It is likely that studies of gene–environment interactions may prove to be the most fruitful of future research. Pediatr Blood Cancer 2009;53:941–952. © 2009 Wiley‐Liss, Inc.     

骨髓间充质干细胞移植治疗小儿重度脑性瘫痪的疗效观察

目的观察自体骨髓间充质干细胞移植治疗重度脑性瘫痪儿童的临床疗效。方法对50例重症脑性瘫痪患儿进行骨髓间充质干细胞移植,移植前、后6个月进行自身对照,比较患儿粗大运动和综合功能的进步程度,并随访移植后0、1、3、6、12个月患儿一般情况。结果 50例患儿自体骨髓间充质干细胞培养均成功。移植后6个月失访1例,至12个月失访4例,余46例完成观察。移植后6例患儿在手术后3～5 d即出现显著临床改善,大部分患儿在移植后3个月左右运动能力进步,6个月之后进步幅度减缓。移植前6个月综合功能评估进步程度为(19.14±9.82)%,移植后6个月为(28.49±10.52)%,移植后进步显著大于移植前(P=0.001),其中以运动和认知改善明显。粗大运动功能评估总百分比从移植前的(23.80±10.64)%,上升到移植后(27.31±11.72)%,平均每月上升(1.05±0.49)%,显著大于移植前6个月进步幅度(P=0.001)。结论自体骨髓间充质干细胞移植对康复治疗效果不佳的重症脑瘫患儿有明显临床改善作用,能够有效促进患儿各功能区的发育。     

Hepatic dysfunction and cardiovascular abnormalities. Occurrence in infants, children, and young adults

In infants and children, the effect of heart failure and/or cyanotic heart disease on the liver has not been well documented, nor has there been any comparison between the degree of liver dysfunction and hemodynamic factors. Sixty-five patients with cardiovascular abnormalities were examined. Hepatic function, as indicated by laboratory data and histologic liver studies, was compared with the following categories of cardiovascular dysfunction: hypoxemia, systemic venous congestion, and low cardiac output. If any one of these factors was present, or any combination, abnormalities of liver function were usually noted. Patients with both hypoxemia and systemic venous congestion had marked hepatic dysfunction. Those with low cardiac output had the most severe abnormalities. Serial studies indicated that liver function correlated with cardiac status.