Final height of patients who underwent bone marrow transplantation during childhood.

OBJECTIVE: To determine the impact on final adult height of bone marrow transplantation. METHODS: The final height of 28 long term survivors (18 males; 10 females), allografted before or at the onset of puberty, at a median age of 10.8 years (range 6.3 to 14.6) and who did not receive growth hormone (GH) treatment or other growth promoting agents, was evaluated. Median follow up period after bone marrow transplantation was 7.9 years (range 3.2 to 11.4), and age at the most recent evaluation 18.1 years (range 15.6 to 24.5). Height values were expressed in standard deviation score (SDS) from the mean of the normal population. Height at bone marrow transplantation was compared with final height as well as with parental genetic height. Patients were divided into three groups: severe aplastic anaemia (SAA): three patients given no radiotherapy; leukaemia-total body irradiation (TBI): 14 patients with acute or chronic leukaemia conditioned with chemotherapy and TBI; leukaemia-TBI with previous cranial radiation therapy (CRT): 11 patients. None of the patients had solid tumour. RESULTS: There was a decrease in final height SDS compared to pre-transplantation height SDS (paired t test, p < 0.0001). All patients except one reached an adult height above -2.0 SDS. A significant decrease in height SDS was found in the TBI and the CRT groups (paired t test, p = 0.02 and p = 0.0002, respectively). Whereas height SDS value at the time of transplant was higher than the genetic height SDS, final height SDS values were lower. CONCLUSIONS: Despite the decrease in height SDS found after bone marrow transplantation, 27 of the 28 patients spontaneously achieved what is considered to be a normal height SDS (above -2.0 SDS). This should be taken into account when considering GH treatment in children who underwent bone marrow transplantation for malignant haematological diseases.     

Final height and puberty in 40 patients after antileukaemic treatment during childhood

Endocrine dysfunction and damage of the epiphysial growth plates have been reported as late effects of antileukaemic treatment during childhood. It is a common opinion that cranial irradiation (CI) is the most important factor for blunted growth. Accordingly, recent therapeutic strategies in acute lymphoblastic leukaemia (ALL) avoid cranial irradiation. Here we analysed longitudinal data on growth and puberty of 54 children in first complete remission, who were treated with 18 Gy CI or not submitted to radiotherapy. Two chemotherapeutic protocols were compared which were similar during the induction period but differed in the intensity of maintenance therapy. In cranial irradiated patients both in males and females the pubertal growth spurt started at a mean age of 1.2 years (SD: 0.93 years) earlier than controls. Age at diagnosis and age at pubertal growth spurt were significantly correlated (r = 0.35, P = 0.017). Similarly, menarche occurred at a mean age (n = 22) of 12.1 years and was correlated with the age at start of therapy in girls who were treated with 18 Gy CI (r = 0.61, P = 0.01). Adult height was reached spontaneously in 30 patients treated during prepubertal age and in 10 treated shortly before or during puberty. In all prepubertal patients treated for 2–3 years with intensive maintenance therapy blunted growth resulted in a significant loss of −1.85 H-SDS (median, P = 0.0051) compared to height at diagnosis. However, if continuation treatment used only methotrexate and 6-mercaptopurine (i.e. BFM protocol) final height equalled projected adult height, despite 18 Gy CI. Conclusions (1) multiagent chemotherapy is of major impact for growth and puberty; (2) 18 Gy cranial irradiation is below the critical dosage responsible for blunted growth; (3) loss in potential growth might be prevented by current CT strategies; (4) onset of puberty depends on age when antileukaemic therapy is applied. Received: 22 April 1996 / Accepted: 24 September 1996     

儿童肝移植术后的随访与治疗

目的评估复旦大学附属儿科医院肝移植患儿术后疗效。方法回顾性分析2002年10月至2005年5月期间8例小儿肝移植术后的临床效果和生活质量。本组男4例,女4例,肝移植年龄4—67个月,体重6—19kg。6例亲体活体肝移植,1例劈裂式肝移植,1例减体积肝移植。结果围手术期死亡1例,手术存活率87、5％;手术成功患儿中1例于术后8个月死于消化道出血,1年生存率为75．O％,其他6例存活至今,最长生存期43个月。术后并发症：急性排斥反应2例;远期感染：巨细胞病毒感染2例,Epstein—Barr病毒感染1例,乙型肝炎病毒感染1例;低蛋白血症3例。远期外科并发症：门静脉血栓1例,下腔静脉和肝静脉狭窄1例。他克莫司（FK506）的副作用：高血压3例,肾脏损害1例,肝脏损害1例,腹泻1例。所有存活患儿无心理异常;1例术前体格发育落后者,术后发生了生长追赶。结论肝移植改善了小儿终末期肝病的预后。儿童肝移植后并发症多见。周密的术后随访与管理有助于发现各种内外科并发症和保证术后生活质量。     

Infections after bone marrow transplantation in childhood]

In 66 children having undergone bone marrow transplantation (BMT) the occurrence of infections was studied retrospectively. Bacterial infections were mostly found in the early period after transplantation before marrow engraftment. The analysis of positive blood cultures showed a dominance of gram-positive bacteria, especially of coagulase-negative staphylococci. Cytomegalovirus (CMV) infections were most important, because of its high rate and the risk of CMV associated interstitial pneumonia (IP), two patients suffered from. Infections from herpes simplex virus (HSV), varizella zoster virus (VZV) and Epstein Barr virus (EBV) had no influence on prognosis. In fungal infections the systemic aspergillosis was the most important complication. To increase the effectiveness and safety of therapy the serum levels of antibiotics and antifungal drugs should be determined.     

Longitudinal gonadal function after bone marrow transplantation for acute lymphoblastic leukemia during childhood

Total body irradiation and high-dose chemotherapy, applied as a preparatory regimen for bone marrow transplantation (BMT) in children with acute lymphoblastic leukemia (ALL), are particularly hazardous to the gonads and, in addition, can impair hypothalamo pituitary-gonadal control. Longitudinal data on pubertal development and gonadal function in these patients are limited. Twenty-one ALL patients (15 males, 6 females) who had successfully undergone allogeneic BMT before puberty (age at BMT: 3.4-12.3 yr) were followed up in University Children's Hospital, Tübingen, Germany over 2 (minimum) to 14 (maximum) years. Tanner development scores, serum testosterone and estradiol, basal follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were analyzed. During pubertal age, the levels of FSH and LH rose consecutively, resulting in noticeably elevated serum concentrations in 100% and 89%, respectively, of boys older than 14 years and in 75% and 75%, respectively, of girls older than 13 years. Nevertheless, pubertal development has been normal in all patients except in one boy and two girls who required substitution with sexual steroids, as timely puberty (i.e. boys < 14 years, girls < 13 years) did not start. In males with normal puberty, testosterone levels, however, were found to be low-normal. In conclusion, after BMT preceded by total body irradiation for childhood ALL, gonadal function is impaired. Even if normal pubertal development occurs, deficiencies in long-term endocrine function cannot be ruled out. In view of the high FSH levels, the prognosis for fertility is doubtful.     

Assessment of nephrotoxicity of high-cumulative dose of liposomal amphotericin B in a pediatric patient who underwent allogeneic bone marrow transplantation

We describe a 9-yr-old boy who received the highest cumulative dose so far reported of liposomal amphotericin B.The patient underwent an allogeneic bone marrow transplantation (BMT) for adrenoleucodystrophy, after a conditioning regimen with busulfan, thiothepa and cyclophosphamide. Rabbit antithymoglobulin, cyclosporin and prednisone were used as prophylaxis against graft vs. host disease (GVHD). Post-transplant Epstein-Bar-virus-related lymphoma was diagnosed on day +68 and was treated with donor-derived lymphocytes. The patient developed a severe form of GVHD, and a progressive worsening of his neurological status because of progression of his underlying disease. Death from septic shock occurred 23 months after BMT. During prolonged hospitalization, 19,750 mg of liposomal amphotericin B, about 1000 mg/kg, were given for prophylactic or empirical therapeutic purposes without significant nephrotoxicity. This case suggests that liposomal amphotericin B is safe and well-tolerated even if is administered for long periods and a cumulative dose fivefold greater than the nephrotoxic threshold of amphotericin B deoxycholate is achieved.     

Chemotherapy versus bone marrow transplantation in childhood acute lymphoblastic leukaemia

Twenty-five years ago over 90% of children with acute lymphoblastic leukaemia (ALL) died of this disease. Dramatic improvement has been achieved since then by employing risk-adapted, aggressive polychemotherapy protocols. More than 90% of children with ALL treated according to, for example BFM-protocols, have nowadays cure rates in the range of 70%–80%. However, 10% of patients do not initially respond adequately to standard induction chemotherapy. They are characterized by distinct chromosomal abnormalities such as translocation (9; 22) or combinations of early treatment failure and other risk factors as cytogenetic abnormalities, lineage-specific surface markers or tumour load at diagnosis. In this group of patients in first complete remission and certainly in the vast majority of relapsed patients, allogeneic bone marrow transplantation (BMT) has evolved as an alternative approach allowing further intensification of myeloablation and the introduction of an additional antileukaemic alloreactivity. Nevertheless, the decision for a marrow transplant in children has to be made very carefully because of a significant increase in treatment related mortality and BMT-specific risks like acute and chronic graft-versus-host disease with a critical iatrogenic chronic morbidity. This is even more evident, if mismatched or unrelated transplants are being considered. The indications for one or the other treatment modality according to the current BFM strategy are discussed.     

非亲缘异基因骨髓移植治疗儿童白血病

目的　评价非亲缘异基因骨髓移植 (URD BMT)治疗儿童急性和慢性白血病的临床疗效。方法　 6例白血病患儿 ,其中慢性髓系白血病 2例 ,急性淋巴细胞白血病 3例 (第 1次完全缓解 ) ,急性早幼粒细胞白血病 1例 (第 2次完全缓解 ) ,由台湾慈济骨髓捐赠中心提供无关供者骨髓。预处理方案为马利兰 环磷酰胺 (Bu/Cy2 )方案 ,急性移植物抗宿主病 (aGVHD)预防为霉酚酸酯(MMF)、环孢菌素A(CsA)加氨甲喋呤 (MTX)联合方案 ;以前列素E1预防肝静脉闭塞病 (VOD) ,以巨细胞病毒 (CMV)抗原血症监测和更昔洛韦预防CMV病。供、受者间HLA基因位点型全相合 3例 ,1个基因位点型不合 2例 ,2个基因位点型不合 1例。结果　 6例患儿经DNA短串联重复序列多态性分析证明为供髓植入 ,中性粒细胞 >0 5× 10 9/L的中位天数为 14 5 (13～ 18)d ,血小板 >2 0×10 9/L的中位天数为 16 (11～ 2 3)d。发生Ⅱ～Ⅳ度aGVHD 2例 (33% ) ,局限性慢性移植物抗宿主病(cGVHD) 3例 ,未发生广泛性cGVHD。中位随访时间 4 12 (187～ 1338)d ,全部患儿均无病生存。结论非亲缘异基因骨髓移植是治疗儿童急性和慢性白血病的有效方法。     

Renal function after conditioning therapy for bone marrow transplantation in childhood

The knowledge of renal function in the course of BMT is poor. We prospectively investigated glomerular and tubular function in 42 children who underwent BMT because of malignancy. Seventeen children were transplanted autologously. Investigations were performed before and immediately after the conditioning regimen. Inulin- and creatinine clearance, albuminuria, urine excretion of α₁-microglobulin, β-N-acetylglucosaminidase, alanine-aminopeptidase, intestinal alkaline phosphatase, and Tamm-Horsfall-Protein as well as sodium-and phosphatreabsorption were measured. The patients were classified regarding use of total body irradiation (fTBI) in the conditioning regimen. Before CR: Glomerular filtration rate (GFR) was not influenced by the underlying diagnosis of previous treatment. Mean GFR was elevated compared with the reference group. Microalbuminuria was elevated in 15% of patients, and mean levels were higher than in the reference group. Proximal tubular dysfunction was indicated by an elevated excretion of α₁-MG in 54% of β-NAG in 66%, of AAP in 40%, and of IAP in 47%. Fractional sodium excretion was abnormal in 21%, phosphate reabsorption in 5% and THP-excretion in 7% of the patients. After CR: Creatinine clearance was not affected by CR. After CR α₁-MG, β-NAG, FE_Na, AAP, and IAP were increased compared with values before CR. TP/Cl_α was decreased. Excretion of THP was not altered by CR. In patients without fTBI there was a greater increase in α₁-MG excretion and decrease in phosphate reabsorption after CR compared with patients conditioned with fTBI. We conclude that significant proximal tubular dysfunction is present in about 50–60% of patients before and in nearly all after CR. Distal tubular function was less severely affected. Severity of nephrotoxicity after CR did not correlate with pre-existing abnormalities. Med. Pediatr. Oncol. 28:274–283. © 1997 Wiley-Liss, Inc.     

Sensory-motor and cognitive functioning in children who have undergone bone marrow transplantation

Sensory-motor and cognitive functioning was investigated in a group of 32 children treated with bone marrow transplantation (BMT), 1-6 years after treatment. Twenty-five of the patients had suffered from leukemia. The BMT procedure had involved a regimen of cytostatic drugs and, for leukemia patients, total body irradiation at a dose of 10 Gy, administered in one session. Cytostatic drugs and irradiation are known to be potentially neurotoxic, particularly when combined. The examination involved four neuropsychological tests of sensory-motor and cognitive functioning, as well as an age-appropriate intelligence test. For control the bone marrow donors (n = 32), siblings of the patients, were also investigated. A pronounced delay in motor development was found in four children, who had been treated with BMT including total body irradiation before 3 years of age. Patients between 3 and 11 years of age at BMT were at a slight disadvantage, compared to donors, on tasks involving perceptual and fine motor speed. In older patients no deficits were observed.     

单倍体骨髓移植治疗儿童难治复发性白血病

目的探讨供者应用粒细胞集落刺激因子(G-CSF)和受者联合应用多种免疫抑制剂单倍体骨髓移植治疗儿童难治复发性白血病的可行性.方法8例难治复发性儿童白血病患儿中,高危急性非淋巴白血病1例,急性淋巴白血病第2次完全缓解(CR2)及以上的病例6例,慢性粒细胞白血病加速期1例,在清髓性预处理后接受单倍体供者的骨髓.供者应用G-CSF250μg,连用7d后采髓,受者移植物抗宿主病(GVHD)的预防除环孢菌素A(CSA)和氨甲蝶呤(MTX)外,在-4至-1d(移植前为"-”)应用抗胸腺细胞球蛋白(ATG)5mg/(kg*d),+7d(移植后为"+”)开始加服霉酚酸酯(MMF).结果8例患儿均植入成功,中性粒细胞大于0.5×109/L和血小板大于20×109/L的中位天数分别是18d(范围16～21d)和19.5d(范围17～27d).急性Ⅱ°～Ⅳ°GVHD发生4例(50%),其中2例急性Ⅱ度肠道GVHD,2例急性Ⅲ度肠道GVHD,可评价的5例患儿均发生慢性GVHD,无一例发生广泛性慢性GVHD.中位随访时间是510d(范围390～720d),死亡3例,其中死于急性GVHD2例,死于感染1例.无病存活5例.结论单倍体骨髓移植治疗儿童难治复发性白血病是一种有效和安全方法,对我国单亲家庭拓宽供髓来源有重要的实用价值.     

Pulmonary function in patients undergoing bone marrow transplantation

Pulmonary function was studied prospectively in 25 children with leukemia and aplastic anemia undergoing bone marrow transplantation (BMT). Whereas 11 patients have died, only one did so primarily due to interstitial pneumonia. Fourteen patients (56%) survived a median of at least 36 months. Seventeen patients received pulmonary function tests (PFTs). Four patients transplanted for leukemia in relapse following preparation with a very intensive regimen (cyclophosphamide, 200 mg/kg, total body irradiation, 1,000 rad, BCNU, cytosine arabinoside) developed restrictive lung changes. Patients undergoing BMT for aplastic anemia and leukemia in remission prepared with more commonly used and less intensive regimens maintained normal pulmonary function. As new regimens are devised, PFTs should be utilized to characterize the pulmonary toxicity of these regimens as well.     

Evans syndrome after unrelated bone marrow transplantation for refractory cytopenia of childhood

Post‐transplant ES, which is often resistant to therapies, has seldom been described. This report describes a case of ES after UBMT for RCC. A five‐yr‐old boy developed RCC with no evidence of monosomy 7. Because no matching family donors were available for SCT and immunosuppressive therapy was ineffective, UBMT was performed when he was six yr old. The conditioning regimen included TAI (3 Gy) and administration of FLU, CY, and rabbit antithymocyte globulin. The recovery of blood cells was good. He displayed grade II acute GVHD involving only the skin. ES developed on day 66, with positive results for Epstein–Barr virus DNA and HHV 6. Cytopenia was resolved with treatment with RTX, GCV, an escalated dose of steroids, high‐dose gammaglobulin, and romiplostim. No relapse has occurred since discontinuing steroids on day 177 and romiplostim on day 268. Post‐SCT ES after UBMT is rare, and the risk factors and therapies are unclear. Prospective analysis and collection of cases from multiple centers are required for clarification.     

Long-term outcome in women who underwent anti-reflux surgery in childhood

BackgroundThe purpose of ureterocystoneostomy to correct vesicoureteral reflux is to thereby prevent recurrent febrile urinary tract infections (UTIs). The objective of this study was to determine the frequency of UTI in adult women who underwent reimplantation as children, with the emphasis on infections during pregnancy.Patients and methodsIncluded in the study were women over 20 years of age who underwent surgery for primary reflux between 1969 and 2004. A total of 392 patients were identified and information on their case history, surgery and follow-up was collected from the medical records. A questionnaire, requesting information on their present state of health, and occurrences of lower or upper UTI since the age of 16 and during any pregnancies, was sent to 337 of these patients.ResultsIn all, 242 (84%) of the questionnaires were returned. UTIs had occurred in 42% of the women before they had any sexual activity; thereafter the frequency increased to 61%. In 113 of the 282 women, 242 pregnancies were recorded. UTI occurred during 59 pregnancies (24%): 19% lower, 5% upper. Risk factors for UTI during pregnancy were infections as adults or decreased differential renal function (≤ 30%).ConclusionsThere is an ongoing risk of UTI in adult women after anti-reflux surgery in childhood. During pregnancy, these women represent a population at risk who should be observed very closely.     

Evaluation of coagulation in pediatric bone marrow transplantation patients

A hypercoagulable state is frequently described in adult patients undergoing bone marrow transplantation (BMT). In this study, the coagulation profile of 29 children was prospectively investigated in the pre- and post-transplant period. A significant rise in the activated partial thromboplastin time (aPTT) values was detected on days 7 and 14 after transplantation. Moreover, an increase in the d-dimer level was also notable, regardless of the clinical condition of the patients. The other coagulation parameters investigated (i.e. protein S, protein C, anti-thrombin III, factor VIII, von Willebrand factor, and prothrombin time) remained essentially unchanged. However, hyper-fibrinogenemia was observed in all patients with chronic myeloid leukemia (CML) (n=5) before and after transplantation. In summary, in the present study pediatric bone marrow transplantation patients did not show a hyper-coagulable state after marrow infusion. However, a significant rise in PTT and d-dimer values were noted.     

Successful renal transplantation following prior bone marrow transplantation in pediatric patients

Improving survival rates following pediatric bone marrow transplantation (BMT) will likely result in greater numbers of children progressing to end-stage renal disease (ESRD) because of prior chemotherapy, irradiation, sepsis, and exposure to nephrotoxic agents. Renal transplantation remains the treatment of choice for ESRD; however, the safety of renal transplantation in this unique population is not well established. We report our experience with living related renal transplantation in three pediatric patients with ESRD following prior BMT. Two patients with neuroblastoma and ESRD because of BMT nephropathy, and one patient with Schimke immuno-osseous dysplasia and ESRD because of immune complex mediated glomerulonephritis and nephrotic syndrome. Age at time of BMT ranged from 2 to 7 yr. All patients had stable bone marrow function prior to renal transplantation. Age at renal transplant ranged from 8 to 14 yr. All three patients have been managed with conventional immunosuppression, as no patient received a kidney and BMT from the same donor source. These patients are currently 7 months to 6 yr status post-living related transplant. All have functioning bone marrow and kidney transplants, with serum creatinine levels ranging 0.6-1.2 mg/dL. There have been no episodes of rejection. One patient with a history of grade III skin and grade IV gastrointestinal-graft-vs.-host disease (GI-GVHD) prior to transplantation, had a mild flare of GI-GVHD (grade I) post-renal transplant and is currently asymptomatic. The incidence of opportunistic infection has been comparable with our pediatric renal transplant population without prior BMT. One patient was treated for basal cell carcinoma via wide local excision. Renal transplantation is an excellent option for the treatment of pediatric patients with ESRD following BMT. Short-term results in this small population show promising patient and graft survival, however long-term follow-up is needed. Pre-existing immune system impairment and bone marrow function should be taken into consideration when weighing different immunosuppressive agents for renal transplantation. Patients who have undergone renal transplantation following BMT are at high risk for opportunistic infections and malignancy, and need life-long medical surveillance.