SAA, severe aplastic anaemia; Haem malignancy, haematological malignancy; cGVHD, chronic graft versus host disease; HDC, high-dose chemotherapy; TBI, total body irradiation; AUTO, autologous; ALLO, allogeneic; CRAB, cyclophosphamide, TBI, cytosine arabinoside, BCNU; PFT, pulmonary function tests; SD scores, standard deviation scores; TLCO, transfer factor for carbon monoxide; TLC, total lung capacity; FVC, forced vital capacity; FeV1, forced expiratory volume in 1 s; DLCO, diffusion capacity for carbon monoxide.
Non-endocrine late complications of bone marrow transplantation in childhood: part I
Article first published online: 3 JUL 2002
British Journal of Haematology
Volume 118, Issue 1, pages 3–22, July 2002
How to Cite
Leiper , A. D. (2002), Non-endocrine late complications of bone marrow transplantation in childhood: part I. British Journal of Haematology, 118: 3–22. doi: 10.1046/j.1365-2141.2002.03470.x
- Issue published online: 3 JUL 2002
- Article first published online: 3 JUL 2002
- bone marrow transplantation;
- late complications;
- total body irradiation
Current estimations indicate that greater than 30 000 allogeneic and autologous haematopoietic stem cell transplants (HSCT) are undertaken every year, worldwide, and that this figure is rapidly growing. Approximately one-fifth are performed in paediatric patients and it is estimated that a minimum of 1500–2000 of these annually will become long-term survivors (Boulad et al, 1998). Overall, autologous transplants, including those using peripheral blood stem cells, are commoner than allogeneic HSCT (Boulad et al, 1998; Horowitz, 1999), but in children the donor source is still mainly allogeneic marrow. This is confirmed by unpublished analysis of British paediatric data, taken from the United Kingdom Childrens' Cancer Study Group Registry between 1993 and September 2000. Out of the 2331 transplantation procedures performed, 1700 were allogeneic. The commonest indication for allogeneic transplantation in children is leukaemia, with 62% undergoing bone marrow transplantation (BMT) for this or myelodysplasia, 36% for non-malignant conditions and 2% for other cancers.
With increasing numbers of long-term survivors, delayed complications, often presenting years after BMT, are becoming a concern. Late sequelae may arise as a result of the disease for which transplantation was performed or from toxicity associated with the wide variety of conditioning regimens. Most of the latter will include high-dose chemotherapy, alone or accompanied by radiotherapy, in the form of total body irradiation (TBI) or total lymphoid irradiation (TLI) and/or agents to effect T-cell depletion. The total dose of TBI usually varies from 7·5 Gy given as a single fraction up to 15 Gy given in multiple fractions over a period of 3–4 d. Additional damage may be sustained through the toxic effects of some antibiotics and antifungals, or from immunosuppressive agents used for prevention and treatment of graft-versus-host disease (GVHD) or from the pathological process of chronic GVHD itself. Other potential variables influencing the impact of late sequelae are the total dose, dose rate and method of fractionation of the radiotherapy, the age and sex of the child, and genetic influences.
Particularly difficult to disentangle from sequelae related to the BMT procedure itself, but integral to the outcome, is the effect of previous treatment, especially in the case of malignant disease. This review would be incomplete without relevant discussion of some of these important aspects. As many of the childhood studies are very small and in themselves inconclusive, larger, mixed studies and some adult data have been included when I have felt it to be important to the evidence. Part I of this review describes cardiac, pulmonary, renal, neurological and neuropsychological late sequelae of bone marrow transplantation. The second part deals with ocular, audiological, dental, salivary and skeletal delayed complications, second malignant neoplasms, overall morbidity, late mortality and quality of life. The endocrine system is particularly vulnerable to damage by radiation and alkylating agents in the growing child (Leiper et al, 1987; Boulad et al, 1998; Cohen et al, 1999), but endocrinopathy will not be included here. Deeg, Sanders, Kolb and Bender-Gotze have reviewed late complications of BMT in adults and children, covering the early period of transplantation up to the end of the eighties (Sanders et al, 1989; Deeg, 1990; Kolb and Bender-Gotze, 1990; Sanders, 1990; Bender-Gotze, 1991). This review focuses mainly on paediatric literature published over the last decade.
- Top of page
- Neuropsychological sequelae
- Note added in proof
Survivors of childhood cancer represent one of the largest new groups at risk of premature cardiovascular disease (Lipshultz & Sallan, 1993). Many of the multimodal agents used in attempts to cure cancer are now shown to be cardiotoxic and, in the transplant setting, a constellation of adverse influences may injure the heart. These include electrolyte disturbance and sepsis (Parrillo, 1985; Martino et al, 1990), pre-existing iron overload in thalassaemia (Mariotti et al, 1993), radiation (Donaldson & Kaplan, 1982; Arsenian, 1991; Hancock et al, 1993; Jakacki et al, 1993), although less likely at lower doses of 15–26Gy (Donaldson & Kaplan, 1982; Hancock et al, 1993), and antineoplastic agents used both in the initial treatment of malignancy and in the conditioning regimen. For example, damage caused by anthracyclines in the conventional treatment of childhood leukaemias may manifest as acute or late cardiotoxicity (Lipshultz et al, 1991; Sorensen et al, 1997; Nysom et al, 1998a; Levitt, 1999), and acute toxicity from cyclophosphamide is reported in adults (Santos et al, 1970; Mills & Roberts, 1979; von-Bernuth et al, 1980; Braverman et al, 1991) and children following BMT (Steinherz et al, 1981; Shaw et al, 1986). Other commonly used chemotherapeutic drugs, especially the alkylating agents, are also cardiotoxic (Vaickus & Letendre, 1984; Bearman et al, 1990; Kanj et al, 1991; Pihkala et al, 1994) and the concomitant or sequential use of these, especially cyclophosphamide (Steinherz et al, 1981) or radiation (Billingham et al, 1977), may augment anthracycline damage. Thus, it becomes hard to separate the contribution to cardiotoxic injury by previous chemoradiotherapy from that posed by the BMT procedure itself.
Data regarding late cardiotoxicity in children after BMT is sparse, with no large studies (Uderzo et al, 1991; Larsenet al, 1992a; Liesner et al, 1994; Pihkala et al, 1994; Rovelli et al, 1995; Thuret et al, 1995; Eames et al, 1997; Leahey et al, 1999). Generally, late cardiotoxicity may present in a number of ways depending on the type and combination of cardiotoxic agent. These include clinically significant congestive cardiac failure, arrhythmias, fatal cardiomyopathy, pericardial and valvular disease, non-specific changes or reduced total QRS voltage on electrocardiogram (ECG), or asymptomatic reduction of left ventricular fractional shortening on echocardiography (ECHO) (Larsen et al, 1992b; Lipshultz & Sallan, 1993; Steinherz et al, 1995). The incidence is therefore is difficult to define, and most of the general overview studies of late sequelae after BMT in paediatric patients report sporadic cases of clinically significant cardiomyopathy, or small numbers of patients with abnormal left ventricular fractional shortening or reduced contractility on ECHO (Uderzo et al, 1991; Michel et al, 1997; Leahey et al, 1999). However, one study found no cardiac abnormalities in 13 patients with acute leukaemia transplanted in first remission (Thuret et al, 1995), while as many as 28% of a small number of BMT patients (8) with acute myeloid leukaemia (AML) and myelodysplasia, treated at Great Ormond Street Hospital for children, London, UK, had reduced fractional shortening on ECHO (Liesner et al, 1994). These children were included in a larger cohort of 83 patients transplanted for leukaemia since 1980 at our centre with minimum survival of 3 years (median 7·9 years; 3·5–16·9 years). Twenty-four out of 78 evaluated (31%) had abnormal fractional shortening (< 28%) post transplant. This had deteriorated in at least half the patients from pretransplant values and almost all had received TBI. Clinically significant cardiomyopathy with cardiac failure developed in 3·5%. At follow up, 13 patients had a shortening fraction of < 25% (unpublished data, Pitcher et al, 1998).
The Great Ormond Street Hospital long-term study of 33 patients with AML and myelodysplasia (8 BMT), and another of 52 (26 BMT) with the same diagnosis, carried out in Philadelphia, compare late sequelae after BMT with those of chemotherapy alone, with follow up between 1 and 15·5 years (Liesner et al, 1994; Leahey et al, 1999). The BMT preparative regimens differed in that the British patients mainly received TBI, while the majority of American children received busulphan (Bu) and cyclophosphamide (Cy). In the two studies, all but one patient underwent BMT in first remission and most patients had received anthracyclines, in both the BMT and chemotherapy groups. Mean anthracycline dosage was generally higher in those who were not transplanted.
Both studies reported that cardiac function in those undergoing BMT was no worse than with chemotherapy alone and, indeed, the mean shortening fractions in the comparison groups were within the normal range in both studies [although significantly reduced compared with normal subjects in Liesner et al (1994)]. However, the incidence of cardiac dysfunction was much higher in theLondon study with 28% of the BMT and 35% of the chemotherapy patients suffering an abnormal reduction in the shortening fraction (< 28%). This compared with 4% and 17% in the American study. Late cardiac failure occurred in two patients in each study 3–15 years later, none of whom had undergone marrow transplantation and all of whom had received high doses of anthracyclines. These findings suggest a role for pre-existing damage by anthracyclines, and some of the differences in incidence in the two studies could be partly explained by the added cardiotoxicity of TBI in Liesner's group, or possibly by differing methods of anthracycline administration. The incidence of an abnormal shortening fraction found by Leahey et al (1999) was comparable to that found by a French study of 45 similar patients transplanted in first remission using both types of conditioning chemotherapy (Michel et al, 1997), see also `note added in proof'.
Recently, the subclinical nature of some cardiac defects have been further explored in longer term studies in both adults and children, using more complex techniques, such as radionuclide angiography, cardiopulmonary exercise testing or dobutamine stress echocardiography, in addition to standard methods (Larsen et al, 1992a; Mariotti et al, 1993; Carlson et al, 1994; Pihkala et al, 1994; Eames et al, 1997).
In a cross-sectional study of 20 subjects studied prior to BMT and 31 others after BMT, cardiac performance was assessed during exercise, via cycle ergometry, and left ventricular size and fractional shortening, using resting echocardiography. Significant pulmonary limitations were excluded using spirometry. It was found that adults and children with oncological diagnoses had serious limitations in cardiac performance on exercise, after BMT (reduced exercise times, maximal oxygen consumption, anaerobic thresholds and cardiac output), although all had normal oxygen consumption and cardiac indices at rest, and few patients had ECHO abnormalities. However, impaired exercise performance was found even in those patients tested before BMT and there was no difference in this respect between patients studied before or after BMT, suggesting that previous conventional cancer therapy had contributed to cardiotoxicity (Larsen et al, 1992a).
Pihkala's group from Helsinki, Rovelli's Italian group and Eames' group from Minneapolis have reported the first studies dedicated to assessing cardiac or cardiopulmonary function in long-term childhood survivors of BMT (Pihkala et al, 1994; Rovelli et al, 1995; Eames et al, 1997). The vast majority of patients in these three studies had received cyclophosphamide, anthracyclines (median dose 140 mg/m2, 250 mg/m2 and 370 mg/m2 respectively) and two-thirds or more in each study had received TBI or total lymph irradiation (TLI). All 42 patients in the Italian study were asymptomatic and had normal fractional shortening on echocardiography, before and up to 4 years post BMT (Rovelli et al, 1995). Acute, mainly reversible, ECG changes were seen after conditioning chemotherapy in this and the Finnish study (Pihkala et al, 1994; Rovelli et al, 1995). Pihkala et al (1994) undertook a retrospective study in 30 children undergoing autologous and allogeneic BMT for malignant and non-malignant disorders. Myocardial function was evaluated by a series of post-BMT investigations including ECG, chest radiography, radionuclide cineangiography and detailed echocardiography. All patients in this study were asymptomatic at the time of follow up. Overall, 15–25% of patients had evidence of late subclinical cardiotoxicity at a median follow up of 4·8 years (0·5–10·7 years) and several patients had subnormal function on more than one test. Thirteen per cent of those transplanted had abnormal contractility on ECHO, 26% of those tested had reduced left ventricular ejection fraction (LVEF < 50%) on radionuclide angiography, in addition to 24% with persistence of acute ECG changes (> 15% reduction of QRS voltage sum on ECG), all of whom had abnormal left ventricular systolic function (Pihkala et al, 1994).
In an attempt to further determine cardiac function, long-term prevalence, severity and type of cardiac abnormality post BMT, and risk factors involved, Eames et al (1997) evaluated cardiac function cross-sectionally in 63 patients undergoing bone marrow transplantation at < 18 years of age. Evaluation consisted of review of past cardiac studies and assignation to a New York heart association (NYHA) class based on activity and cardiac symptoms, exercise and resting ECG, echocardiography, chest radiograph pulmonary function, and an exercise treadmill test, assessing a number of parameters of cardiopulmonary function.
Overall, 41·3% had cardiac abnormalities detected at mean follow up of 3·3 years (1–16·3 years), which had not been present in the majority in the pre-BMT assessment. More than two-thirds of these defects were subclinical. The cardiac abnormalities were reduced LVEF on echocardiography in four patients and abnormalities of the resting ECG in 10 (16·4%), despite all but one having a normal shortening fraction. Abnormalities of LVEF were less common, although the incidence of cardiac dysfunction was generally higher than the 15–25% found by Pihkala et al (1994). As in the other studies, the majority of patients were asymptomatic. However, the most significant finding in this study from Minneapolis was the high prevalence of abnormalities on the treadmill exercise test (74% of those tested) which had unmasked cardiac dysfunction. Only 13% of patients in the study were symptomatic, all with treadmill test impairment, but there were no cases of cardiac failure or life-threatening cardiomyopathy (Eames et al, 1997). This was similar to the exposure of cardiac dysfunction by exercise reported by Larsen et al (1992a).
As yet, there is no definite evidence in children that BMT worsens cardiac function. Our own unpublished data and that of some other authors suggest that it does (Pihkala et al, 1994; Eames et al, 1997), although Pihkala et al (1994) only had ECG data prior to BMT, while others do not (Larsen et al, 1992a, Rovelli et al, 1995).
The Minneapolis group found no correlation between cardiac dysfunction, previous therapy, type of BMT regimen or length of follow up. Neither was there a correlation with high-dose cyclophosphamide or TBI fractionation (Eames et al, 1997). TBI was not found to worsen outcome in this or other studies (Rovelli et al, 1995; Eames et al, 1997; Michel et al, 1997), and there was no difference between Bu/Cy and Cy/TBI in the French study (Michel et al, 1997), or between single fraction versus fractionated TBI (Pihkala et al, 1994; Eames et al, 1997). However, Pihkala's group felt that TBI played an important role as QRS changes occurred in all those who received it, and that myocardial changes seemed worse after cyclophosphamide than with high dose Ara-C (Pihkala et al, 1994).
Clearly, anthracyclines had an adverse influence on cardiac function in patients treated for AML and myelodysplastic syndrome (MDS) with either chemotherapy alone or BMT (Liesner et al, 1994; Leahey et al, 1999), and in previously treated patients with oncological diagnoses undergoing BMT (Larsen et al, 1992a). However, despite some adult studies suggesting an increased risk of cardiotoxicity post BMT with pretreatment with anthracyclines (Cazin et al, 1986; von Herbay et al, 1988) and a minor, but significant, change in shortening fraction after BMT in children who had received > 300 mg/m2 anthracyclines (Rovelli et al, 1995), few firm conclusions can be drawn about exacerbation of dysfunction by BMT.
In conclusion, late cardiac dysfunction found after BMT is multifactorial in origin. Factors which may increase the risk for its development include previous anthracycline usage, TBI, cyclophosphamide, as well as other cardiotoxic drugs, but there is a clear need for prospective, longitudinal studies with large numbers for further elucidation. Damage is often subclinical and may not be picked up by routine methods of investigation, but by using exercise testing and more invasive techniques, such as radionuclide angiography, the damage can be exposed. Although acute cardiotoxicity may improve at least in the short term, cardiac decompensation may occur many years after treatment has finished. Life-long surveillance is needed therefore to ascertain the significance of these subclinical defects.
- Top of page
- Neuropsychological sequelae
- Note added in proof
The prognosis for survival following BMT is generally good, although dependent on the indication for BMT and disease status at the time. Nonetheless, pulmonary complications remain a significant cause of mortality and morbidity following allogeneic BMT (Krowka et al, 1985; Soubani et al, 1996; Palmas et al, 1998) and account for 10–40% of transplant-related deaths (Krowka et al, 1985; Breuer et al, 1993, Palmas et al, 1998). Fungal and cytomegalovirus (CMV) are the major post-BMT pulmonary infections, whereas idiopathic interstitial pneumonitis, a restrictive disorder, and the obstructive disorder bronchiolitis obliterans are the major non-infectious complications in children (Stokes, 1994). Interstitial pneumonitis, renowned for its early development (< 100 d) in 10–20% of allogeneic transplant recipients, may also have a late onset (> 100 d) in a minority (Breuer et al, 1993; Soubani et al, 1996). All may potentially contribute to long-term sequelae.
Despite a profusion of literature reporting late-onset obstructive airways disease and restrictive pulmonary disease predominantly in adults reviewed by Soubani et al (1996) and Breuer et al (1993), there are comparatively few reports of late pulmonary dysfunction in children after allogeneic or autologous BMT (Table I). The incidence of chronic pulmonary symptoms in childhood is difficult to determine but approximately 10–20% of predominantly adult long-term survivors will develop symptoms associated with abnormal pulmonary function tests (Wyatt et al, 1984; Urbanski et al, 1987; Schwarer et al, 1992; Palmas et al, 1998). However, this cannot be directly extrapolated to children because of the growth potential of the lungs.
|Reference||Numbers evaluable||Type of study||Diagnosis||Groups compared when applicable||Type of BMT||Conditioning regimen||Age at BMT years* (range)||Follow-up years from BMT* (range)||Type of lung disease||% abnormal PFTs at follow up|
|Serota et al (1984)||17||Prospective||Leukaemia SAA||Leukaemia v SAA||ALLO||HDC + TBI HDC||11 (4–24) 14·5 (2·5–21)||3 (2·7–6·3)||Restrictive||Leukaemia: CRAB 100% Cyclo + TBI minimal SAA: minimal|
|Uderzo et al (1991)||35||Retrospective, longitudinal||Haem malignancy||–||ALLO & AUTO||HDC ± TBI||9·2 (1·75–18)||3·25 (1·2–9·5)||Restrictive Obstructive||40%|
|Kaplan et al (1992)||46||Retrospective, longitudinal||Haem malignancy SAA||cGVHD v no cGVHD||ALLO||HDC + TBI||(2·7–24·4)||Up to 7||Restrictive Obstructive||No difference between groups|
|Kaplan et al (1994)||46||Retrospective, longitudinal||Haem malignancy SAA||Lymphoma/ leukaemia v SAA||ALLO||HDC + TBI||11·7 mean (2·7–24·4)||Up to 7||Restrictive within leukaemic group||No difference between groups|
|Schultz et al (1994)||67||Retrospective||Various malignant and non-malignant conditions||Obstructive disease only||ALLO||None (2) HDC ± TBI||7·4||> 1·5||Obstructive||19·4%|
|Quigley et al (1994)||25||Retrospective, longitudinal||Neoplastic disease||–||ALLO & AUTO||HDC ± TBI||9 (4–15)||Up to 1·25||Restrictive Diffusion defect||Minimal. Most returned to baseline|
|Rovelli et al (1995)||28||Retrospective, longitudinal||Haem malignancy||–||ALLO & AUTO||HDC + TBI||9·5 (6–18)||> 2–4||Diffusion defect||Minimal. Most indices normal|
|Nysom et al (1996)||25||Population- based, long- itudinal, retrospective||Leukaemia lymphoma||BMT v 348 population controls||ALLO||Cyclo- phosphamide + TBI||11·3 (5·7–17·6)||8 (4–13)||Restrictive Diffusion defect||SD scores TLCO – 1·0 TLC – 1·2 FVC – 0·8 FeV1/FVC + 0·9|
|Fanfulla et al (1997)||27||Prospective longitudinal||Haem malignancy||–||ALLO & AUTO||HDC ± TBI||12||1·5||Restrictive Diffusion defect||57% at 1·5 years|
|Cerveri et al (1999)||52||Cross-sectional||Haem malignancy||–||ALLO & AUTO||HDC ± TBI||9 (mean) (2–17)||5 (mean) (3–11)||Restrictive Diffusion defect||38% (Restrictive: 23%, Isolated: diffusion defect) 15% (A)|
|Fulgoni et al (1999)||44 21(A) 23(B)||Cross-sectional||ALL||(A) BFM-type chemotherapy v (B) BMT and chemotherapy||ALLO & AUTO||(A) None (B) HDC + TBI||(1–15)||(A) 6(2–10) from end of therapy (B) 4(3–10)||Restrictive Diffusion defect||(A) 20% DLCO (B) 58% DLCO 9% FVC 9% FEV|
|Arvidson et al (1994)||27||Prospective longitudinal||Haem malignancy||–||AUTO||HDC + TBI v HDC||9·8 (1·9–17·8)||4·1 (1·1–7·6)||Restrictive Diffusion defect||100% DLCO|
|Nenadov Beck et al (1995)||32||Cross-sectional||Solid tumours||–||AUTO||HDC||6·9 (0·75–17)||7 (3–11·5)||Restrictive Diffusion defect||47%|
|Neve et al (1999)||18||Prospective longitudinal||Neuroblastoma Stage IV||Consolidation 1 block (II) v 2 blocks (1 + II)||AUTO||HDC + TBI||1·5–6·9||2– >4||Restrictive Diffusion defect Clinical disease 1 block 40% 2 blocks 100%||100% (66% symptomatic)|
The main characteristics of the paediatric BMT studies are shown in Table I. The small sample size and heterogeneity of study populations and treatments is almost certainly responsible for some of the conflicting data. During a follow-up period of 1–13 years, both long-term obstructive disease (Johnson et al, 1984; Uderzo et al, 1991; Kaplan et al, 1992; Schultz et al, 1994) and restrictive disease has been reported (Serota et al, 1984; Uderzo et al, 1991; Kaplan et al, 1992, 1994; Arvidson et al, 1994; Quigley et al, 1994; Jenney et al, 1995; Nenadov Beck et al, 1995; Rovelli et al, 1995; Nysom et al, 1996; Fanfulla et al,1997; Cerveri et al, 1999; Fulgoni et al, 1999; Neve et al, 1999).
Among long-term survivors with pulmonary disease, chronic GVHD has been identified as a major risk factor for the development of progressive airflow obstruction in the large, predominantly adult series, suggesting that it may be a pulmonary manifestation (Clark et al, 1987; Holland et al, 1988; Prince et al, 1989; Tait et al, 1991; Schwarer et al,1992; Curtis et al, 1995; Soubani et al, 1996; Palmas et al, 1998). This is also suspected from its infrequent or absent association with autologous BMT in adults (Holland et al, 1988; Paz et al, 1992; Schwarer et al, 1992) and children (Arvidson et al, 1994; Nenadov Beck et al, 1995; Fanfulla et al, 1997; Cerveri et al, 1999; Neve et al, 1999). However, its rare development in the autologous situation implicates additional aetiological factors (see Risk factors). It is defined as a Fev1/FVC < 70% and Fev1 < 80% of predicted and the mortality may be high (Clark et al, 1989).
The weight of evidence indicates that post-transplantation obstructive lung disease is less common in children, with the majority of studies showing little or no obstructive change (Kaplan et al, 1992, 1994; Arvidson et al, 1994; Quigley et al, 1994; Nenadov Beck et al, 1995; Rovelli et al, 1995; Nysom et al, 1996; Fanfulla et al, 1997; Cerveri et al, 1999; Fulgoni et al, 1999; Neve et al, 1999). Its association with chronic GVHD is less well established (Uderzo et al, 1991; Schultz et al, 1994; Sargent et al, 1995; Kleinau et al, 1997). Kaplan et al (1992) did not find an association between chronic GVHD and obstructive airways disease in a small series of transplanted young adults and children. In contrast, a relatively high incidence of obstructive lung disease (19·4%) was found among 89 children who had undergone allogeneic BMT more than 1·5 years before, which was strongly associated with chronic GVHD (Schultz et al, 1994).
Recently, late-onset pulmonary disease, in which no infectious agents are identifiable, has been collectively termed the late onset pulmonary syndrome (LOPS), and broadened to include the spectrum of obstructive and restrictive disease, reported in two mixed studies of adults and children (Schwarer et al, 1992; Palmas et al, 1998). Histologically, the pathological processes include bronchiolitis obliterans (BO), leading to progressive obstructive airways disease, bronchiolitis obliterans with organizing pneumonia (BOOP), diffuse alveolar damage (DAD), and interstitial pneumonia which may be lymphocytic or non-classifiable (Schwarer et al, 1992; Palmas et al, 1998). LOPS commonly develops between 6 and 12 months after BMT, but can develop at any time up to 20 months (Schwarer et al, 1992; Breuer et al, 1993; Palmas et al, 1998). Clinically, it is characterized by cough, dyspnoea and sometimes wheeze, but signs may be minimal and plain radiography of the chest may be normal or show diffuse or patchy infiltrates (Schwarer et al, 1992; Palmas et al, 1998). High-resolution computerized tomography (CT) is a useful non-invasive technique in evaluation of obstructive disease in children (Sargent et al, 1995). Immunosuppressive therapy has limited success in severe cases of LOPS with Fev1 < 45% or Forced expiratory ratio (FEV1/VC) < 50% (Curtis et al, 1995; Palmas et al, 1998), although BOOP has a better prognosis (Kleinau et al, 1997; Palmas et al, 1998). BOOP may or may not be associated with chronic GVHD in case reports of children (Mathew et al, 1994; Kleinau et al, 1997).
However, apart from these overt cases of clinical disease, the subclinical nature of pulmonary dysfunction in children is becoming apparent and most children appear to be symptom-free despite abnormal lung function, even when quite severely so (Uderzo et al, 1991; Arvidson et al, 1994; Nenadov Beck et al, 1995; Nysom et al, 1996; Fanfulla et al, 1997; Cerveri et al, 1999; Fulgoni et al, 1999).
A homogeneous study from Copenhagen, with long follow up, evaluated longitudinal pulmonary function data in a population-based cohort of 25 survivors of allogeneic transplantation for childhood leukaemia or lymphoma. Lung volumes and transfer factor of the lung for carbon monoxide (TLCO) were reduced immediately after BMT, but increased or stabilized over the subsequent years. However, at the last follow up (4–13 years), despite the absence of symptoms, patients still had a significantly reduced transfer factor, total lung capacity (TLC) and forced vital capacity (FVC), and an increased forced expiratory volume in 1 s to FVC ratio (Fev1/FVC), indicative of a persistent diffusion defect and restrictive disease (Nysom et al, 1996).
The transient reductions in lung volumes and transfer factor, approximately 3–6 months after BMT, followed by a late increase, have been found in other paediatric studies with shorter follow up (Serota et al, 1984; Uderzo et al, 1991; Arvidson et al, 1994; Kaplan et al, 1994; Quigley et al, 1994; Fanfulla et al, 1997; Neve et al, 1999). Improvement in pulmonary function is generally seen within the first year after BMT. The partial recovery and long-term residual impairment of lung volumes and transfer factor, found by Nysom et al (1996), is typical of these otherstudies. Only one short-term evaluation shows returnto baseline values (Quigley et al, 1994). Two small longitudinal studies, however, detected continuing decline in some indices of pulmonary function up to 4 years, although remaining within normal limits in Rovelli's study (Rovelli et al, 1995; Neve et al, 1999). An isolated reduction in diffusing capacity (reduced TLCO), may be the only abnormality demonstrated by the group from Pavia in three papers (Fanfulla et al, 1997; Cerveri et al, 1999; Fulgoni et al, 1999) and others (Arvidson et al, 1994). This occurred in 15% of Cerveri's cohort of 52 leukaemia patients, while 23% had a full restrictive defect. Only 62% had completely normal lung function.
Some paediatric BMT studies have shown a reduction in diffusing capacity, with or without restrictive changes, in some patients prior to BMT (Quigley et al, 1994; Fanfulla et al, 1997; Leneveu et al, 1999; Neve et al, 1999). Only 65% of Fanfulla's cohort had normal lung function at baseline and 44% of Neve's. This leads to the suggestion that pulmonary function defects may be engendered by antineoplastic treatment, prior to BMT. Corroborating data show similar impairment of lung function and exercise capacity in survivors of childhood leukaemia and lymphoma, many of whom had never undergone BMT or received mediastinal radiation (Shaw et al, 1989; Jenney et al, 1995; Nysom et al, 1998b, 1998c). In contrast, a recent cross-sectional study of survivors of childhood acute lyphoblastic leukaemia (ALL), treated with Berlin–Frankfurt–Münster (BFM)-type chemotherapy alone or with chemotherapy followed by BMT, concluded that intensive front-line treatment was not associated with late pulmonary dysfunction in most cases,but that, in agreement with Jenney et al (1995), re-treatment including BMT can frequently injure the lung (Fulgoni et al, 1999). Nonetheless, worse lung function and clinical sequelae occurred in a small number of children after autologous BMT, treated more intensively for neuroblastoma, before BMT (Neve et al, 1999), and in patients transplanted for haematological malignancy beyond second complete remission, in whom 54% had impaired function, compared with 21% in first remission (Cerveri et al, 1999) (Table I). Children transplanted for leukaemia may have a worse outcome than those transplanted for aplastic anaemia, once again suggesting the influence of pretreatment (Serota et al, 1984). This could not be formally confirmed by statistical comparison of these two groups by Kaplan et al (1994). However, abnormal pulmonary function tests (PFT) before BMT are not usually considered to be a contraindication to BMT in children (Fanfulla et al, 1997), although some groups argue that pre-BMT tests are predictive for later lung disease in adults (Soubani et al, 1996).
The role of chronic GVHD in the development of airflow obstruction has already been discussed. Other factors implicated in an increased risk of obstructive disease, in the predominantly adult literature, are the prolonged use of methotrexate, decreased immunoglobulins, increasing recipient age, male gender and lack of human leucocyte antigen (HLA) matching, and recurrent pulmonary infection (Clark et al, 1987; Holland et al, 1988; Schwarer et al, 1992; Breuer et al, 1993; Soubani et al, 1996). Schultz et al (1994), in their paediatric study, agreed that acute and chronic GVHD, HLA disparity and increasing age correlated with obstructive lung disease, but methotrexate prophylaxis, cytomegalovirus (CMV) reactivity in either donor or recipient, and TBI did not.
The aetiology of restrictive disease is probably multifactorial. From adult studies, it appears to include the toxic effects of chemotherapy and radiation, and GVHD (Tait et al, 1991; Beinert et al, 1996; Soubani et al, 1996). It may be exacerbated by previous pulmonary infections in both adults (Soubani et al, 1996) and children (Jenney et al, 1995; Nenadov Beck et al, 1995; Cerveri et al, 1999). In children, although no association was found between long-term pulmonary dysfunction and cytomegalovirus reactivation post BMT by Cerveri et al (1999), a previous study from the same group and Quigley's group found that CMV seropositivity was associated (Quigley et al, 1994; Fanfulla et al, 1997). Quigley et al (1994) also found an association between restrictive disease and chronic GVHD, but others did not (Kaplan et al, 1992; Fanfulla et al, 1997; Cerveri et al, 1999). The use of TBI, particularly when delivered at a high dose and dose rate, and as a single fraction, has been associated with restrictive disease in predominantly adult series (Keane et al, 1981; Barrett et al, 1983, Tait et al, 1991). Paediatric data is conflicting and inconclusive but three groups reported worse lung function with TBI (Serota et al, 1984; Arvidson et al, 1994; Quigley et al, 1994). Others found no such association with late dysfunction (Schultz et al, 1994; Fanfulla et al, 1997; Cerveri et al, 1999).
Cytotoxic agents commonly used in conditioning regimens [cyclophosphamide, busulphan, melphalan and BCNU (carmustine)] may induce interstitial pulmonary fibrosis of late onset and methotrexate may also cause pneumonitis (Twohig & Matthay, 1990). Cerveri et al (1999) found no difference between TBI or busulphan in the conditioning regimen, while Quigley et al (1994) have shown that busulphan-containing regimens tend to give rise to less impairment of pulmonary function in the short term than regimens including other combinations or TBI. A late pulmonary restrictive syndrome has been associated with cytotoxic conditioning regimens (various combinations of busulphan, BCNU, and cyclophosphamide and melphalan) in 47% of children with solid tumours after autologous BMT, although the aetiology was probably multifactorial because of previous multimodal therapy (Nenadov Beck et al, 1995).
Data available regarding pulmonary dysfunction and its relationship to young age is inconclusive. Some suggest better pulmonary function if BMT is performed early in life (Kaplan et al, 1992; Arvidson et al, 1994; Quigley et al, 1994; Leneveu et al, 1999), while other studies show worse function (Neve et al, 1999) or no effect of age (Kaplan et al, 1994; Nenadov Beck et al, 1995; Cerveri et al, 1999). Smoking may worsen lung function in transplant recipients and therefore this activity should be discouraged in long-term survivors (Lund et al, 1995; Tyc et al, 1997; Cerveri et al, 1999). Although lung cancer is reported following BMT, the risk is not high (Curtis et al, 1997) and there were no cases in a large paediatric cohort (Socie et al, 2000).
The risk of infectious complications is increased in association with chronic GVHD due to impaired secretory IgA, splenic dysfunction and drug-induced immuno-suppression (Krowka et al, 1985; Breuer et al, 1993; Soubani et al, 1996; Engelhard, 1998). The most frequent are sinopulmonary bacterial infections with encapsulated bacteria. The commonest pathogens are Streptococcus pneumoniae and other gram-positive organisms but Haemophilus influenzae and Pseudomonas are also important, along with opportunistic infections by Candida, Aspergillus and Pneumocystis (Breuer et al, 1993; Soubani et al, 1996; Engelhard, 1998). There is a small but life-long risk of serious pneumococcal infection and currently vaccination only offers incomplete protection, but new conjugate vaccines are being developed (Engelhard, 1998).
In conclusion, further long-term studies are needed to ascertain whether these lung changes will become more significant with increasing age, exposure to smoking and other pollutants and allergens. In the shorter term, however, one could be more optimistic about the effect of BMT on pulmonary function in the paediatric population than in adults and obstructive disease is less common.
- Top of page
- Neuropsychological sequelae
- Note added in proof
Acute renal insufficiency is common after BMT, occurring in 34–50% of children (Van Why et al, 1991; Kist-van Holte et al, 1998). Potential nephrotoxic insults during the transplant period include sepsis and shock (Zager et al, 1989; Gruss et al, 1995), the use of cyclosporine for GVHD (Atkinson et al, 1983; Hows et al, 1983), tubular toxins such as aminoglycoside antibiotics and amphotericin (Churchill & Seely, 1977; Zager et al, 1989; Emminger et al, 1991), veno-occlusive disease (Zager et al, 1989; Gruss et al, 1995), GVHD (Miralbell et al, 1996), conditioning chemotherapy (Patzer et al, 1997) and radiation (Keane et al, 1976; Krochak & Baker, 1986; Lawton et al, 1997). It is not surprising therefore that reports of late renal toxicity are beginning to emerge in 11–54% of paediatric BMT recipients, depending on the variable definitions of renal dysfunction (Guinan et al, 1988; Tarbell et al, 1988; Lonnerholm et al, 1991; Van Why et al, 1991; Liesner et al, 1994; Cohen et al, 1995; Kumar et al, 1996; Kist-van Holte et al, 1998; Leahey et al, 1999). This appears to be higher than the reported incidence of BMT nephropathy in adults (Cohen et al, 1995).
Cohen's group from Wisconsin has attempted to define the mortality rate from BMT nephropathy. They defined late BMT nephropathy as azotaemia occurring > 100 d from BMT, with concurrent hypertension and anaemia, in the absence of identifiable nephrotoxins. Sixty-one adult and 32 paediatric cases of late chronic renal failure corresponding to this definition were identified from their own centre and from 21 other reports located by literature review, including many of the paediatric publications cited here. Follow-up data were available from only a third of these reports, from which the overall mortality of 33% was calculated. This may be an overestimate but actuarial survival differed between the exponential pattern of adults and the children's linear decline (Cohen et al, 1995).
Kamil (1978) and Bergstein et al (1986) were the first to report radiation nephritis in children following TBI and chemotherapy in preparation for BMT. Other early publications, like that of Bergstein et al (1986), reported a nephropathy akin to haemolytic uraemic syndrome (HUS) in children undergoing allogeneic or autologous BMT for leukaemia or neuroblastoma, with onset 3–10 months from BMT (Guinan et al, 1988; Tarbell et al, 1988; Antignac et al, 1989). Since then, there have been further reports (Lonnerholm et al, 1991; Van Why et al, 1991; Locatelli et al, 1993a; Cole et al, 1994; Cohen et al, 1995), some including adults (Lonnerholm et al, 1991; Cohen et al, 1995). Cohen et al (1995) have identified two general patterns of evolution of the disease in those developing late BMT nephropathy (> 100 d). One presents with a rapid decline in kidney function (acute form), accompanied by a haemolytic syndrome similar to that described, with the highest mortality. The second variant shows a slower decline in renal function, usually with stabilization or, sometimes, slow progression (Cohen et al, 1995). Occasional improvement or progression to end-stage renal failure has also been reported (Guinan et al, 1988; Tarbell et al, 1988; Antignac et al, 1989; Lonnerholm et al, 1991; Van Why et al, 1991; Locatelli et al, 1993a).
The so-called acute form presents a picture of severe anaemia, microscopic haematuria, proteinuria, elevation of blood urea and creatinine, hypertension and evidence of microangiopathic intravascular haemolysis (Bergstein et al, 1986; Chappell et al, 1988; Guinan et al, 1988; Tarbell et al, 1988; Locatelli et al, 1993a; Cohen et al, 1995). At other times, presentation may be insidious, with isolated renal impairment and without evidence of haemolysis (Antignac et al, 1989; Lonnerholm et al, 1991; Van Why et al, 1991; Cohen et al, 1993, 1995). Histopathologically, there is severe glomerulopathy, the hallmark of which is extensive mesangiolysis, accompanied by focal thickening and splitting of the glomerular basement membrane (Bergstein et al, 1986; Guinan et al, 1988; Tarbell et al, 1988; Antignac et al, 1989; Lonnerholm et al, 1991; Locatelli et al, 1993b).
The clinico-pathological findings and timing of onset are compatible with radiation nephritis (Bergstein et al, 1986; Guinan et al, 1988; Tarbell et al, 1988; Antignac et al, 1989; Lonnerholm et al, 1991; Cohen et al, 1993, 1995). This is thought to be stimulated by injury to the vascular endothelium and typically presents 6–12 months after BMT (Luxton & Kunkler, 1964; Keane et al, 1976; Krochak & Baker, 1986), the latent period being attributed to slow endothelial turnover and progressive tissue damage (Krochak & Baker, 1986; Baker & Krochak, 1989).
The tolerance of renal tissue to radiation damage lies in the region of 20–25 Gy of radiation delivered to both kidneys, which are higher doses than those used in paediatric BMT (Luxton & Kunkler, 1964; Keane et al, 1976; Lawton et al, 1991). The patients reported by Guinan et al (1988) and Tarbell et al (1988) had all received multiagent conditioning chemotherapy, in addition to radiation, particularly those with neuroblastoma who had received the nephrotoxic radiation sensitizer cis-platinum. Out of 44 children transplanted for stage IV neuroblastoma or ALL, 29 survived for at least 3 months, 11 of whom suffered renal dysfunction 3·5–7 months after BMT. The incidence was 71% for neuroblastoma compared with 35% for leukaemia (Tarbell et al, 1988). This and other paediatric studies, as well as adult data (Lawton et al, 1991; Cohen et al, 1993), have led to the conclusion that intensive multiagent conditioning, added to TBI, may sensitize the kidney to radiation damage at lower doses than would normally be expected (Bergstein et al, 1986; Guinan et al, 1988; Antignac et al, 1989; Lonnerholm et al, 1991; Van Why et al, 1991; Cole et al, 1994; Cohen et al, 1995). Animal and human data are available, showing the potentiation of radiation injury by chemotherapeutic agents and other nephrotoxins such as cyclosporin A (CsA), antifungals and aminogycoside antibiotics (Phillips et al, 1975; Doll et al, 1986; Moulder & Fish, 1989; Moulder et al, 1990; Lawton et al, 1991, 1994, 1997).
Over the last decade, the incidence of florid clinical disease has almost certainly declined with increasing awareness of potential late sequelae of BMT. More recently, researchers have concentrated on late dysfunction, variously defined by tests of renal function. A significant amount of renal impairment, particularly glomerular, has been found in children transplanted for malignant and non-malignant disease (Berg & Bolme, 1989; Lonnerholm et al, 1991; Van Why et al, 1991; Kumar et al, 1996; Kist-van Holte et al, 1998).
In a prospective study of 72 recipients (22 children, 50 adults) of autologous BMT for haematological and lymphoid malignancy, with relapse-free survival of > 6 months from BMT and up to 5 years follow up, Lonnerholm et al (1991) found a 17% incidence of renal impairment, with onset 3–6 months after BMT. Late renal dysfunction was defined as > 25% decrease in glomerular filtration rate (GFR). Four children (16%), all asymptomatic, had renal impairment. The single most important risk factor for renal dysfunction was radiation, but renal damage was more frequent in patients with lymphomas (mainly adults) conditioned with BEAC (BCNU, etoposide, cytarabine, cyclophosphamide) (Lonnerholm et al, 1991). Van Why et al (1991) defined renal insufficiency as doubling of the baseline serum creatinine or creatinine clearance of < 50 ml/min/1·73m2 in their retrospective evaluation of 64 paediatric patients transplanted for malignant disease or immunodeficiency, surviving beyond the first 60 d from BMT. With up to 11 years (mean 17·5 months) of follow up, they found 28% of the patients had late renal dysfunction (> 60 d after BMT) compared with 50% in the early period (< 60 d after BMT). Early insufficiency was not predictive of late insufficiency and only one third of those with late insufficiency had early insufficiency (Van Why et al, 1991). A similar observation was made in a retrospective study of 17 BMT survivors up to 10·8 years post BMT(Kumar et al, 1996), but not by Kist-van Holte et al, 1998). In the latter's recent retrospective study of 90 evaluable children undergoing allogeneic BMT for haematological disorders and immunodeficiency, they noted that chronicrenal dysfunction, defined as an estimated GFR < 85ml/min/1·73 m2 1 year from BMT, correlated with high serum creatinine in the first 3 months after BMT. Twenty-eight per cent of the children were affected, despite a normal GFR, prior to BMT (Kist-van Holte et al, 1998). A significant reduction in the GFR 1 year from BMT compared with pre-BMT values and/or control values was also reported by a Swedish group in 44 children with ALL, AML and severe aplastic anaemia, although there was no further annual reduction thereafter. Patients with ALL had the greatest impairment at 3–5 years after BMT (Berg & Bolme, 1989).
Berg & Bolme (1989) also noted a reduction in glomerular function of patients with ALL, although not AML, before BMT, suggesting that prior treatment may contribute to late sequelae after BMT. In two other long-term studies of 33 children with AML/MDS (8 BMT) from our own centre and 52 (26 BMT) from Philadelphia, renal function was found to be compromised equally in those treated using chemotherapy alone or using BMT, supporting the concept of damage by prior chemotherapy (Leisner et al, 1994; Leahey et al, 1999). In contrast, others have found normal glomerular function pre BMT (Guinan et al, 1988; Kumar et al, 1996; Kist-van Holte et al, 1998), or even increased glomerular filtration and microalbuminuria in one prospective study examining the direct effect of conditioning in 42 children transplanted for malignancy (Patzer et al, 1997). Hyperfiltration has also been found up to 10 years after BMT (Kumar et al, 1996). Other models of hyperfiltration (diabetes, nephrectomy, nephrotic syndrome) may lead to progressive renal disease. In addition, Patzer et al (1997) found a high incidence of proximal tubular dysfunction, both before (60%) and immediately after conditioning (100%). Preliminary 2 years follow-up data suggest long-lasting minimal tubular dysfunction, with variable recovery.
Late hypertension has been reported in 11–16% of children (Van Why et al, 1991; Cohen et al, 1995; Kumar et al, 1996; Leahey et al, 1999). Although invariably part of HUS, it may also occur without and there is some evidence that good control of the blood pressure may slow the progress of renal impairment (Cohen et al, 1995). In the analysis of Van Why et al (1991), early hypertension was not predictive of late hypertension but there was a strong association with CsA usage and renal insufficiency.
There is much discussion in the literature about the role of commonly used nephrotoxins in the development of late renal dysfunction. CsA has been established as a cause of early renal insufficiency associated with microangiopathy, hypertension and HUS (Shulman et al, 1981; Atkinson et al, 1983; Hows et al, 1983). Although CsA, in addition to TBI, was implicated in the study of Van Why et al (1991), its presence is not essential to the development of a late nephropathy, which has occurred in patients who have never received this medication (Kamil, 1978; Bergstein et al, 1986; Chappell et al, 1988; Guinan et al, 1988; Antignac et al, 1989; Cohen et al, 1995). The concomitant use of CsA with other nephrotoxins, such as amphotericin B, or theaminoglycoside antibiotics may exacerbate renal dysfunction (Shulman et al, 1981; Hows et al, 1983; Kennedy et al, 1983; Emminger et al, 1991). Although Van Why et al (1991) found amphotericin and CsA, given both in the early and late periods after BMT, to be independently predictive of renal insufficiency in the same time period, and TBI but not chemotherapy conditioning to be predictive in both, others have not deemed these medications to be the primary cause of late nephropathy (Cohen et al, 1993, 1995). The use of liposomal amphotericin B (AmBisome) substantially reduces glomerular toxicity, even in children with established renal impairment (Chisholm et al, 1999).
As previously discussed, it is generally accepted that radiation plays a major aetiological role in the development of renal impairment in children following BMT. Most studies implicate TBI (Bergstein et al, 1986; Guinan et al, 1988; Tarbell et al, 1988; Antignac et al, 1989; Lonnerholm et al, 1991; Van Why et al, 1991; Cohen et al, 1995), corroborated by animal studies (Moulder & Fish, 1989). In adults, renal shielding is protective against nephropathy and there is a correlation between renal impairment and higher doses of TBI (Miralbell et al, 1996; Lawton et al, 1997). Dose rates, interfraction interval as well as fraction size may be important (Moulder & Fish, 1989; Lawton et al, 1991). Nonetheless, TBI did not appear to be a risk factor and the dose and number of fractions did not correlate with the estimated GFR in the Leiden study in which two-thirds of patients had 5–8 Gy of single fraction radiation (Kist-van Holte et al, 1998).
It has been suggested that young age at BMT may be a risk factor in the development of renal damage (Bergstein et al, 1986; Guinan et al, 1988; Tarbell et al, 1988; Antignac et al, 1989), and there is animal data from irradiated perinatal dogs and mice supporting this concept (Guttman & Kohn, 1963; Phemister et al, 1973). However, young age at BMT was not found to be a risk factor for late renal dysfunction by Lonnerholn et al (1991).
Thus, the evidence points to radiation being the single most important factor associated with late nephropathy. Undoubtedly, other nephrotoxins such as chemotherapy, antibiotics, antifungals and CsA may potentiate radiation-induced renal damage, and the judicious use of liposomal amphotericin and avoidance of prolonged courses of aminoglycosides when possible are likely to be of benefit. The late, and in some cases insidious, onset of renal impairment and hypertension in BMT survivors necessitate vigilance in the long term. Prompt treatment of hypertension should be instituted and particular attention paid to children during periods of growth acceleration, when renal function can further deteriorate.
- Top of page
- Neuropsychological sequelae
- Note added in proof
In contrast to the vast body of literature relating to neurotoxicity following central nervous system (CNS) treatment in acute lymphoblastic leukaemia, the paediatric literature evaluating neuropsychological sequelae after BMT is sparse but expanding. The extent and severity of late sequelae is yet to be established. As the majority of transplants are performed for high risk and relapsed leukaemia, clearly previous CNS directed therapy is relevant to outcome. It is generally accepted, although confused by conflicting data and methodological pitfalls, that cranial radiotherapy, young age at treatment and increasing length of follow up all have an adverse effect on cognitive function (Jannoun, 1983; Cousens et al, 1988; Copeland, 1992; Jankovic et al, 1994; Christie et al, 1995; Anderson et al, 1997; Smibert et al, 1996). A variety of deficits in the neuropsychological domains of intelligence, memory, attention, academic achievement, visual–spatial and fine motor skills are found.
The contribution of intrathecal and systemic methotrexate to neuropsychological sequelae and the interplay between this and cranial irradiation has been extensively reviewed by others (Cousens et al, 1988; Stehbens et al, 1991; Copeland, 1992; Roman & Sperduto, 1995). In addition, other factors may also have a detrimental influence on outcome, such as higher radiation dose (Christie et al, 1994; Davidson et al, 1994; Roman & Sperduto, 1995; Smibert et al, 1996), female gender (Bleyer et al, 1990; Christie et al, 1994, 1995; Waber et al, 1995) and psychosocial functioning (Stehbens et al, 1991; Copeland, 1992; Eiser, 1998; Hill et al, 1998). For this population of leukaemic children, the addition of total body irradiation or other neurotoxic chemotherapy in the transplant conditioning regimen may lead to cumulative neurotoxicity with deficits in both neurological and neuropsychological functioning (Wiznitzer et al, 1984; Wheeler et al, 1988; McGuire et al, 1991; Christie et al, 1994; Davidson et al, 1994; Sanders et al, 1994; Keime-Guibert et al, 1998; Arvidson et al, 1999).
The interpretation of neuropsychological assessment after BMT has been problematic because of the heterogeneity of the population studied, small sample size, lack of long-term prospective data and methodological shortcomings. The difficulties are underscored by a recent report of two pairs of monozygotic twins from a longitudinal study assessing the neurodevelopmental results of BMT, in which individual, environmental, treatment and disease variables exert an impact on the outcome, in both the affected and unaffected twin (McCabe et al, 1997).
I have tried to categorize the studies into those in which patients treated with previous cranial irradiation have been included and those in which cranial radiation has not been a confounding factor. Details of these studies are shown in Table II.
|References||Number of evaluable patients||Type of study||Conditioning and groups compared||Previous* cranial radiotherapy||Length of follow up (years)||Neuropsychological deficits Y/N||Disease treated|
|Simms et al (1998)||122 Pre BMT 51 Post BMT||Prospective longitudinal||Chemo + TBI v chemo||–||1||N No difference between groups||Malignant and non- malignant disease|
|Kramer et al (1997)||67||Prospective longitudinal||Chemo ± TBI||–||1 3||Y Y but stable||Malignant and non-malignant disorders|
|Kramer et al (1992)||22||Prospective||Chemo + TBI < 15 Gy (15) v chemo (7)||–||1||No difference between groups but individual deficits||Malignant and non- malignant disorders|
|Phipps et al (1995)||25||Prospective longitudinal||Chemo ± TBI or TLI (1)||–||0·5–1||N but psycho-social difficulties||Malignant and non- malignant disorders|
|Thuret et al (1995)||12||Cross-sectional||Chemo||–||2–10||N||Acute leukaemia 1st CR|
|Chou et al (1996)||10 20||Longitudinal||Chemo + TBI Chemo + TBI||– –/+(3)||1 + 3 1 + 3||Y Y||Immunodeficiency Leukaemia|
|Arvidson et al (1999)||26||Longitudinal and cross-sectional||No TBI TBI only TBI + CRT||– – +||2–10||N Y Y||Haem malignancy|
|Cool (1996)||76||Prospective longitudinal||Chemo ± TBI||–/+(19)||1–4/5||Y||Haem malignant and non-malignant|
|Smedler et al (1990)||32||Cross-sectional||BMT/TBI (25) v sibling donors||–/+(4)||1–6||Y < 3–11y at BMT N > 12y at BMT||Leukaemia (25) SAA|
|Smedler & Bolme (1995)||10 < 3 years at BMT||Cross-sectional||TBI (8)||–/+(2)||2–4||Y||Leuk, SAA and Nbl|
|Smedler et al (1995)||30||Longitudinal||BMT/TBI (24) v sibling donors||–/+(4)||5–10||Y < 3–11y at BMT N > 12y at BMT||Leuk or SAA|
|Sanders et al (1994)||231||Longitudinal Pre-BMT + at LTFU||No TBI TBI only TBI + CRT||– – + > 16Gy||1–14||N N Y||Haem malignant disease|
|Christie et al (1994)||14||Cross-sectional||CRT + TBI/BMT (8) or CRT × 2||+ +||5·6–15·5||Y||ALL|
|Davidson et al (1994)||24||Cross-sectional||TBI||+||Median 4·2||Few functional deficits||ALL|
|McGuire et al (1991)||178 (110 pre BMT) (68 LTFU)||Retrospective cross-sectional||TBI/BMT v sibling controls||+ (35 pre) + (45 post BMT)||1–12||Y||Haem malignant disease|
Previous cranial radiation
In a small cohort of children studied at Great Ormond Street hospital, Christie et al (1994) specifically addressed the effect of adding a second course of irradiation, either as cranial or total body irradiation, to a previous course of cranial irradiation. Only two out of 14 children performed at age-appropriate levels for neuropsychological function while, in the others, verbal IQ, attention and concentration were selectively reduced. Poor cognitive outcome correlated with high doses of radiotherapy, young age at relapse and the shorter interval between radiotherapeutic treatments. Girls showed greater impairment than boys (Christie et al, 1994). However, in another study in which functional outcome was defined by educational performance and employment history and all 24 survivors of BMT had received previous cranial irradiation in addition to TBI, all were in normal school or employment. The worst outcomes were seen in children who were young at the time of initial treatment, who suffered a CNS relapse and who received the highest cumulative doses of cranial radiation (Davidson et al, 1994).
Other studies in which patients with previous cranial radiation have been included, have supported the conclusion that both young age at BMT and cumulative CNS radiation exposure, from a combination of cranial and total body irradiation, might adversely effect neuropsychological development of children (McGuire et al, 1991; Cool, 1996; Arvidson et al, 1999; Leung et al, 2000 – see `note added in proof'). However, age < 6 years at BMT was not an additive factor to CNS irradiation in a cohort of 231 children, comparing those who were cranially irradiated previously (total CNS irradiation > 16 Gy) with those who were either non-irradiated or who had received TBI alone. Cranially irradiated patients had a greater fall in full-scale IQ of 1·6 points per year than the other two groups (Sanders et al, 1994).
Pre-BMT data indicate that children with prior cranial irradiation already show declining IQ scores and below average academic achievement (Cool, 1996) and have been confirmed in another study (Pot-Mees, 1989). By 1 year post BMT, differential effects were seen on academic achievement in the BMT group, although major declines did not occur compared with other cancer patients. By 4–5 years after BMT in a subset of children, one-fifth of whom had previous cranial irradiation, declining scores over time occurred on IQ, achievement, memory and fine motor evaluations. Learning problems were 3–4-fold higher than in the general population. Younger children seemed to be particularly at risk if < 3 years of age at diagnosis (Cool, 1996).
This was confirmed in a series of small studies by a Swedish group who found young age to be a critical factor for neurocognitive impairment, particularly when children with malignancy, who had received TBI, were 3 years or less at BMT. Motor delay was a prominent feature. Those treated at a similar age for aplastic anaemia with cyclophosphamide had normal development (Smedler et al, 1990; Smedler & Bolme, 1995).
In a third publication, and in comparison with a control group comprised of donors of the BMT recipients, the authors carried out successive cognitive function tests longitudinally in paediatric BMT recipients who had received TBI for leukaemia or chemotherapy alone for aplastic anaemia. No pre-BMT tests were done and 4 of the 30 had previous cranial irradiation. Noticeably, there were no neuropsychological defects in either the older age group treated between 12 and 17 years of age or among the non-irradiated aplastic anaemia patients. However, in the younger age group treated with BMT/TBI between 3 and 11 years of age, gradual declines in cognitive function occurred over the next 5–10 years, despite initially performing as well as the donor controls (Smedler et al, 1995). This illustrates how cognitive outcome may decline progressively, in keeping with other long-term data with up to 14 years follow up (McGuire et al, 1991; Sanders et al, 1994; Cool, 1996; Arvidson et al, 1999). Details of the study of Arvidson et al (1999) are shown in Table II.
Some other authors have also reported early declines within 1 year (Parth et al, 1989; Kramer et al, 1997) and between 1 and 5 years (Wiznitzer et al, 1984; Chou et al, 1996), while others have not (Pot-Mees, 1989; Kramer et al, 1992; Phipps et al, 1995; Thuret et al, 1995; Simms et al, 1998). It is noteable that the majority of the latter studies do not include patients cranially irradiated prior to TBI, and follow up is short.
No previous cranial radiation
Neurocognitive function is further examined in a series of prospective studies of short duration in which none of the patients have received prior cranial radiotherapy (Kramer et al, 1992, 1997; Phipps et al, 1995; Simms et al, 1998). This is more relevant to the modern treatment of leukaemia in which cranial irradiation is usually excluded.
Kaleita et al (1989), in a case report, were optimistic in reporting normal development in four children undergoing BMT, three of whom had TBI at < 2 years of age, followed up for approximately 2–6 years.
Phipps et al (1995) showed stable cognitive and neuropsychological function in their prospective longitudinal study of 25 patients, 6–12 months after BMT. In contrast, declines were observed in psychosocial factors of social competence, self-esteem and general emotional wellbeing. In another prospective study of 22 children who were assessed pre-BMT and 1 year later, overall no deterioration in cognitive or psychological functioning was found at 1 year follow up, although individual decrements in IQ were found of 10 points or more (Kramer et al, 1992). However, in a more recent publication, the same author prospectively evaluated a larger group of children. On this occasion, analysis of variance indicated a significant decline in IQ between baseline and the 1-year evaluation, but no further changes occurred between the 1- and 3-year evaluations for either cognitive or adaptive behaviour scores. Age and radiation dose did not predict the outcome in either study (Kramer et al, 1992, 1997), and neither did diagnosis or gender of the child in the later of the two studies (Kramer et al, 1997). In a small group of immunodeficient patients without previous cranial radiotherapy prior to TBI, declines in cognitive function were also noted at 1 year with some improvement by 3 years. Similar deficits were found in a group of leukaemia patients, most of whom had not received cranial irradiation previously (Chou et al, 1996).
In a well-designed recent study, prospective evaluation of neuropsychological function was undertaken pre-BMT in122 children and adolescents with malignant and non-malignant haematological disorders and no previous cranial radiation, who had undergone allogeneic or autologous BMT. Fifty-one surviving patients were studied again at 1 year post BMT, and comparison was made between those prepared for BMT with chemotherapy alone and those receiving chemotherapy and TBI. The results suggested that global and specific areas of neuropsychological functioning were not impaired in either group, and regression analysis failed to identify treatment, age or gender effects (Simms et al, 1998). As in some of the other studies, individuals were identified who had clinically significant decrements in test scores.
In none of these four studies (Kramer et al, 1992, 1997; Phipps et al, 1995; Simms et al, 1998) did patients receive doses to the cranium of more than 16 Gy, which was found to be detrimental by Sanders et al (1994). This might explain the absence of the predictive influence of young age and radiation dose on neuropsychological outcome, highlighted by Kramer et al (1992, 1997) and Simms et al (1998).
There is little data on the neuropsychological impact of high-dose chemotherapy conditioning regimens. Neither Simms et al (1998) nor Arvidson et al (1999) detected significant declines in cognitive function post BMT in those prepared with chemotherapy alone compared with those who received TBI conditioning. In general, those prospective studies including patients conditioned with chemotherapy and TBI and chemotherapy alone showed no measurable effects, in either the short term (Kramer et al, 1992; Phipps et al, 1995; Simms et al, 1998) or longer term (Sanders et al, 1994). Kramer's later study found significant declines in cognitive ability following BMT in all patients, even when they were not exposed to neurotoxic agents such as busulphan or TBI. There was no significant difference in outcome between children receiving bulsulphan or TBI and children receiving neither treatment (Kramer et al, 1997). This might be accounted for by small study size or the psycho-social variables associated with BMT (Pot-Mees, 1989; Kramer et al, 1997). In a small pilot study of 10 children treated for brain tumours with intensive chemotherapy but no cranial irradiation and BMT (2·1–8·9 years of age), with average follow up of 38 months, patients were performing within the low average range for overall intelligence, verbal IQ and reasoning, and performance IQ and abstract visual reasoning (Sands et al, 1998).
In summary, the bulk of the research data available support the conclusion that the neuropsychological dysfunction appears to occur more commonly in the younger age group, particularly those < 3 years of age at BMT, and in those who have been previously exposed to cranial radiotherapy in addition to TBI. Except for these risk groups, most other patients appear to experience little or no neuropsychological impairment. It is clear, however, that deterioration can occur with increasing length of follow up, and it is important that methodologically sound, long-term prospective studies are performed before definitive answers will be available. All young children should undergo psychological assessment with a full battery of tests, post BMT, with regular re-appraisal.
- Top of page
- Neuropsychological sequelae
- Note added in proof
Neurological complications are usually an early event after BMT and may be transient or result in a high mortality (Patchell et al, 1985; Gallardo et al, 1996; Graus et al, 1996). They are normally classified as due to CNS infections, metabolic encephalopathies or thrombotic and haemorraghic cerebrovascular events. Also, they may be related to neurotoxicity of drugs used in the conditioning regimens (Sureda et al, 1989; Wolff et al, 1989), to immunosuppressives, such as cyclosporine (Reece et al, 1991) and steroids (Patchell, 1994), or to antimicrobials and antifungals for the treatment of infections (Pavletic et al, 1996).
Long-term neurological complications after BMT are rare and prospective data are lacking. Similarly, paediatric data is scarce (Wiznitzer et al, 1984; Christie et al, 1994; Davidson et al, 1994). Previous treatment for leukaemia, using systemic and/or intrathecal methotrexate and cranial radiation, may be associated with magnetic resonance imaging (MRI) and CT scan changes (Peylan Ramu et al, 1978; Chessells et al, 1990; Hertzberg et al, 1997) which may be asymptomatic or associated with neurological or neuropsychological deficits (Peylan Ramu et al, 1978; Brouwers et al, 1985; Chessells et al, 1990; Stehbens et al, 1991; Hertzberg et al, 1997). Leucoencephalopathy with multifocal, demyelinating white matter changes and the grey matter changes of mineralizing microangiopathy are characteristic (Stehbens et al, 1991; Hertzberg et al, 1997). One study found an incidence of leucoencephalopathy of 7% in a mixed age group of patients undergoing BMT for acute leukaemia. It reported that clinically evident leucoencephalopathy was exclusive to patients who had received CNS irradiation and/or intrathecal chemotherapy prior to BMT, in addition to intrathecal methotrexate, after BMT (Thompson et al, 1986). Wiznitzer et al (1984), in their paediatric series of 57 children (median age 11 years) with up to 81 months of follow up, revealed a high incidence of neurological complications (59%), but these were mainly acute neurological events and included CNS leukaemic relapse. However, they found that the combination of prior treatment and BMT conditioning predisposed patients to neurological and neuropsychological sequelae.
In the small series of doubly irradiated patients reported by Christie et al (1994) from our own centre, either TBI or a second course of cranial radiation was additional to an initial course. Soft neurological signs, predominantly of impaired coordination, were detected in all patients several years later even though no major deficits occurred. This finding was corroborated by a normal functional outcome in the study of Davidson et al (1994). However, with the passage of time, two patients from Christie's cohort, now young adults, have developed neurological symptoms suggestive of vasculitis (headaches and transient ischaemic attacks, hemiplegic migraine) and one other has psychotic episodes (unpublished observations).
Vasculopathy, strokes and migraine-like episodes have been documented in cranially irradiated adults and children (Nishizawa et al, 1991; Foreman et al, 1995; Shuper et al, 1995; Keime-Guibert et al, 1998), and after BMT (Padovan et al, 1999) and reduced brain perfusion has been shown to occur after treatment of ALL, which did not necessarily include radiation (Harila-Saari et al, 1997). These changes are, almost certainly, responsible for some of the late neurological effects.
It has been postulated also that late vasculitic complications in adults may be a manifestation of chronic GVHD or immunosuppressive treatment (Padovan et al, 1998, 1999). Chronic GVHD has been implicated in the rare development of polymyositis, myasthenia gravis and peripheral neuropathies similar to the Guillain–Barre syndrome, all of which improve with immunosuppressive therapy (Patchell, 1994). Neurological complications are also less frequent in those undergoing autologous BMT (Snider et al, 1994; Padovan et al, 1998).
There is an increased prevalence of primary CNS lymphomas after BMT and CNS involvement occurs in 15–25% of patients with post-transplant lymphoproliferative disease (Cohen, 1991; Patchell, 1994). Other CNS tumours occur following BMT, especially in children (Curtis et al, 1997; Socie et al, 2000), and meningiomas are increasingly reported after radiotherapy (Foreman et al, 1995; Salvati et al, 1996; Meignin et al, 1998).
Late CNS infections, usually in the form of acute or chronic meningitis or focal brain disease, occur particularly when immunosuppression is prolonged, for example by chronic GVHD and its treatment. The subject has been fully reviewed by Patchell (1994). The commonest bacterial infections are those due to Streptococcus pneumoniae, Haemophilus influenzae and Listeria monocytogenes. Fungal, parasitic and viral infections also occur, particularly involving Aspergillus fumigatus, Cryptococcus neoformans, Toxoplasma gondii, cytomegalovirus, Herpes simplex, Varicella zoster and Epstein–Barr virus (EBV) (Patchell, 1994; Gallardo et al, 1996; Padovan et al, 1998). In the only long-term study available to us, albeit in adults, the prevalence of late CNS infection (Aspergillus and toxoplasmosis) was 7% (Padovan et al, 1998).
Current studies do not adequately explore late neurological complications in survivors of BMT in childhood and prospective, very long-term studies are required to ascertain the impact of this procedure on both cognitive and neurological function.
- Top of page
- Neuropsychological sequelae
- Note added in proof
Throughout this article, each section has been summarized briefly. In addition to sporadic cases of florid organ failure or neurological decline, the outstanding observation emerging from this literature review is the subclinical nature of the diverse late sequelae of childhood BMT. This is particularly true of cardiac, pulmonary and renal dysfunction, in which the incidence of subclinical defects may be high. In the case of malignant disease at least, some of the damage can be traced back to injury by previous treatment. This is illustrated by the role of anthracycline therapy in cardiac dysfunction, cranial irradiation in neuropsychological impairment, nephrotoxic agents in renal impairment and conventional chemotherapy in restrictive pulmonary change. There is evidence that intensifying frontline treatments and transplanting beyond second remission is likely to increase the toll of dysfunction after BMT, for example on the lung. Likewise, exclusion of neurotoxic cranial radiotherapy from treatment of ALL has greatly improved the prognosis for cognitive function post BMT. In general, BMT for non-malignant disorders appears to generate fewer late complications than for malignant disease, although there is little literature pertaining to metabolic disorders.
The addition of TBI and other preparative regimens appears to compound the damage. TBI may impair function more than chemotherapy in the target organs reviewed here, although evidence in the paediatric literature is slim for all but cognitive dysfunction and late nephropathy. In the latter, potentiation of radiation injury by intensive multiagent conditioning and other nephrotoxins is seemingly beyond doubt. The adverse effect of TBI is more clearly illustrated in Part II of this review (and in reviews of the endocrine literature). However, adult and animal data suggest that higher radiation dose, faster dose rate and single fraction TBI also have a more damaging effect on pulmonary and renal tissue than lower total dose and dose rate and TBI in multiple fractions. The vulnerability of the very young brain to damage is clearly demonstrated, but a strong relationship with young age is not demonstrable with regards to the other organs discussed in this section, although it cannot be excluded.
With an increasing number of unrelated and family mismatched transplants being performed, it is likely that the hitherto low incidence of chronic GVHD in childhood may increase. Although there is little evidence linking chronic GVHD with obstructive pulmonary disease in the paediatric literature reviewed to date, it is likely that future larger studies may reveal a link with more severe late pulmonary sequelae.
The ultimate burden of morbidity from BMT is unknown and it may be years before the effect of time and environmental influences are manifest. Some conditions are slowly progressive and the patient may be asymptomatic even in the face of quite advanced disease. In the long-term follow up of children, it is clear that there is a substantial legacy from treatment which includes bone marrow transplantation, particularly in those with malignant disease and a watchful eye is therefore mandatory.
Note added in proof
- Top of page
- Neuropsychological sequelae
- Note added in proof
Although the study of Leung et al (2000) is quoted in part 2 of this review series, I would also like to acknowledge their contribution to cardiac and neuropsychological data not quoted in the text here. In their study of 77 long term survivors of childhood acute myeloid leukaemia with minimal survival of 10 years (median follow up 16·7 years), treated with either chemotherapy along (44), chemotherapy and cranial irradiation (18) or chemotherapy, TBI and BMT (15), they found that cardiac dysfunction was not more frequent in those who received TBI and BMT than in the others, despite a significant incidence of cardiomyopathy (7%). However, the dose of anthracyclines administered in the BMT group was lower than that in the other two groups.
They also found a higher incidence of cognitive difficulties in the two irradiated groups of AML patients and confirmed a relationship to young age at diagnosis and radiation exposure and higher dose of radiation (Leung et al, 2000).
- Top of page
- Neuropsychological sequelae
- Note added in proof
I would like to thank Dr R. Skinner, Dr M. Jenney and DrG. Levitt for their helpful criticism. and Judith Russell and Judith Mott for their invaluable secretarial assistance.
- Top of page
- Neuropsychological sequelae
- Note added in proof
- 1997) Neurobehavioural sequelae following cranial irradiation and chemotherapy in children: an analysis of risk factors. Pediatric Rehabilitation, 1, 63–76. , , & (
- 1989) Delayed renal failure with extensive mesangiolysis following bone marrow transplantation. Kidney International, 35, 1336–1344. , , , & (
- 1991) Cardiovascular sequelae of therapeutic thoracic radiation. Progress in Cardiovascular Diseases, 33, 299–311. (
- 1994) Pulmonary function after autologous bone marrow transplantation in children. Bone Marrow Transplantation, 14, 117–123. , , , , , , , , & (
- 1999) Neuropsychological functioning after treatment for hematological malignancies in childhood, including autologous bone marrow transplantation. Pediatric Hematology and Oncology, 16, 9–21.DOI: 10.1080/088800199277551 , , & (
- 1983) Cyclosporin A associated nephrotoxicity in the first 100 days after allogeneic bone marrow transplantation: three distinct syndromes. British Journal of Haematology, 54, 59–67. , , , , , & (
- 1989) The response of the microvascular system to radiation: a review. Cancer Investigation, 7, 287–294. & (
- 1983) Interstitial pneumonitis following bone marrow transplantation after low dose rate total body irradiation. International Journal of Radiation Oncology, Biology and Physics, 9, 1029–1033. , & (
- 1990) Radionuclide ejection fractions in the evaluation of patients being considered for bone marrow transplantation: risk for cardiac toxicity. Bone Marrow Transplantation, 5, 173–177. , , , , , & (
- 1996) Late pulmonary impairment following allogeneic bone marrow transplantation. European Journal of Medical Research, 1, 343–348. , , , , , & (
- 1991) Late effects of allogeneic bone marrow transplantation in children. Pediatrician, 18, 71–75. (
- 1989) Renal function in children following bone marrow transplantation. Transplantation Proceedings, 21, 3092–3094. & (
- 1986) Radiation nephritis following total-body irradiation and cyclophosphamide in preparation for bone marrow transplantation. Transplantation, 41, 63–66. , , & (
- 1980) Cyclophosphamide cardiotoxicity. European Journal of Pediatrics, 134, 87–90. , , , , , & (
- 1977) Adriamycin cardiotoxicity: endomyocardial biopsy evidence of enhancement by irradiation. American Journal of Surgical Pathology, 1, 17–23. , , , , & (
- 1990) Influence of age, sex, and concurrent intrathecal methotrexate therapy on intellectual function after cranial irradiation during childhood: a report from the Children's Cancer Study Group. Pediatric Hematology and Oncology, 7, 329–338. , , , , , , , , , , , & (
- 1998) Late complications after bone marrow transplantation in children and adolescents. Current Problems in Pediatrics, 28, 273–297. , & (
- 1991) Cyclophosphamide cardiotoxicity in bone marrow transplantation: a prospective evaluation of new dosing regimens. Journal of Clinical Oncology, 9, 1215–1223. , , , & (
- 1993) Pulmonary complications of bone marrow transplantation. Respiratory Medicine, 87, 571–579. , , & (
- 1985) Long-term neuropsychologic sequelae of childhood leukemia: correlation with CT brain scan abnormalities. Journal of Pediatrics, 106, 723–728. , , & (
- 1994) Subclinical disturbances in cardiac function at rest and in gas exchange during exercise are common findings after autologous bone marrow transplantation. Bone Marrow Transplantation, 14, 949–954. , , & (
- 1986) Cardiac complications after bone marrow transplantation. A report on a series of 63 consecutive transplantations. Cancer, 57, 2061–2069. , , , , , , & (
- 1999) Late pulmonary sequelae after childhood bone marrow transplantation. Thorax, 54, 131–135. , , , , , , , & (
- 1988) Haemolytic uraemic syndrome after bone marrow transplantation: an adverse effect of total body irradiation? Bone Marrow Transplantation, 3, 339–347. , , & (
- 1990) Neurotoxicity in lymphoblastic leukaemia: comparison of oral and intramuscular methotrexate and two doses of radiation. Archives of Disease in Childhood, 65, 416–422. , , , , & (
- 1999) Liposomal amphotericin B (AmBisome) in children with febrile neutropenia and renal dysfunction. International Journal of Pediatric Hematology/Oncology, 6, 173–182. , , & (
- 1996) Toxicities of total-body irradiation for pediatric bone marrow transplantation. International Journal of Radiation Oncology, Biology and Physics, 34, 843–851. , , , , , , , & (
- 1994) Neuropsychological and neurological outcome after relapse of lymphoblastic leukaemia. Archives of Disease in Childhood, 70, 275–280. , , , , & (
- 1995) Intellectual performance after presymptomatic cranial radiotherapy for leukaemia: effects of age and sex. Archive of Disease in Childhood, 73, 136–140. , , & (
- 1977) Nephrotoxicity associated with combined gentamicin-amphotericin B therapy. Nephron, 19, 176–181. & (
- 1987) Risk factors for airflow obstruction in recipients of bone marrow transplants. Annals of Internal Medicine, 107, 648–656. , , , , & (
- 1989) Obstructive lung disease after allogeneic marrow transplantation. Clinical presentation and course. Annals of Internal Medicine, 111, 368–376. , , & (
- 1999) Final height of patients who underwent bone marrow transplantation for hematological disorders during childhood: a study by the Working Party for Late Effects-EBMT. Blood, 93, 4109–4115. , , , , , , , , , , , & (
- 1993) Clinical course of late-onset bone marrow transplant nephropathy. Nephron, 64, 626–635. , , , & (
- 1995) Bone marrow transplant nephropathy: radiation nephritis revisited. Nephron, 70, 217–222. , & (
- 1991) Epstein-Barr virus lymphoproliferative disease associated with acquired immunodeficiency. Medicine, 70, 137–160. (
- 1994) Intensive conditioning regimen for bone marrow transplantation in children with high-risk haematological malignancies. Medical and Pediatric Oncology, 23, 464–469. , , , , & (
- 1996) Long-term neuropsychological risks in pediatric bone marrow transplant: what do we know? Bone Marrow Transplantation, 18, S45–S49. (
- 1992) Neuropsychological and psychosocial effects of childhood leukemia and its treatment. CA: a Cancer Journal of for Clinicians, 42, 283–295. (
- 1988) Cognitive effects of cranial irradiation in leukaemia: a survey and meta-analysis. Journal of Child Psychology and Psychiatry and Allied Disciplines, 29, 839–852. , , & (
- 1995) Chronic airflow obstruction in long-term survivors of allogeneic bone marrow transplantation. Bone Marrow Transplantation, 16, 169–173. , , , & (
- 1997) Solid cancers after bone marrow transplantation. New England Journal of Medicine, 336, 897–904.DOI: 10.1056/NEJM199703273361301 , , , , , , , , , , & (
- 1994) Functional neurological outcome in leukaemic children receiving repeated cranial irradiation. Radiotherapy and Oncology, 31/2, 101–109. , , & (
- 1990) Delayed complications and long-term effects after bone marrow transplantation. Hematology and Oncology Clinics of North America, 4, 641–657. (
- 1986) Vascular toxicity associated with antineoplastic agents. Journal of Clinical Oncology, 4, 1405–1417. , & (
- 1982) Complications of treatment of Hodgkin's disease in children. Cancer Treatment Reports, 66, 977–989. & (
- 1997) Cardiovascular function in children following bone marrow transplant: a cross-sectional study. Bone Marrow Transplantation, 19, 61–66. , , , , , , & (
- 1998) Practitioner review: long-term consequences of childhood cancer. Journal of Child Psychology and Psychiatry and Allied Disciplines, 39, 621–633. (
- 1991) Amphotericin B serum levels in pediatric bone marrow transplant recipients. Bone Marrow Transplantation, 7, 95–99. , , , & (
- 1998) Bacterial and fungal infections in children undergoing bone marrow transplantation. Bone Marrow Transplantation, 21, S78–S80. (
- 1997) Pulmonary complications and respiratory function changes after bone marrow transplantation in children. European Respiratory Journal, 10, 2301–2306. , , , , , & (
- 1995) Intracranial large vessel vasculopathy and anaplastic meningioma 19 years after cranial irradiation for acute lymphoblastic leukaemia. Medical and Pediatric Oncology, 24, 265–268. , , , & (
- 1999) Lung function in survivors of childhood acute lymphoblastic leukemia. Chest, 116, 1163–1167. , , , , , & (
- 1996) Neurologic complications after allogeneic bone marrow transplantation. Bone Marrow Transplantation, 18/6, 1135–1139. , , , , , , , , & (
- 1996) Neurologic complications of autologous and allogeneic bone marrow transplantation in patients with leukemia: A comparative study. Neurology, 46/4, 1004–1009. , , , , , , & (
- 1995) Acute renal failure in patients following bone marrow transplantation: prevalence, risk factors and outcome. American Journal of Nephrology, 15, 473–479. , , , , , , , & (
- 1988) Intravascular hemolysis and renal insufficiency after bone marrow transplantation. Blood, 72, 451–455. , , , & (
- 1963) Age at exposure and the acceleration of intercapillary glomerulosclerosis in mice. Laboratory Investigation, 12, 250–256. & (
- 1993) Cardiac disease following treatment of Hodgkin's disease in children and adolescents. Journal of Clinical Oncology, 11, 1208–1215. , & (
- 1997) Brain perfusion after treatment of childhood acute lymphoblastic leukemia. Journal of Nuclear Medicine, 38, 82–88. , , , , , , & (
- 1988) Cardiac damage in autologous bone marrow transplant patients: an autopsy study. Cardiotoxic pretreatment as a major risk factor. Klinische Wochenschreibe, 66, 1175–1181. , , & (
- 1997) CNS late effects after ALL therapy in childhood. Part I: Neuroradiological findings in long-term survivors of childhood ALL – an evaluation of the interferences between morphology and neuropsychological performance. The German Late Effects Working Group. Medical and Pediatric Oncology, 28, 387–400.DOI: 10.1002/(SICI)1096-911X(199706)28:6<387::AID-MPO1>3.0.CO;2-C , , , , , , , , , , & (
- 1998) A comparative study of the long term psychosocial functioning of childhood acute lymphoblastic leukemia survivors treated by intrathecal methotrexate with or without cranial radiation. Cancer, 82, 208–218. , , , , , , , , , , , & (
- 1988) Bronchiolitis obliterans in bone marrow transplantation and its relationship to chronic graft-v-host disease and low serum IgG. Blood, 72, 621–627. , , , & (
- 1999) Hematopoeitic Cell Transplantation (ed. by E.Donnal Thomas, K.G.Blume & S.J.Forman), p. 12. (
- 1983) Nephrotoxicity in bone marrow transplant recipients treated with cyclosporin A. British Journal of Haematology, 54, 69–78. , , , , & (
- 1993) Cardiac dysfunction following spinal irradiation during childhood. Journal of Clinical Oncology, 11, 1033–1038. , , , & (
- 1994) Association of 1800 cGy cranial irradiation with intellectual function in children with acute lymphoblastic leukaemia. ISPACC. International Study Group on Psychosocial Aspects of Childhood Cancer. Lancet, 344, 224–227. , , , , , , , , , , , & (
- 1983) Are cognitive and educational development affected by age at which prophylactic therapy is given in acute lymphoblastic leukaemia? Archives of Disease in Childhood, 58, 953–958. (
- 1995) Lung function and exercise capacity in survivors of childhood leukaemia. Medical and Pediatric Oncology, 24, 222–230. , , & (
- 1984) Chronic obstructive airways disease after bone marrow transplantation. Journal of Pediatrics, 105, 370–376. , , , & (
- 1989) Normal neurodevelopment in four young children treated with bone marrow transplantation for acute leukemia or aplastic anemia. Pediatrics, 83, 753–757. , , & (
- 1978) Radiation nephritis following BMT. (Abstract). Kidney International, 14, 713. (
- 1991) Myocardial ischemia associated with high-dose carmustine infusion. Cancer, 68, 1910–1912. , , , & (
- 1992) Chronic graft-versus-host disease and pulmonary function. Pediatric Pulmonology, 14, 141–148. , , , , & (
- 1994) Late effects of bone marrow transplantation on pulmonary function in children. Bone Marrow Transplantation, 14, 613–621. , , , , & (
- 1981) Idiopathic interstitial pneumonia following bone marrow transplantation: the relationship with total body irradiation. InternationalJournal of Radiation Oncology, Biology and Physics, 7, 1365–1370. , & (
- 1976) Radiation-induced renal disease. A clinicopathologic study. American Journal of Medicine, 60, 127–137. , , , & (
- 1998) Neurological complications of radiotherapy and chemotherapy. Journal of Neurology, 245, 695–708.DOI: 10.1007/s004150050271 , & (
- 1983) Acute renal toxicity with combined use of amphotericin B and cyclosporine after marrow transplantation. Transplantation, 35, 211–215. , , , , & (
- 1998) Bone marrow transplantation in children: consequences for renal function shortly after and 1 year post-BMT. Bone Marrow Transplantation, 22, 559–564. , , , , & (
- 1997) Bronchiolitis obliterans organizing pneumonia and chronic graft-versus-host disease in a child after allogeneic bone marrow transplantation. Bone Marrow Transplantation, 19, 841–844. , , , , , , , & (
- 1990) Late complications after allogeneic bone marrow transplantation for leukaemia. Bone Marrow Transplantation, 6, 61–72. & (
- 1992) A prospective study of cognitive functioning following low-dose cranial radiation for bone marrow transplantation. Pediatrics, 90, 447–450. , , , & (
- 1997) Cognitive and adaptive behavior 1 and 3 years following bone marrow transplantation. Bone Marrow Transplantation, 19, 607–613. , , & (
- 1986) Radiation nephritis. Clinical manifestations and pathophysiologic mechanisms. Urology, 27, 389–393. & (
- 1985) Pulmonary complications of bone marrow transplantation. Chest, 87, 237–246. , & (
- 1996) Kidney function in long-term pediatric survivors of acute lymphoblastic leukemia following allogeneic bone marrow transplantation. Pediatric Hematology and Oncology, 13, 375–379. , & (
- 1992a) Exercise assessment of cardiac function in children and young adults before and after bone marrow transplantation. Pediatrics, 89, 722–729. , , & (
- 1992b) Electrocardiographic changes and arrhythmias after cancer therapy in children and young adults. American Journal of Cardiology, 70, 73–77. , , , , & (
- 1991) Late renal dysfunction in adult survivors of bone marrow transplantation[published erratum appears in Cancer 1991 September 1; 68 (5): 1112]. Cancer, 67, 2795–2800. , , , , , & (
- 1994) Effect of nephrotoxic drugs on the development of radiation nephropathy after bone marrow transplantation. International Journal of Radiation Oncology, Biology and Physics, 28/4, 883–889. , & (
- 1997) Long-term results of selective renal shielding in patients undergoing total body irradiation in preparation for bone marrow transplantation. Bone Marrow Transplantation, 20, 1069–1074. , , , , , , & (
- 1999) Late effects of chemotherapy compared to bone marrow transplantation in the treatment of pediatric acute myeloid leukaemia and myelodysplasia. Medical and Pediatric Oncology, 32, 163–169. , , , , & (
- 1987) The effect of total body irradiation and bone marrow transplantation during childhood and adolescence on growth and endocrine function. British Journal of Haematology, 67, 419–426. , , , , , & (
- 1999) Respiratory function in children undergoing bone marrow transplantation. Pediatric Pulmonology, 28, 31–38.DOI: 10.1002/(SICI)1099-0496(199907)28:1<31::AID-PPUL6>3.3.CO;2-A , , , , , , & (
- 2000) Late effects of treatment in survivors of childhood acute myeloid leukaemia. Journal of Clinical Oncology, 18, 3273–3279. , , , , , , , , , , , , , & (
- 1999) Cardioprotection. British Journal of Haematology, 106, 860–869. (
- 1994) Late effects of intensive treatment for acute myeloid leukemia and myelodysplasia in childhood. Journal of Clinical Oncology, 12, 916–924. , , & (
- 1993) Cardiovascular abnormalities in long-term survivors of childhood malignancy [editorial; comment]. Journal of Clinical Oncology, 11, 1199–1203. & (
- 1991) Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. New England Journal of Medicine, 324, 808–815. , , , , & (
- 1993a) Successful bone marrow transplantation in children with severe aplastic anemia using HLA-partially matched family donors. American Journal of Hematology, 42, 328–333. , , , , , , , , , , , & (
- 1993b) Late effects in children after bone marrow transplantation: a review. Haematologica, 78, 319–328. , , & (
- 1991) Renal function after autologous bone marrow transplantation. Bone Marrow Transplantation, 8, 129–134. , , , , , , , & (
- 1995) Decreased lung function in one year survivors of allogeneic bone marrow transplantation conditioned with high-dose busulphan and cyclophosphamide. European Respiratory Journal, 8, 1269–1274. , , , & (
- 1964) Radiation nephritis. Acta Radiologica Therapy Physical Biologica, 2, 169–178. & (
- 1997) Neurodevelopmental side effects of bone marrow transplantation: two case illustrations of identical twins. Journal of Pediatric Hematology/Oncology, 19, 145–150. , & (
- 1991) Neuropsychological function in children given total body irradiation for marrow transplantation. (Abstract). Experimental Hematology, 19, 578. , , , & (
- 1993) Cardiac study by dobutamine stress echocardiography in thalassemic patients. Bone Marrow Transplantation, 12, 14–15. , , , , & (
- 1990) Catheter-related right-sided endocarditis in bone marrow transplant recipients. Review of Infectious Diseases, 12, 250–257. , , , , , , , & (
- 1994) Bronchiolitis obliterans organizing pneumonia (BOOP) in children after allogeneic bone marrow transplantation. Bone Marrow Transplantation, 13, 221–223. , , , & (
- 1998) Meningioma in long-term survivors after allogeneic bone marrow transplantation. Bone Marrow Transplantation, 22/7, 723–724. , , , , , & (
- 1997) Late effects of allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: the impact of conditioning regimen without total-body irradiation – a report from the Societe Francaise de Greffe de Moelle. Journal of Clinical Oncology, 15, 2238–2246. , , , , , , , , , , , , , , , , & (
- 1979) Cyclophosphamide-induced cardiomyopathy: a report of two cases and review of the English literature. Cancer, 43, 2223–2226. & (
- 1996) Renal toxicity after allogeneic bone marrow transplantation: the combined effects of total-body irradiation and graft-versus-host disease. Journal of Clinical Oncology, 14, 579–585. , , , , , , , & (
- 1989) Late toxicity of total body irradiation with bone marrow transplantation in a rat model. International Journal of Radiation Oncology, Biology and Physics, 16, 1501–1509. & (
- 1990) Hepatic function and drug pharmacokinetics after total body irradiation plus Bone Marrow Transplantation. International Journal of Radiation Oncology, Biology and Physics, 19, 1389–1396. , , & (
- 1995) Long-term pulmonary sequelae after autologous bone marrow transplantation in children without total body irradiation. Bone Marrow Transplantation, 16, 771–775. , , & (
- 1999) Longitudinal clinical and functional pulmonary follow-up after megatherapy, fractionated total body irradiation,and autologous bone marrow transplantation for metastaticneuroblastoma. Medical and Pediatric Oncology, 32, 170–176. , , , , & (
- 1991) Post-irradiation vasculopathy of intracranial major arteries in children – report of two cases. Neurologia Medico-Chirurgica, 31, 336–341. , , , , , & (
- 1996) Lung function after allogeneic bone marrow transplantation for leukaemia or lymphoma. British Journal of Cancer, 74, 432–436. , , , , , & (
- 1998a) Late cardiotoxicity following anthracycline therapy for childhood cancer. Progress in Pediatric Cardiology, 8, 121–138. , & (
- 1998b) Pulmonary function after treatment for acute lymphoblastic leukaemia in childhood. British Journal of Cancer, 78, 21–27. , , , & (
- 1998c) Risk factors for reduced pulmonary function after malignant lymphoma in childhood. Medical and Pediatric Oncology, 30, 240–248. , , & (
- 1998) Neurological and neuroradiological findings in long-term survivors of allogeneic bone marrow transplantation. Annals of Neurology, 43, 627–633. , , , , & (
- 1999) Angiitis of the central nervous system after allogeneic bone marrow transplantation? Stroke, 30/8, 1656. , , , , , & (
- 1998) Late-onset noninfectious pulmonary complications after allogeneic bone marrow transplantation. British Journal of Haematology, 100, 680–687.DOI: 10.1046/j.1365-2141.1998.00617.x , , , , , , , , , & (
- 1985) Cardiovascular dysfunction in septic shock: new insights into a deadly disease. International Journal of Cardiology, 7, 314–321. (
- 1989) Motor and cognitive testing of bone marrow transplant patients after chemoradiotherapy. Perceptual and Motor Skills, 68, 1227–1241. , , , & (
- 1994) Neurological complications of organ transplantation. Annals of Neurology, 36, 688–703. (
- 1985) Neurologic complications of bone marrow transplantation. Neurology, 35, 300–306. , , , & (
- 1997) Renal function after conditioning therapy for bone marrow transplantation in childhood. Medical and Pediatric Oncology, 28, 274–283.DOI: 10.1002/(SICI)1096-911X(199704)28:4<274::AID-MPO6>3.0.CO;2-F , , , , , , , & (
- 1996) Drug-induced parkinsonism after allogeneic bone marrow transplantation. Bone Marrow Transplantation, 17/6, 1187. , , & (
- 1992) Bronchiolitis obliterans after autologous bone marrow transplantation. Chest, 101, 775–778. , , , & (
- 1978) Abnormal CT scans of the brain in asymptomatic children with acute lymphocytic leukemia after prophylactic treatment of the central nervous system with radiation and intrathecal chemotherapy. New England Journal of Medicine, 298, 815–818. , , , & (
- 1973) Renal failure in perinatally irradiated beagles. Radiation Research, 55, 399–410. , , & (
- 1975) Modification of radiation injury to normal tissues by chemotherapeutic agents. Cancer, 35, 1678–1684. , & (
- 1995) Psychological effects of bone marrow transplantation on children and adolescents: preliminary report of a longitudinal study. Bone Marrow Transplantation, 15, 829–835. , , , , & (
- 1994) Effects of bone marrow transplantation on myocardial function in children. Bone Marrow Transplantation, 13, 149–155. , , , , , , & (
- 1998) Late effects of bone marrow transplantation for childhood leukaemia – the medical cost of cure. (Abstract). Bone Marrow Transplantation, 21, S81. , , , & (
- 1989) The psychological effects of bone marrow transplantation in children. MD Thesis, Eburon, Delft, The Netherlands. (
- 1989) Longitudinal changes in pulmonary function following bone marrow transplantation. Chest, 96, 301–306. , , , & (
- 1994) The effects of bone marrow transplantation on pulmonary function in children. Pediatric Pulmonology, 18, 361–367. , & (
- 1991) Neurologic complications in allogeneic bone marrow transplant patients receiving cyclosporin. Bone Marrow Transplantation, 8, 393–401. , , , , , , , , , & (
- 1995) Neuropsychological effects of cranial radiation: current knowledge and future directions. International Journal of Radiation Oncology, Biology and Physics, 31, 983–998. & (
- 1995) Cardiac and respiratory function after bone marrow transplantation in children with leukaemia. Bone Marrow Transplantation, 16, 571–576. , , , , & (
- 1996) High-dose radiation-induced meningiomas following acute lymphoblastic leukemia in children. Childs Nervous System, 12, 266–269. , & (
- 1989) Long term effects and quality of life in children and adults after marrow transplantation. Bone Marrow Transplantation, 4, 27–29. , , , , , & (
- 1994) Negative impact of prior central nervous system (CNS) irradiation on growth and neurophychological function (NPsF) after total body irradiation (TBI) and bone marrow transplant (BMT) (Abstract). Bone Marrow Transplantation, 84, 250a. , , & (
- 1990) Late effects in children receiving total body irradiation for bone marrow transplantation. Radiotherapy and Oncology, 18, 82–87. (
- 1998) Pilot neuropsychological findings from a treatment regimen consisting of intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors. Childs Nervous System, 14, 587–589.DOI: 10.1007/s003810050277 , & (
- 1970) Marrow transplants in man utilising cyclophosphamide: summary of the Baltimore experience. Experimental Hematology, 20, 78–81. , , , , , & (
- 1995) Obstructive lung disease in children after allogeneic bone marrow transplantation: evaluation with high-resolution CT. American Journal of Roentgenology, 164, 693–696. , , , , & (
- 1994) Obstructive lung disease in children after allogeneic bone marrow transplantation. Blood, 84, 3212–3220. , , , , , , , , , & (
- 1992) A chronic pulmonary syndrome associated with graft-versus-host disease after allogeneic marrow transplantation. Transplantation, 54, 1002–1008. , , , & (
- 1984) Pulmonary function in patients undergoing bone marrow transplantation. Medical and Pediatric Oncology, 12, 137–143. , , , & (
- 1989) Pulmonary function in childhood leukaemia survivors. Medical and Pediatric Oncology, 17, 149–154. , & (
- 1986) Busulphan and cyclophosphamide cause little early toxicity during displacement bone marrow transplantation in fifty children. Bone Marrow Transplantation, 1, 193–200. , , , & (
- 1981) Nephrotoxicity of cyclosporin A after allogeneic marrow transplantation: glomerular thromboses and tubular injury. New England Journal of Medicine, 305, 1392–1395. , , , , & (
- 1995) ‘Complicated migraine-like episodes’ in children following cranial irradiation and chemotherapy. Neurology, 45, 1837–1840. , , , & (
- 1998) Neuropsychological outcome of children undergoing bone marrow transplantation. Bone Marrow Transplantation, 22, 181–184. , , , & (
- 1995) Neuropsychological deficits in very young bone marrow transplant recipients. Acta Paediatrica, 84, 429–433. & (
- 1990) Sensory-motor and cognitive functioning in children who have undergone bone marrow transplantation. Acta Paediatrica Scandinavica, 79, 613–621. , , & (
- 1995) Total body irradiation: a neuropsychological risk factor in pediatric bone marrow transplant recipients. Acta Paediatrica, 84, 325–330. , & (
- 1996) Risk factors for intellectual and educational sequelae of cranial irradiation in childhood acute lymphoblastic leukaemia. British Journal of Cancer, 73, 825–830. , , & (
- 1994) Neurologic complications after high-dose chemotherapy and autologous bone marrow transplantation for Hodgkin's disease. Neurology, 44/4, 681–684. , & (
- 2000) New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. Journal of Clinical Oncology, 18, 348–357. , , , , , , , , , , , , , & (
- 1997) Anthracycline dose in childhood acute lymphoblastic leukemia: issues of early survival versus late cardiotoxicity. Journal of Clinical Oncology, 15, 61–68. , , , & (
- 1996) Pulmonary complications of bone marrow transplantation. Chest, 109, 1066–1077. , & (
- 1991) CNS prophylaxis of childhood leukemia: what are the long-term neurological, neuropsychological, and behavioral effects? Neuropsychology Review, 2, 147–177. , , , , , & (
- 1981) Cardiac changes with cyclophosphamide. Medical and Pediatric Oncology, 9, 417–422. , , , , , & (
- 1995) Cardiac failure and dysrhythmias 6–19 years after anthracycline therapy: a series of 15 patients. Medical and Pediatric Oncology, 24, 352–361. , & (
- 1994) Pulmonary complications of tissue transplantation in children. Current Opinion in Pediatrics, 6, 272–279. (
- 1989) High-dose busulfan and seizures [letter]. Annals of Internal Medicine, 111, 543–544. , , & (
- 1991) Subclinical pulmonary function defects following autologous and allogeneic bone marrow transplantation: relationship to total body irradiation and graft-versus-host disease. International Journal of Radiation Oncology, Biology and Physics, 20, 1219–1227. , , , , , & (
- 1988) Late onset of renal dysfunction in survivors of bone marrow transplantation. International Journal of Radiation Oncology, Biology and Physics, 15, 99–104. , , , , & (
- 1986) The risks of central nervous system relapse and leukoencephalopathy in patients receiving marrow transplants for acute leukemia. Blood, 67, 195–199. , , , & (
- 1995) Long-term side-effects in children receiving allogeneic bone marrow transplantation in first complete remission of acute leukaemia. Bone Marrow Transplantation, 15, 337–341. , , , , , & (
- 1990) Pulmonary effects of cytotoxic agents other than bleomycin. Clinics in Chest Medicine, 11,31–35. & (
- 1997) Tobacco use among pediatric cancer patients: recommendations for developing clinical smoking interventions. Journal of Clinical Oncology, 15, 2194–2204. , , , & (
- 1991) Evaluation of late side-effects after bone marrow transplantation in children with leukemia. Bone Marrow Transplantation, 8, 44–46. , , , , , , , , & (
- 1987) Idiopathic small airways pathology in patients with graft-versus-host disease following allogeneic bone marrow transplantation. American Journal of Surgical Pathology, 11, 965–971. , , , , , , , & (
- 1984) Pericarditis induced by high-dose cytarabine therapy. Archives of Internal Medicine, 144, 1868–1869. & (
- 1991) Renal insufficiency after bone marrow transplantation in children. Bone Marrow Transplantation, 7, 383–388. , , & (
- 1995) Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: cranial radiation requires an accomplice [see comments]. Journal of Clinical Oncology, 13, 2490–2496. , , , , , , , , , & (
- 1988) Medical cost of curing childhood acute lymphoblastic leukaemia. British Medical Journal (Clinical Research Edition), 296, 162–166. , , & (
- 1984) Neurological complications of bone marrow transplantation in childhood. Annals of Neurology, 16, 569–576. , , & (
- 1989) High-dose thiotepa with autologous bone marrow transplantation for metastatic malignant melanoma: results of phase I and II studies of the North American Bone Marrow Transplantation Group. Journal of Clinical Oncology, 7, 245–249. , , , , , , , & (
- 1984) Airways obstruction associated with graft versus host disease after bone marrow transplantation. Thorax, 39, 887–894. , , , , , , , , & (
- 1989) Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients. American Journal of Kidney Diseases, 13, 210–216. , , , , , , & (