Tumour recurrence and enlargement in patients with craniopharyngioma with and without GH replacement therapy during more than 10 years of follow-up.

OBJECTIVE: Most patients who have been treated for craniopharyngioma (CP) are GH deficient (GHD). GH replacement therapy (GHRT) may stimulate tumour regrowth; and one of the concerns with long-term GHRT is the risk of tumour progression. Therefore, the objective was to study tumour progression in CP patients on long-term GHRT. DESIGN: Case-control study. PATIENTS AND METHODS: The criteria for inclusion of cases were: i) GHD caused by CP; ii) GHRT >3 years; and iii) regular imaging. This resulted in 56 patients (mean age at diagnosis 25±16 years) with a mean duration of GHRT of 13.6±5.0 years. As controls, 70 CP patients who had not received GHRT were sampled with regard to follow-up, gender, age at diagnosis and initial radiation therapy (RT). RESULTS: The 10-year tumour progression-free survival rate (PFSR) for the entire population was 72%. There was an association (hazard ratio, P value) between PFSR and initial RT (0.13, 0.001) and residual tumour (3.2, 0.001). The 10-year PFSR was 88% for the GHRT group and 57% for the control group. Substitution with GHRT resulted in the following associations to PFSR: GHRT (0.57, 0.17), initial RT (0.16, <0.001), residual tumour (2.6, <0.01) and gender (0.57, 0.10). Adjusted for these factors, the 10-year PFSR was 85% for the GHRT group and 65% for the control group. CONCLUSIONS: In patients with CP, the most important prognostic factors for the PFSR were initial RT and residual tumour after initial treatment. Long-term GHRT did not affect the PFSR in patients with CP.

Exercise echocardiography reveals subclinical cardiac dysfunction in young adult survivors of childhood acute lymphoblastic leukemia.

OBJECTIVE: Anthracyclines (AC) have contributed significantly to increased survival rate in acute lymphoblastic leukemia (ALL), although the use of these drugs is limited due to cardiotoxicity. The aim was to evaluate heart muscle function in asymptomatic adult survivors of ALL treated in early childhood in relation to the combined effects of AC and other potential cardiotoxic factors. PROCEDURE: Twenty-three young adult ALL survivors who had all received treatment with median 120 (120-400) mg AC/m(2) before the onset of puberty were examined median 21 years after remission and compared with 12 healthy controls. Basal echocardiography including two-dimensional (2D) M-mode and Doppler examination was performed, followed by a maximal exercise stress test and stress echocardiography immediately after stress test and after 5 min recovery. RESULTS: We found significant differences in systolic function between patients and controls at maximal exercise despite absence of reported symptoms from the patients. The most marked difference was in ejection fraction at stress 59.5% (32.6-81.1) and 77.3% (66.2-85.3), respectively (P < 0.00006). Ten out of 23 patients reduced their ejection fraction at stress compared with at rest; this was not found in any of the controls. Cardiovascular risk factors such as GH deficiency and a high proportion of trunk fat did not have an impact on cardiac function. CONCLUSIONS: With very long follow up in a homogenous cohort of ALL survivors, we found subclinical cardiac dysfunction with exercise stress echocardiography even after low doses of AC.

Bone mineral density and bone turnover in young adult survivors of childhood acute lymphoblastic leukaemia.

OBJECTIVE: Treatment for childhood leukaemia induces many risk factors for development of decreased bone mineral density (BMD). Physical activity is also known to affect BMD. The aim was to study BMD and markers of bone turnover in a well-defined group of survivors of acute lymphoblastic leukaemia (ALL) who had all reached final height as well as peak bone mass, taking both previous treatment and physical activity into consideration. DESIGN: All patients treated for ALL before the onset of puberty in the region of western Sweden, between 1973 and 1985, in first remission were included. Thirty-five out of forty-seven patients aged 20-32 years participated. Nineteen patients had received cranial radiotherapy, and the median follow-up time was 20 years. METHODS: BMD was assessed using dual-energy X-ray absorptiometry (DEXA). Serum concentrations of markers of bone turnover were analysed. Physical performance was measured using a performance exercise capacity stress test. RESULTS: BMD was slightly reduced in lumbar spine (-0.4 SD), but not in femoral neck or total body. BMD in femoral neck was correlated to physical performance and dose of corticosteroid, but no correlation was found with spontaneous growth hormone (GH) secretion. Markers of bone turnover were also correlated to physical performance, but not to GH secretion. CONCLUSIONS: Physical fitness seems to be the most important factor in developing and preserving normal bone mineral density in ALL patients. We propose that lifestyle education promoting physical activity is encouraged from an early point in time for these patients.

Body composition in young adult survivors of childhood acute lymphoblastic leukaemia.

OBJECTIVE: Obesity is frequently reported in patients treated for childhood leukaemia. Obesity, particularly abdominal obesity, is one of the main characteristics of the metabolic syndrome and a risk factor for cardiovascular disease and non-insulin-dependent diabetes mellitus (NIDDM). DESIGN: All patients treated for acute lymphoblastic leukaemia (ALL) before the onset of puberty in the region of western Sweden, between 1973 and 1985, and in first remission, were included. 35 out of 47 patients aged 20-32 years participated. 19 patients had received cranial radiotherapy, and the median follow-up time was 20 years. The focus of this report was to study body composition and signs of the metabolic syndrome and correlate the findings to spontaneous growth hormone (GH) secretion. METHODS: Body composition was assessed using dual-energy X-ray absorbtiometry (DEXA). We analyzed serum concentrations of insulin, glucose, leptin and lipids. RESULTS: No patient was obese according to World Health Organization criteria (body mass index, BMI > or = 30 kg/m2) but one-third were overweight (BMI 25-29.9 kg/m2). The maximal GH peak during 24 h (GHmax) was correlated to percentage of total body fat (r = -0.42; P = 0.017), trunk fat (r = -0.5; P = 0.005) and fat-free mass (r = 0.42; P = 0.017). GHmax was also correlated to s-triglycerides (r = -0.54; P = 0.001), low-density lipoprotein-cholesterol (r = -0.382; P = 0.024) and high-density lipoprotein-cholesterol (r = 0.45; P = 0.007). CONCLUSIONS: We found little effect on BMI but an increased percentage of total body fat, especially trunk fat, and a tendency for an unfavourable lipid profile in adult survivors of childhood leukaemia. These findings were related to low endogenous GH secretion due to cranial irradiation.

Young adult survivors of childhood acute lymphoblastic leukemia: spontaneous GH secretion in relation to CNS radiation.

BACKGROUND: Young adults who are long-term survivors of acute lymphoblastic leukaemia (ALL) in early childhood usually do well and do not have to go to regular medical checkups. Many of these survivors did receive prophylactic cranial radiotherapy during their oncological treatment. The effect of cranial irradiation on the hypothalamus is considered to be progressive. Therefore, late effects, such as reduced growth hormone (GH) secretion, may remain undetected until adulthood. PROCEDURE: Records from all patients treated for ALL before the onset of puberty in the region of West Sweden, between 1 January 1973 and 31 December 1985 were included, provided they were in first remission with a minimum follow-up time of 15 years, and a minimum age of 20. These criteria were met by 47 young adults aged 20-32 years, of whom 35 agreed to participate. We studied spontaneous GH secretion over 24 hr, IGF-I and IGFBP-3, final height and BMI. The patients had been treated according to three consecutive Swedish childhood leukaemia group protocols. The median follow-up time was 20 years, and 19 of the patients had been treated with cranial irradiation (CRT+), 16 had not (CRT-). RESULTS: CRT+ patients had significantly lower maximal peaks of GH than CRT- patients. Fifty percent of the CRT+ patients had a GH(max) below the cut-off level (3.3 microg/l), for GH treatment. CRT- patients all had GH(max) levels considered within the normal range. Final height of all the patients, except one CRT+ women, was in the range of expected midparental height, the median loss in final height in the CRT+ patients was 0.8 standard deviation (SD). No patient in this study was obese by definition (BMI <30 kg/m(2)). IGF-I and IGFBP-3 concentrations did not correlate to variations in spontaneous GH secretion in these patients. CONCLUSIONS: In spite of the little effect on final height, we found impaired spontaneous GH secretion in 79% of young adults 20-32 years of age, and GH deficiency (GHD) in 47% after low-dose cranial irradiation in early childhood. The consequences of this low-GH secretion need to be investigated.

High-dose methotrexate: on the relationship of methotrexate elimination time vs renal function and serum methotrexate levels in 1164 courses in 264 Swedish children with acute lymphoblastic leukaemia (ALL).

PURPOSE: The objectives of the present study were to determine the relationship between methotrexate (MTX) elimination time and various aspects of renal function and to evaluate the prognostic value of elevated serum MTX and creatinine for delayed MTX elimination. PATIENTS AND METHODS: The majority of the 264 children were being treated for ALL. According to the NOPHO-92 protocol, 5 or 8 g MTX/m(2) was administered over 24 h. Serum creatinine was assessed daily. In 11 patients from one centre, renal function was studied in more detail using serum cystatin C, iohexol clearance, and urinary albumin, IgG and protein HC. RESULTS: Increased serum creatinine correlated significantly with the elimination time of MTX, whereas no indications were found of tubular or barrier function damage. Of the 1164 courses, 44 had delayed elimination of MTX (>/=120 h). Serum MTX >150 microM at the end of infusion had a sensitivity of 0.27 and a specificity of 0.94 to predict delayed MTX elimination, and >/=50% increase in serum creatinine during the first treatment day (creatinine ratio) had a sensitivity of 0.32 and a specificity of 0.99. The corresponding risk ratios were 5 and 19 for MTX >150 micro M and creatinine ratio, respectively. In courses with a normal elimination time (<72 h), 99% of the courses had a rise in serum creatinine of less than 50%. CONCLUSIONS: Elevation of serum creatinine by more than 50% is a better predictor of delayed elimination than the level of serum MTX at the end of MTX infusion, especially if information on previous creatinine measurements is used to reduce the impact of an occasionally low serum creatinine value before the start of the MTX infusion.

Proinflammatory cytokines mediate the systemic inflammatory response associated with high-dose cytarabine treatment in children.

BACKGROUND: Treatment with high-dose cytarabine (1-beta-D-arabinofuranosylcytosine) is often associated with an acute febrile reaction sometimes including abdominal pain, myalgia, and rash. The similarity of these symptoms to those caused by hypersecretion of cytokines in the systemic inflammatory response syndrome (SIRS) prompted us to investigate the plasma levels of proinflammatory cytokines during treatment of children with high-dose cytarabine. PROCEDURE: Sixteen children treated for hematological malignancies and in clinical remission were studied during treatment with six infusions of cytarabine given every 12 hr at a dose of 2 g/m(2). Blood samples for analysis of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1gamma (IL-1gamma), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10) and interleukin-1 receptor antagonist (IL-1ra) were obtained prior to treatment and subsequently at 12, 36 and 60 hr. Additional samples were collected as soon as fever occurred. RESULTS: Thirteen of 16 patients developed fever at a median time of 30 hr following start of treatment. At 12 hr levels of TNF-alpha were elevated followed by a rise in IL-6, IFN-alpha, and IL-1ra, peaking at the onset of fever. Thereafter these levels slowly declined whereas low IL-10 levels became detectable. CONCLUSIONS: We conclude that high-dose cytarabine treatment often induces release of TNF-alpha followed by the sequential release of other proinflammatory cytokines. Most likely these cytokines mediate the development of symptoms comprising the cytarabine syndrome.