Endothelial function in young adult survivors of childhood acute lymphoblastic leukemia

BACKGROUND: Adult survivors of childhood acute lymphoblastic leukemia (ALL) have an earlier than expected mortality from cardiovascular disease. This study examined endothelial function in 75 young (age 30.2+/-7.1 y) adult survivors of childhood ALL who received chemotherapy without cranial radiation (n=25) or chemotherapy combined with cranial radiation (n=50) compared with a healthy control group of similar sex, age, and weight (n=59). PROCEDURE: As part of a clinical follow-up study, endothelial-dependent flow-mediated dilation (FMD: % change in artery diameter after 5 min of occlusion) was assessed using high-resolution ultrasound of the brachial artery. Fifteen minutes after the measurement of FMD, sublingual nitroglycerin (0.4 mg) was administered and the brachial artery was imaged using ultrasound to assess endothelial-independent dilation (EID). All ultrasound imaging data were adjusted for baseline diameter. RESULTS: The healthy comparison group had a significantly greater FMD response (9.5%+/-2.9%) than both the chemotherapy only (6.5%+/-2.6%) and chemotherapy combined with radiation (7.1%+/-2.6%) groups. No statistical differences were observed in nitrate-mediated EID between the healthy comparison group (27.0%+/-5.0%) and the chemotherapy only (24.7%+/-6.7%) or chemotherapy combined with radiation (25.2%+/-7.1%) groups. Among the ALL survivors, female subjects had a significantly greater FMD and nitrate-mediated EID than male subjects even after correcting for baseline brachial artery diameter. CONCLUSIONS: These data suggest that young adults treated for ALL during childhood are at risk for impaired FMD regardless of whether or not they received cranial irradiation. The extent to which this mechanism relates to early development of cardiovascular disease in long-term childhood ALL survivors remains to be determined.     

Long-term neurocognitive outcomes in young adult survivors of childhood acute lymphoblastic leukemia

Five-year survival rates of childhood acute lymphoblastic leukemia (ALL) exceed 80% due to central nervous system-directed treatment including cranial radiation (CRT) and chemotherapy. However, these treatments are associated with neurocognitive compromise, the extent of which is correlated with higher dose and younger age at treatment. The aims of this study were to explore long-term neurocognitive outcomes in adult survivors of childhood ALL, and to identify measures sensitive to neurotoxicity in long-term survivors. We examined 24 adults who received 18 Gy CRT and chemotherapy for treatment of ALL between ages 2 and 15 years (median, 5.5). Time since diagnosis ranged from 6 to 26 years (median, 16.6). Younger age at diagnosis and longer time since diagnosis were associated with lower scores on a computerized battery that requires speed and accuracy across a number of domains (MicroCog), and other standardized neurocognitive tests. When compared with population norms, MicroCog indices were below average in survivors diagnosed with ALL before age 5, but only the reasoning/calculation index was below average in survivors diagnosed with ALL after age 5. In contrast, intelligence quotient (IQ) scores were average. In addition to confirming earlier studies showing that younger children are more vulnerable to treatment-related neurotoxicity, here we show that deficits exist many years post treatment even with a relatively lower dose of CRT, and that these deficits are especially evident on tasks involving rapid processing of information.     

Cardiovascular risk factors in young adult survivors of childhood acute lymphoblastic leukemia

PURPOSE: To assess cardiovascular risk factors (CVRF) in young adult survivors of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Twenty-six subjects (median age, 20.9 years; median interval since completion of therapy, 13.3 years) were evaluated. Ten participants had received cranial irradiation (CRT), whereas 16 had received only chemotherapy. Primary outcome measures included body mass index (BMI), blood pressure, fasting lipoprotein, glucose, and insulin levels. Secondary measures included insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 levels, physical activity index, a 7-day dietary recall, tobacco product use, and measurement of the intima-media thickness (IMT) of the common carotid artery. RESULTS: Sixty-two percent (16/26) of participants had at least one CVRF potentially related to their cancer treatment (obesity, dyslipidemia, increased blood pressure, or insulin resistance), with 30% (7/26) having more than two CVRF. Thirty-one percent (8/26) of subjects were obese (BMI > or = 30). Subjects who were treated with CRT (BMI, 30.4 +/- 6.7) had an increased BMI (P = 0.039) in comparison with those who received only chemotherapy (BMI, 25.4 +/- 5.1). Triglyceride and very low-density lipoprotein C levels were significantly higher in those treated with CRT (P = 0.027 and 0.022, respectively). The IGF-1 was inversely correlated with IMT (total group, -0.514, P = 0.009; females only, -0.729, P = 0.003). CONCLUSIONS: Young adult survivors of childhood ALL, especially those treated with CRT, are at risk for obesity and dyslipidemia, insulin resistance, hypertension, and cardiovascular disease. Further investigation of these risks is warranted.     

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.     

Changes in bone mineral density in survivors of childhood acute lymphoblastic leukemia

BACKGROUND: There is little information about factors modulating bone mineral density (BMD) in survivors of childhood acute lymphoblastic leukemia (ALL). PROCEDURE: We analyzed data from 57 survivors (26 male, 52 Caucasian) who underwent two serial quantitative computed tomography (QCT) studies of BMD. Using multiple linear regression, we evaluated the association of BMD change with demographic variables, treatment history, hormone therapy, exercise, and tobacco and alcohol use. RESULTS: The median age was 3.4 years (range, 0.9-17.4 years) at diagnosis of ALL; the median age at the first QCT (Study I) was 15.0 years (range, 10.6-31.0 years) and at the second QCT (Study II) was 18.2 years (range, 14.2-35.3 years). Mean height increased 4.7 cm and mean weight increased 8.8 kg between Studies I and II. While the mean BMD increased 9.33 mg/cc (P = 0.003), the BMD Z-score increased only slightly (0.21 SD, P = 0.035). Cortical bone density increased significantly (approximately 25.3 mg/cc; P = 0.001), but the ratio of trabecular to cortical BMD decreased significantly (P = 0.045). Factors independently associated with unfavorable BMD changes included older age at diagnosis (P = 0.001), female sex (P = 0.018), and nutritional supplementation (0.032). Alcohol (P = 0.009) was an unfavorable factor in a univariable analysis. CONCLUSIONS: Bone mineral accretion during adolescence is attenuated in childhood ALL survivors by a comparative deficit in trabecular versus cortical bone deposition. BMD is influenced favorably by exercise in early adolescence and unfavorably by the use of nutritional supplements and alcohol. These results provide new information about behavioral factors that affect bone accrual in survivors of childhood ALL and warrant definitive evaluation in a larger cohort.     

Screening survivors of childhood acute lymphoblastic leukemia for obesity, metabolic syndrome, and insulin resistance

Acute lymphoblastic leukemia (ALL) survivors were screened for risk factors of cardiovascular disease. Forty-four ALL survivors in first remission were enrolled. Twenty-six also received 12-18 Gy cranial radiotherapy (RT). Patients' body mass indexes (BMIs) at dignosis and during the study were compared. Metabolic syndrome (MS) evaluation was performed in patients, parents, and siblings older than 6?years. Homeostasis Model Assessment (HOMA) index of the survivors was also calculated. In survivors with impaired fasting glucose levels, oral glucose tolerance test (OGTT) was performed. Thyroid functions and IGF-1 and/or IGFBP-3 levels of the survivors who received cranial RT were evaluated. Median age of the survivors was 11.5?years (6-23). At diagnosis, mean BMI percentile was 46.7 (3-95) and mean z-score was -0.09 ± 1.14; during the study, these values rose to 71.1 ± 25.6 (3-100) and 0.8 ± 0.94, respectively (P < .001). One patient (2.2%) and nine survivors (20%) were obese at diagnosis and during the study, respectively (P = .005). Survivors had significantly higher BMI percentile and BMI z-score compared to their siblings (P = .006 and P = .011, respectively). The study group was small and we could not show a correlation of the patients' obesity with RT, thyroid functions, IGF-1, and IGFBP-3 levels. In three survivors (6.8%), there was MS. Maternal and paternal MS was not found as a risk factor for MS of the survivors (P = .1, P = .5, respectively). The HOMA index revealed insulin resistance (IR) in 12 (27.2%) of the survivors, whereas OGTT revealed abnormal glucose regulation and/or IR in four. As a conclusion, ALL survivors have high risk for obesity and MS.     

Poor adherence to dietary guidelines among adult survivors of childhood acute lymphoblastic leukemia

Recent studies indicate that survivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk of obesity and cardiovascular disease, conditions that healthy dietary patterns may help ameliorate or prevent. To evaluate the usual dietary intake of adult survivors of childhood ALL, food frequency questionnaire data were collected from 72 participants, and compared with the 2007 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Cancer Prevention recommendations, the Dietary Approaches to Stop Hypertension (DASH) diet, and the 2005 United States Department of Agriculture (USDA) Food Guide. Mean daily energy intake was consistent with estimated requirements; however, mean body mass index was 27.1 kg/m2 (overweight). Dietary index scores averaged fewer than half the possible number of points on all 3 scales, indicating poor adherence to recommended guidelines. No study participant reported complete adherence to any set of guidelines. Although half the participants met minimal daily goals for 5 servings of fruits and vegetables (WCRF/AICR recommendations) and 相似文献   

Reduction of adult height in childhood acute lymphoblastic leukemia survivors after prophylactic cranial irradiation

BACKGROUND: Impaired linear growth is a well-recognized complication in long-term childhood ALL survivors who received cranial irradiation. However, as many patients achieve a final height between the 5th and the 95th centile, the true incidence of linear growth impairment might be underestimated. METHODS: Reduction of adult height (RAH) was estimated in adult childhood ALL survivors with and without cranial irradiation. RAH was calculated as the difference between target height (TH) and final height (FH). TH was calculated according to the formula TH = {[(height father + height mother +/- 12)/2] + 3}. RAH was assessed in 79 adult childhood ALL survivors in first complete remission who had received cranial irradiation 25 Gy (Group I, n = 53), 18 Gy (Group II, n = 10) or chemotherapy alone (controls, n = 16). RESULTS: RAH was 8.6 +/- 8.2 cm in Group I (P = 0.001 vs. controls), 6.2 +/- 3.2 cm in Group II (P = 0.01 vs. controls), and 1.7 +/- 4.6 in controls (chemotherapy only). There was no significant difference between Group I and Group II. In Group I females had more RAH than males (P = 0.02). RAH was related to younger age at diagnosis (P = 0.001). CONCLUSIONS: The deficit between target height and final height highlights the reduction of adult height in the majority of male and female childhood ALL survivors who had received prophylactic cranial irradiation, in particular in those who were diagnosed at a younger age. This reduction would have been masked if patients FH was only compared with standard methods. RAH might be a sensitive predictor for growth hormone deficiency as these results suggest that radiation-induced growth hormone deficiency in these patients is the rule rather than the exception.     

Body composition, muscle strength deficits and mobility limitations in adult survivors of childhood acute lymphoblastic leukemia

BACKGROUND: Chronicity of muscle weakness from cancer and its treatment may be problematic, particularly in those treated for cancer during childhood. We compared body composition, muscle strength, and mobility between 75 adult survivors of childhood acute lymphoblastic leukemia (ALL) and expected values based on population normative data. METHODS: Subjects were young adults treated for childhood ALL between 1970 and 1986, selected randomly from participants in an ongoing study of cancer survivors. DeXA scans were performed to evaluate body composition, and myometry used to measure strength. Mobility was evaluated with the Timed Up and Go (TUG) and 2-min walk (TMW). One sample t-tests compared ALL survivors to population norms. RESULTS: Males had 4.5% and females had 2.3% more body fat than expected (expected males 21.5%, females 36.0%). Males were 76.7 Newtons and females were 58.6 Newtons weaker in quadriceps strength than expected (expected males 569.87 N, females 464.67 N). Males walked 100.88 m and females walked 85.38 m less on the TMW (expected values: males 304.23 m, females 276.26 m), and took longer to complete the TUG (males 5.82 vs. 2.84 sec, females 5.88 vs. 3.00 sec) than expected. Treatment with cranial radiation and current growth hormone (GH) deficiency were associated with lower body weakness among females. CONCLUSIONS: Young adult survivors of childhood ALL have strength and mobility deficits. Decreased strength may reduce ability to participate in physical activity, perpetuating fitness deficits in survivors of childhood ALL.     

Bone mineral density in survivors of childhood acute lymphoblastic leukemia

The aim of our study was to evaluate bone metabolism with measurement of bone mineral density (BMD) after management (chemo-, radiotherapy) for childhood acute lymphoblastic leukemia (ALL). Bone mineral density (g/cm2) of lumbar spine was measured by dual energy X-ray absorptiometry (Norland bone densitometer) in 18 children with ALL and a median of 34 months' post-diagnosis with no history of relapse, secondary malignancy, or transplantation. In addition, patients' BMDs were correlated with particular attention to age, sex and time (years) from completion of chemotherapy. The results were compared with healthy age- and sex-matched controls of the same population and expressed as standard deviation scores (SDS). Mean age of children was 9.8 +/- 3.7 years. Of 18 children (10 boys and 8 girls), 13 were grouped as standard and 5 as high-risk, respectively. Based on z-score values, 9 were classified as normal (z-score <1 SD), 7 as osteopenic (z-score 1-2.5 SD) and 2 as osteoporotic (z-score >2.5 SD). Children with ALL had reduced lumbar BMDs (z score -0.99) in comparison to healthy controls (z score -0.14) (p=0.011), which is indicative of relative osteopenia. Moreover, the reduced BMD was associated with patient age (z score -0.14 and -1.52 for ages <10 and >10 years, respectively, p=0.016). Reduced BMD was not correlated with time from completion of chemotherapy (p=0.33), risk group (p=0.9) and sex (p=0.3). We conclude that children's BMDs are reduced after completion of chemotherapy for ALL. The causes are multifactorial and mainly related to antineoplastic treatments, such as corticosteroids and methotrexate, physical inactivity and cranial irradiation. We suggest that further studies are needed to evaluate the long-term effect on BMD in these children and to prevent pathological fractures later in life.     

Low depressive symptom and mental distress scores in adult long-term survivors of childhood acute lymphoblastic leukemia

Childhood cancer survivors are thought to be at risk of psychological difficulties. We examined the prevalence of depressive symptoms and mental well-being in adult long-term survivors of childhood acute lymphoblastic leukemia (ALL) at a mean age of 20 years after the cessation of therapy. Depressive symptoms were assessed with Beck Depression Inventory (BDI-21) and mental distress with General Health Questionnaire (GHQ-12) among 73 ALL survivors and 146 healthy controls. The ALL survivors obtained significantly lower BDI scores (P=0.046) compared with the controls, indicating less depressive symptoms among the ALL survivors. BDI scores indicated a significantly less frequent moderate or severe depression in the ALL survivors compared with the controls (P=0.039). BDI scores indicated no depression in 80.8% of the ALL survivors and 73.3% of the control group. The female ALL survivors obtained lower BDI scores than did the female controls (P=0.005). No difference was found in GHQ-12 scores between the survivors and the controls. Survivors of ALL reported fewer depressive symptoms and equal mental well-being compared with healthy controls. Our findings support the idea that childhood leukemia survivors' subjective experience of well-being is possibly affected by repressive adaptive style.     

Mediastinal mass in childhood T-cell acute lymphoblastic leukemia: significance and therapy response

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 10-13% of childhood ALL cases. Patients with T-ALL frequently present with unfavorable features at diagnosis and thus are considered to have a higher risk to relapse. Within the last 10 years, the previously dismal prognosis of this ALL subtype has been improved by intensified chemotherapy. However, 30-40% of patients still relapse, so that additional prognostic factors such as the local response of the mediastinal mass to therapy might allow defining the patients at risk in a better manner. PROCEDURE: A retrospective analysis of 116 Austrian patients with T-ALL was performed to assess whether an initial mediastinal mass (70/116) and its response to chemotherapy as measured by thoracic X-rays (32/70) might predict outcome. RESULTS: Neither patients with a mediastinal tumor at the time of diagnosis nor patients with an incomplete response on day 35 or 70 of therapy had a worse prognosis, as compared with the group of patients with no initial tumor and complete regression on day 35 and 70. CONCLUSIONS: We failed to show that in children with T-ALL residual mediastinal tumors are of prognostic relevance. This might suggest that incomplete local response is not necessarily an indication for treatment intensification such as local irradiation, second-look operation, or high-dose chemotherapy with bone marrow rescue. However, due to the relatively small number of patients analyzed, our results have to be validated prospectively on a larger cohort of patients in future clinical trials.     

Fatigue in survivors of childhood acute lymphoblastic and myeloid leukemia in Japan

Background: Fatigue in cancer survivors is a serious problem in pediatric oncology, but reports on this issue are limited, especially in Asian countries. Methods: Sixty‐three patients with acute lymphoblastic leukemia and 18 patients with acute myeloid leukemia who attended a follow‐up outpatient clinic were enrolled. Participants were required to be >8 years of age, in remission, and without any cancer treatment for at least the previous 1 year. A control group consisted of 243 subjects whose age and gender were matched with the patient group. A questionnaire consisting of 12 items was devised for fatigue measurement. Results: Principal factor analysis identified three dimensions, defined as physical fatigue, decreased function, and altered mood. The mean total and the three fatigue dimension scores tended to be higher in the control group, but significant differences between the scores were seen only in the total and physical fatigue scores. Multiple regression analysis indicated an association of present older age or shorter duration after completion of treatment with total and physical fatigue, and an association of presence of total body irradiation with decreased function. Conclusion: Pediatric leukemia survivors in Japan experience equal or less fatigue compared with that of controls in different fatigue dimensions. Elucidation of underlying mechanisms of cancer‐related fatigue including the differences of cultural background among different countries is necessary for future study of this issue.     

Computerized psychometry screening in long-term survivors of childhood acute lymphoblastic leukemia

This study assessed the diagnostic utility of a computerized psychometry battery of tests: the Bexley-Maudsley Automated Psychological Screening Test and Category Sorting Test in the screening for deficits in cognitive function in a population of children who had been treated for acute lymphoblastic leukemia. Central nervous system therapy with radiotherapy and intrathecal chemotherapy has been incriminated as a cause of psychological morbidity in survivors. Twenty-nine children who were surviving in their first hematological remission, following cessation of their treatment for acute lymphoblastic leukemia, were studied. No child had evidence of central nervous system leukemic involvement, and they were all attending normal schools. Their performances were compared with 29 control children matched by age, sex, and social class. The children treated for leukemia showed a reduced ability to sustain attention (p less than 0.025), a reduction in verbal recognition short term memory (p less than 0.02), and difficulties in abstract problem solving (p less than 0.01). These results confirm the presence of neurophysical morbidity in children treated for acute lymphoblastic leukemia. It is suggested that this computerized psychometry test battery is a useful method for examining children at risk of neurological impairment and identifies specific deficits that require further evaluation and remedial help.