Long-term Survivors Of Childhood Leukemia Research Articles

Chronic Graft-Versus-Host Disease in Long-Term Survivors of Childhood Leukemia

Introduction: Hematopoietic stem cell transplantation (HSCT) remains a key treatment of high-risk childhood leukemia despite a wide range of long-term complications. Chronic graft-versus-host disease (cGvHD) is a severe complication of HSCT characterized by the immune response of transplanted cells against the recipient's organs. Adults undergoing HSCT are particularly susceptible to experiencing cGvHD. This complication is generally considered to be much less common when HSCT is performed during childhood and adolescence, though very limited long-term data is available. The present study from the LEA program aims to provide a better understanding of cGvHD and its long-term impact in long-term childhood leukemia survivors. Methods: LEA is a long-term follow-up program involving all childhood acute leukemia survivors treated in the French participating centers since 1980 (clinicaltrials.gov identifier: NCT01756599). The patients eligible to the present study were all patients included in the LEA cohort treated with HSCT. The primary objective of this cross-sectional study was to provide a long-term and comprehensive cGvHD evaluation in childhood leukemia survivors. Secondary objectives included identifying risk factors for cGvHD, assessing the impact of the disease on quality of life (QoL), and evaluating its evolution over time. The long-term cGvHD data were generated during an in-person dedicated follow-up visit by a clinician using 1) a dedicated questionnaire, and 2) the eGVHD application (UZ Leuven, Belgium) for standardizing the evaluation. QoL was evaluated using the SF36 questionnaire. Results: The study included a cohort of 446 patients treated for acute lymphoblastic leukemia (59%), acute myeloid leukemia (34%), or another hematological malignancy (7%). The age at HSCT was 8.9 ±0.3 years (mean ±standard error of mean). The dedicated long-term evaluation of cGvHD was performed 8.8 ±0.3 years after HSCT. The stem cell source was matched sibling donor (32%), mismatched related donor (9%), unrelated donor (37%), and cord blood (22%). HSCT was performed in first complete remission in 47% of patients. Myeloablative conditioning and total body irradiation were administered to 91% and 56% of patients, respectively. Anti-thymocyte globulin and ciclosporin were given to 49% and 94% of patients, respectively. At the time of the study, most patients never experienced (n=324, 73%) or recovered (n=28, 6%) from cGvHD. However, a significant proportion of patients (n=94, 21%) suffered long-term cGvHD of variable severity (45% mild, 33% moderate, and 22% severe) (Figure 1). Patients mostly had isolated organ defects (most frequently skin, eyes, and mouth defects). Multiple organs defects were also reported in some patients without recurrent patterns. At the time of cGvHD evaluation, patients suffering cGvHD mostly remained untreated (83%, n=78). Systemic treatment (ruxolitinib, ciclosporine, ibrutinib, and sirolimus), as well as local treatment were used in 11% and 5% of patients, respectively. cGvHD was significantly associated with several other long-term complications (thyroid function defects, cataract, lung function defects, osteonecrosis, diabetes). In a multivariate analysis (Table 1), age at HSCT was significantly associated with long-term cGvHD (odds ratio 1.06 for each additional year, 95% confidence interval 1.01-1.1, p=0.01). Sex, type of leukemia, time from HSCT, stem cell source, relapse, number of HSCT and total body irradiation were not significantly associated with long-term cGvHD risk. Long-term cGvHD had a marked detrimental effect on QoL, even after adjusting to the total number of other long-term complications. The physical and psychic SF36 adjusted composite scores in patients with versus without cGvHD were 50 ±1.5 versus 55 ±0.7 (p=0.01) and 38 ±1.9 versus 43 ±1.0 (p=0.01), respectively. Conclusion: This study shows that cGvHD is a frequent and severe complication in long-term survivors of childhood leukemia treated with HSCT. Higher age at HSCT is the main risk factor for long-term cGVHD in this population. Long-term cGvHD significantly and independently jeopardizes the survivors' QoL. This complication is probably underrecognized and undertreated. There is a great need for a systematic and standardized cGvHD evaluation in this population.

Right Ventricular Function in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia: From the CTOXALL Study

There are limited data regarding right ventricle (RV) impairment in long-term survivors of childhood acute lymphoblastic leukemia (CLS). The aim of this study was to assess RV function in these patients using echocardiographic conventional measurements and automated RV strain. Echocardiographic recordings of 90 CLS and 58 healthy siblings from the CTOXALL cohort were analyzed. For group comparisons, inverse probability weighting was used to reduce confounding. The CLS group (24.6 ± 9.7 years, 37.8% women) underwent an echocardiographic evaluation 18 (11–26) years after the diagnosis. RV systolic dysfunction was found in 16.7% of CLS individuals using RV free-wall strain (RVFWS) compared to 2.2 to 4.4% with conventional measurements. RV systolic function measurements were lower in the CLS than in the control group: TAPSE (23.3 ± 4.0 vs. 25.2 ± 3.4, p = 0.004) and RVFWS (24.9 ± 4.6 vs. 26.8 ± 4.7, p = 0.032). Modifiable cardiovascular risk factors such as obesity (p = 0.022) and smoking (p = 0.028) were independently associated with reduced RVFWS. In conclusion, RV systolic function impairment was frequent in long-term survivors of childhood leukemia, underscoring the importance of RV assessment, including RVFWS, in the cardiac surveillance of these patients.

Severity of reduced bone mineral density and risk of fractures in long-term survivors of childhood leukemia and lymphoma undergoing guideline-recommended surveillance for bone health

BACKGROUND Survivors of childhood leukemia/lymphoma are at increased risk for reduced bone mineral density (BMD). The authors sought to determine the frequency of reduced BMD detected by off-therapy surveillance, factors associated with reduced BMD, and the association of reduced BMD with fractures. METHODS This cross-sectional study included childhood leukemia/lymphoma survivors attending 2 survivorship clinics who received guideline-recommended BMD surveillance ≥2 years post-therapy with dual-energy x-ray absorptiometry (from January 1, 2004 to August 31, 2016). Lumbar spine BMD z-scores were height-for-age-adjusted. Low and very low BMD were >1 SD and >2 SDs below norms, respectively. Treatment, chronic conditions, and fractures were abstracted from medical records. Logistic regression was used to examine the association of low BMD with patient/treatment factors and fractures. RESULTS In total, 542 patients (51.5% female) with a mean age of 15.5 years (range, 4.4-52.2 years) who were 6 years post-therapy (range, 2.0-35.1 years) were evaluated, including 116 who reported post-therapy fractures. Lumbar spine low BMD was identified in 17.2% of survivors, and very low BMD was identified in 3.5% of survivors, but frequencies varied considerably between subgroups; 10.8% of survivors aged 15 to 19 years at diagnosis had very low BMD. In multivariable analyses, older age at diagnosis, white race, and being underweight were significantly associated with low BMD. Survivors with low BMD had greater odds of nondigit fractures (odds ratio, 2.2; 95% CI, 1.3-3.7) and specifically long-bone fractures (odds ratio, 2.7; 95% CI, 1.5-4.7). CONCLUSIONS In this study of childhood leukemia/lymphoma survivors undergoing guideline-recommended dual-energy x-ray absorptiometry surveillance, patients who were older at diagnosis, white, and underweight were at the highest risk for lumbar spine low BMD. Low BMD was associated with a greater risk of fractures, emphasizing the clinical importance of surveillance.

Effect of Dexrazoxane on Heart Function Among Long-Term Survivors of Childhood Leukemia and Lymphoma: A Report from the Children's Oncology Group (COG)

Background:Dexrazoxane (DRZ) has been shown to have cardioprotective effects among doxorubicin-treated childhood cancer survivors up to 5-years after therapy completion, including effects on fractional shortening (FS%) and other parameters of left ventricular anatomy and function. However, data on longer-term effects are lacking.Methods: COG protocols P9404 (T-cell acute lymphoblastic leukemia/lymphoma; cumulative doxorubicin 360 mg/m2), P9425 (advanced stage Hodgkin lymphoma; cumulative doxorubicin 180-300 mg/m2), and P9426 (low/intermediate stage Hodgkin; cumulative doxorubicin 100-200 mg/m2) were phase 3 randomized clinical trials conducted between 1996 and 2001. Patients were randomly assigned to treatment with or without DRZ (10:1 mg dose ratio of DRZ:doxorubicin); DRZ was given as an intravenous bolus before each doxorubicin dose. Beginning in 2014, a subset of COG institutions began prospectively reassessing the cardiovascular health of long-term survivors in first complete remission treated on these 3 protocols, including echocardiography and selected blood biomarkers (e.g., high-sensitivity troponins, b-type natriuretic peptides [BNP], N-terminal [NT] proBNP). Echocardiograms and blood analytes were all processed centrally, with DRZ status masked.Results: To date, 94 participants (54% DRZ+; 57% male; average doxorubicin dose 279 mg/m2; current mean age 28 years and 16 years since cancer diagnosis) have been recruited from 30 institutions. Participants were similar with respect to demographic and treatment characteristics when compared by DRZ status. Overall, compared with DRZ+ participants, DRZ- participants had non-significantly reduced FS% (mean±SD: 33.0±4.8 vs. 34.8±4.6; p=0.10), but greater myocardial wall stress and dysfunction as measured by BNP (mean±SD: 18.3±14.7 vs. 11.3±10.6 pg/mL; p=0.02) and NT-proBNP (64.8±55.5 vs. 44.5±39.0 pg/mL; p=0.06). When the analysis was restricted to those who received the greatest doxorubicin exposure (P9404 participants, n=41), differences all became statistically significant (FS%: 31.3±3.9 vs. 34.9±3.7, p<0.01; BNP and NT-proBNP: p=0.03 for both). Only a subset of participants (n=43) had ejection fraction evaluable, but DRZ+ patients also were more likely to have greater values (mean±SD: 56.8±6.3 vs. 61.2±6.4; p=0.03). Among all participants, the effects of DRZ on FS% appeared to vary by sex, with females showing significant differences (DRZ- 31.7±2.2 vs. DRZ+ 36.3±4.2; p<0.001) but not males (DRZ- 34.0±6.0 vs. DRZ+ 34.0±4.6; p=0.99). DRZ status was significantly associated with FS% and both BNP and NT-proBNP in multivariate analyses that adjusted for sex, original protocol, race/ethnicity, current age, and age at cancer diagnosis (p<0.05). Other parameters of systolic dysfunction and myocardial injury including wall thickness/dimension ratio and high-sensitivity troponins were similar across study arms, both overall and in subanalyses. Overall, only 3 participants had FS% <28 (DRZ+, n=2). Two other participants reported a history of clinical cardiomyopathy (both DRZ+, one currently on medications). Globally, regardless of DRZ status, participants had a high burden of comorbid cardiovascular conditions: 57% overweight/obese, 37% pre-/hypertensive, 50% with dyslipidemia, and 11% pre-/diabetic.Conclusion: In this preliminary analysis, long-term survivors of childhood cancer treated with doxorubicin and DRZ appeared to have more preserved systolic function and reduced myocardial wall stress compared with survivors treated with doxorubicin alone. Secondary prevention efforts should be directed at treating common but potentially modifiable cardiovascular risk factors in this high-risk young adult population. Accrual of remaining eligible study participants is ongoing and may provide more refined estimates of DRZ's cardioprotective effects in the future. DisclosuresAsselin:Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy. Lipshultz:Clinigen Group: Consultancy, Other: Travel/accommodations for consulting related meeting; Pfizer: Research Funding; Roche Diagnostics: Research Funding.

Moderate dose cranial radiotherapy causes central adrenal insufficiency in long-term survivors of childhood leukaemia

Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy. The survival rate in the Scandinavian countries is now around 85%. ALL patients treated with cranial radiotherapy (CRT) are at risk for growth hormone deficiency (GHD), but little is known about other pituitary insufficiencies, e.g. ACTH. Adult ALL patients (median age at study 25years), treated with 24Gy (18-30) of CRT during childhood were investigated. We performed an insulin tolerance test (ITT) to evaluate cortisol secretion. We measured basal serum ACTH and cortisol levels before and after 5years of GH therapy. 14 out of 37 (38%) ALL patients had a subnormal cortisol response to an ITT (257-478nmol/L) while there was no significant difference in basal cortisol levels between 44 patients and controls (P>0.3). Female, but not male ALL patients had significantly lower ACTH levels compared to controls (P=0.03). After 5years of GH therapy only male ALL patients had significantly lowered basal plasma cortisol (P=0.02). ALL survivors, treated with a moderate dose CRT, have a central adrenal insufficiency 20years after diagnosis. An increased awareness of the risk for an adrenal insufficiency is of importance and life-long surveillance of the entire hypothalamic-pituitary axis is recommended in these patients.

Chemotherapy-related changes in central nervous system phospholipids and neurocognitive function in childhood acute lymphoblastic leukemia

Long-term survivors of childhood leukemia are at risk for neurocognitive impairment, although the neurophysiological basis is not well understood. The purpose of this study was to explore associations between changes in cerebrospinal fluid (CSF) phospholipids and neurocognitive function in children undergoing chemotherapy for acute lymphoblastic leukemia. Seventy-six children were followed prospectively from diagnosis. CSF samples were collected during scheduled lumbar punctures and phospholipids were extracted. Neurocognitive evaluations were conducted annually beginning shortly after diagnosis. Concentrations of sphingomyelin (SM) increased following induction (p = 0.03) and consolidation (p = 0.04), while lysophosphatidylcholine (LPC) increased following induction (p = 0.003). Multivariable analyses demonstrated associations between post-induction SM and motor speed at 1 year (p < 0.001), 2 years (p = 0.001) and 3 years (p = 0.02) following diagnosis. Post-induction LPC was associated with verbal working memory (p = 0.007). Results indicate that early changes in phospholipids are related to neurocognitive decline and suggest a chemotherapy impact on white matter integrity.

Effectiveness of using cardiac biomarkers to detect late anthracycline cardiotoxicity in childhood leukemia survivors.

9592 Background: Cardiotoxicity is usually detected only when clinical symptoms or progressive cardiac dysfunction has already occurred. Cardiac biomarkers (troponin T and N-terminal fragment brain natriuretic peptide precursor) have been hypothesized to reflect subclinical anthracycline cardiotoxicity earlier than echocardiography. This study aims to assess the effectiveness of using cTNT and NTproBNP in asymptomatic long-term survivors of childhood leukemia treated with and without antracyclines (ANT). Methods: Sixty-nine childhood leukemia survivors 5 - 25 years after completion of therapy were evaluated with immunochemical analysis of cTnT and NT-proBNP and echocardiography. Patients from group I (n = 36) received combined therapy with anthracyclines (ANT) with total cumulative dose 95-600 (median 221) mg/m2, patients from group II (n = 33) received therapy without anthracyclines (nonANT). Control group consisted from 44 age- and gender-matched apparently healthy subjects. Results: Levels of NTproBNP were significantly higher in ANT group than in controls (median 51,52 vs 17,37 pg/ml; p=0.0026). Patients treated with ANT had significantly increased median values of NTproBNP compared with patients in non ANT group (51,52 vs 12,24 pg/ml; p=0.0002). CTnT levels remained below the diagnostic cut-off levels in all groups. No patient had echocardiographic abnormalities, but significant differences were found in mean values of left ventricular ejection fraction and deceleration time between patients treated with and without ANT. Conclusions: Assessment of plasma NTproBNP concentrations may be an effective tool for detection of late subclinical cardiac damage in survivors of childhood leukemia previously treated with low ANT doses. Higher NTproBNP levels in patients after ANT therapy might reflect an initial stage of cardiotoxicity before the development of echocardiographic abnormalities. This study was supported by a grant from Ministry of Health 2007/42-UK-18, Slovakia.

High Prevalence of Chronic Fatigue in Long Term Survivors of Childhood Acute Lymphoblastic Leukemia and Lymphoma

Abstract 4225 Introduction:Chronic fatigue is a frequent and distressing late effect after successful cancer treatment. However, few studies have included survivors of childhood cancers. Aims:The primary aim of the study was to assess the prevalence of fatigue in long-term survivors of childhood acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL), and to compare with the Norwegian general population. A secondary aim was to explore the association between cardiac or pulmonary late effects and fatigue in long-term survivors after NHL and HL. Material and method:This population-based cross-sectional study included tumor-free adult survivors of childhood ALL, NHL and HL diagnosed between 1970 and 2002 at an age of <19 years with at least 5 years follow-up time. The enrolled patients underwent extensive biochemical and clinical investigation including echocardiography and estimation of lung volumes and diffusion capacity. Clinical information was retrieved from the patient records. Chalder′s fatigue questionnaire (FQ) was used to assess fatigue. Chronic fatigue (CF) was defined as a substantially increased level of fatigue with duration of more than 6 months. 1423 age and gender matched individuals from the general Norwegian population served as controls. Results:A total of 290 patients completed the questionnaire (ALL 151, NHL 47, HL 92). Median age (range) at assessment was 29.9 (18.3–54.5) years. Median follow-up time from diagnosis was 21.3 (6.9–39.2) years. The overall prevalence of CF was 27% (ALL 23%, NHL 30%, HL 34%), as compared to 8.4% among the controls (p>0.001). There was a tendency towards a higher prevalence of CF by increasing age (32% among subjects aged ≥30 years at follow-up vs. 22% in subjects aged<30 years, p=0.063). This was most pronounced among the ALL survivors (36% among subjects aged ≥30 years years at follow-up vs. 13% among subjects aged <30 years, p=0.001). In ALL survivors, older age at diagnosis was associated with higher prevalence of CF (15% among subjects aged <6 years at diagnosis vs. 32% among subjects aged ≥6 years, p= 0.012). Indeed, among all survivors ≥6 years at diagnosis, the ALL group had a similar prevalence of CF as the two other diagnostic groups; 32%. No association was found between CF and gender, time from diagnosis, radiotherapy, cumulative anthracycline dose, body mass index, proBNP or hypothyreosis. Among the lymphoma survivors the presence of B-symptoms at diagnosis tended to be associated with CF (Presence: CF 48% vs. Absence: CF 29%, p=0.058). In long-term survivors of NHL and HL, no association was found between CF and aortic valve disease, total lung capacity and diffusion capacity. Conclusions:Compared to the general population the prevalence of CF is 3-fold increased in long-term survivors of childhood leukemia and lymphoma. The prevalence is highest in HL (34%), but, rather surprisingly, even ALL survivors have a high occurrence of CF (23%). The lack of association between CF and somatic co-morbidity or dysfunction warrants future studies exploring the etiology of CF in long-term survivors. Disclosures:No relevant conflicts of interest to declare.

Empty sella/pituitary atrophy and endocrine impairments as a consequence of radiation and chemotherapy in long-term survivors of childhood leukemia

Radiation-induced empty sella (ES) or pituitary atrophy/small pituitary and endocrine impairments, including pituitary and gonadal dysfunction, can manifest decades after radiation and chemotherapy in childhood-onset leukemia patients who received prophylactic cranial irradiation or total body irradiation in preparation for bone marrow transplant. Six childhood-onset leukemia patients (age at diagnosis of leukemia; 2.7-10.2years) participated in this study. Magnetic resonance imaging (MRI) of the pituitary gland and endocrinological studies were performed 10.5-32.1years after cranial irradiation. In four of the six patients examined, ES or pituitary atrophy was detected approximately 10.5-19.8years after cranial irradiation. Four patients had hypogonadism (primary, 3; hypothalamic-pituitary, 1) and one had primary hypothyroidism. We conclude that ES or pituitary atrophy and endocrine impairments can manifest decades after radiation and chemotherapy in childhood-onset leukemia. These patients should, therefore, undergo regular follow-up, including pituitary MRI and hormonal examinations.

Symptoms of attention-deficit/hyperactivity disorder in long-term survivors of childhood leukemia.

Survivors of childhood acute lymphoblastic leukemia (ALL) sometimes have clinical features that suggest attention-deficit/hyperactivity disorder (ADHD), though few studies have examined specific symptoms in survivors. Long-term survivors of childhood ALL (n = 161) received a neurological examination, while parents completed rating scales to establish formal criteria for ADHD. Symptom profiles were generated and compared across demographic and treatment characteristics, as well as medical tests associated with brain pathology. Prevalence rates of ADHD were similar in survivors (10.5%) compared to those reported in the general population (7-10%). However, 25.5% of survivors reported symptoms that impair functioning in multiple settings, with attention problems being most common. These symptoms were associated with cranial radiation therapy (CRT) (mean inattentive symptoms [SD] = 3.6 [3.19] for group treated with CRT vs. 1.6 [2.40] for non-CRT group, P = 0.0006), and survivors who demonstrated impaired anti-saccades during the neurologic exam (mean inattentive symptoms [SD] = 3.4 [3.29] for those with impaired anti-saccades vs. 1.4 [2.41] for those with normal anti-saccades; P = 0.0004). The presence of a neurologically-based phenotype of attention problems in survivors of leukemia that is not fully captured by the syndrome of ADHD suggests that treatments specific to childhood ALL should be explored.

Hospitalization Rates Among Long-Term Survivors of Childhood Leukemia and Lymphoma: A Report From the Childhood Cancer Survivor Study (CCSS).

Abstract 4633 BackgroundChronic health conditions are commonly reported by survivors of childhood leukemia and lymphoma. To further understand the socio-economic impact of these reported conditions, we sought to determine overall and cause-specific rates of hospitalization among survivors of childhood leukemia/lymphoma and to compare these rates with those of the U.S. population. MethodsFrom the CCSS, 5,637 5 year survivors of childhood leukemia/lymphoma, who participated in the 2000 follow-up questionnaire, were identified. Data related to hospitalizations occurring during the years 1992-2005 were collected and hospitalization rates among survivors were determined. For comparison, hospitalization rates in the general U.S. population were obtained from the National Hospital Discharge Survey (NHDS). Indirect standardization was used to calculate age- and sex- standardized incidence ratios (SIR) and absolute excess risks (AER). The reasons for hospitalization were described and cause specific hospitalization rates were also compared with those of the general U.S. population. ResultsAt follow up, the mean age was 29.2 years (SD: 7.6; range: 14.0-51.0) and the mean time since diagnosis was 20.8 years (SD: 4.6; range 13.3-31.7). Overall, the hospitalization rates of survivors of childhood leukemia, non-Hodgkin lymphoma (NHL) and Hodgkin disease (HD) were 1.3 (95% CI: 1.2-1.3), 1.2 (95% CI: 1.1, 1.3) and 1.9 times (95% CI: 1.8, 2.0) that of the general U.S. population, respectively. Survivors, regardless of diagnosis, were more likely than the general population to be hospitalized for infection, endocrine, cardiovascular, gastrointestinal and genitourinary reasons, as well as external causes (Figure 1). The greatest AER was associated with hospitalization for neoplasm. Survivors of leukemia and NHL were approximately 5 times [SIRleukemia: 5.4 (95% CI: 4.8; 6.2) and SIRNHL: 4.8; (95% CI: 3.6, 6.1)] and HD survivors 10.2 times (95% CI: 8.9, 11.7) more likely than the general population to be hospitalized for this reason. Survivors of HD had 6.5 times (95%CI: 5.6, 7.5) the rate of hospitalization for cardiovascular causes and 4.4 times (95% CI: 3.6, 5.2) the rate of hospitalization for pulmonary causes when compared with the general U.S. population. These findings are consistent with reports indicating an increased risk for second cancers, particularly breast cancer after chest irradiation, and conditions such as pneumonitis, lung fibrosis, cardiomyopathy and coronary artery disease among Hodgkin patients. Survivors of leukemia had 5.2 times (95% CI: 4.4, 6.2) the rate of hospitalization for neurological reasons compared with the general population, likely reflecting late effects of treatment with cranial and spinal radiation. Interestingly, survivors have a significantly lower rate of hospitalization for psychological reasons when compared with the U.S. population (Figure 1). ConclusionsLong-term survivors of childhood leukemia/lymphoma experience a significantly increased rate of hospitalization. Additional research is needed to further quantify the overall healthcare utilization and economic impact of treatment-related complications as this population ages. These findings also emphasize the importance of ongoing medical surveillance that includes screening and prevention strategies, which may impact the occurrence of serious medical conditions resulting in hospitalization. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

A controlled study on the psychological characteristics of long-term survivors of childhood leukemia

Objective The aim of the study was to evaluate and compare psychosocial functioning of long-term survivors of childhood leukemia, children newly diagnosed as leukemia and age-matched healthy controls. Methods Nineteen long-term survivors of childhood leukemia(Group A), twenty children newly diagnosed as leukemia(Group B) and forty age-matched healthy controls (Group C)completed the questionnaires allowing assessment of symptoms associated with anxiety, depression, self-concept and personality by using the screen for child anxiety related emotional disorders(SCARED), depression self rating scale for children(DSRSC), Piers-Harris children's self-concept scale(PHCSS)and Eysenck personality questionnaire(EPQ), respectively. Results Group A scored significantly higher on subscales of somatization/panic(6.11±4.36), generalized anxiety(5.72±4.56), social phobia(7.67±4.19) and the total scale(25.72±14.72) than Group C(the score was 3.82±1.69,2.84±1.92, 3.95±2.85 and 16.11±11.81, respectively, P＜0.05),the depression score was higher than that of the control group, but have no significant difference(P=0.069). The total score of self-concept of both group A (60.06±8.07)and group B(58.25±6.54) were significantly lower than that of the group C(64.90±7.30)(P＜0.05). Among which, group A scored significantly higher on subscales of anxiety and gregarization than group C(P＜0.05).And Group B scored significantly higher on subscales of behavior, intelligence and anxiety than group C(P＜0.05). The extraversion score of EPQ in group A was lower than that in group B and C,whereas the other three dimensions (P,N,L) of EPQ test showed no difference between the three groups. Conclusion The findings of this study suggest that survivors of childhood leukemia are at risk for psychological difficulties. Key words: Pediatric psychology; Childhood leukemia; Anxiety; Depression; Self-concept

Voxel-based morphometry and diffusion-tensor MR imaging of the brain in long-term survivors of childhood leukemia

The aims of this study were to detect morphological changes in neuroanatomical components in adult survivors of acute lymphoblastic leukemia (ALL). Voxel-based morphometry (VBM) can be used to detect subtle structural changes in brain morphology and via analysis of fractional anisotropy (FA), diffusion-tensor imaging (DTI) can non-invasively probe white matter (WM) integrity. We used VBM and DTI to examine 20 long-term survivors of ALL and 21 healthy matched controls. Ten ALL survivors received chemotherapy and irradiation; ten survivors received chemotherapy alone during childhood. Imaging was performed on a 3.0-T MRI. For VBM, group comparisons of segmented T1-weighted grey matter (GM) and WM images from controls and ALL survivors were performed separately for patients who received chemotherapy alone and who received chemotherapy and irradiation. For DTI, FA in WM was compared for the same groups. Survivors of childhood ALL who underwent cranial irradiation during childhood had smaller WM volumes and reduced GM concentration within the caudate nucleus and thalamus. The FA in WM was reduced in adult survivors of ALL but the effect was more severe after combined treatment with irradiation and chemotherapy. Our results indicate that DTI and VBM can reveal persistent long-term WM and caudate changes in children after ALL treatment, even without T2 changes in conventional imaging.

Late-Occurring Stroke Among Long-Term Survivors of Childhood Leukemia and Brain Tumors: A Report From the Childhood Cancer Survivor Study

Late-Occurring Stroke Among Long-Term Survivors of Childhood Leukemia and Brain Tumors: A Report From the Childhood Cancer Survivor Study

Health status and quality of life in long-term survivors of childhood leukaemia: the impact of haematopoietic stem cell transplantation

We compared late side effects and quality of life (QoL) in 430 survivors of childhood acute leukaemia based on whether they had undergone haematopoietic cell transplantation (n=142) or not (n=288). Mean age was 18.2 years and mean follow-up duration was 11.9 years. Multivariate logistic regression analyses were performed to compare the risk of each type of late effect in the two groups. Based on age, VSP-A or SF36 questionnaires were used to assess QoL. For each QoL dimension, multiple linear regression was done to construct models of association with the treatment group. Transplanted patients experienced more side effects, including height growth failure, gonadal dysfunction, hypothyroidism and cataract. Children and adolescents in the two treatment groups reported similar QoL levels for almost all dimensions except a better perception of school work by young transplanted children and more difficulties in relating to the medical staff for transplanted adolescents. In adults, two differences in physical domain of QoL were detected but the calculated effect sizes were less than 0.2 in each case, suggesting an uncertain clinical significance. In spite of a higher risk of physical adverse events in the transplanted group, very few clinically significant differences in QoL are detectable.

Late-Occurring Stroke Among Long-Term Survivors of Childhood Leukemia and Brain Tumors: A Report From the Childhood Cancer Survivor Study

This report examines the incidence of and risk factors for strokes that occur in > or = 5-year survivors of childhood leukemia and brain tumors. The rate of first occurrence of self-reported late-occurring strokes was determined for leukemia survivors (n = 4,828), brain tumor survivors (n = 1,871), and a comparison group of a random sample of cancer survivor siblings (n = 3,846). Relative risks (RRs) and 95% confidence intervals (CIs) of stroke by treatment exposures were examined by multivariate analyses. Thirty-seven leukemia survivors and 63 brain tumor survivors reported a late-occurring stroke. The rate of late-occurring stroke for leukemia survivors was 57.9 per 100,000 person-years (95% CI, 41.2 to 78.7). The RR of stroke for leukemia survivors compared with the sibling comparison group was 6.4 (95% CI, 3.0 to 13.8; P < .0001). The rate of late-occurring stroke for brain tumor survivors was 267.6 per 100,000 person-years (95% CI, 206.8 to 339.2). The RR of stroke for brain tumor survivors compared with the sibling comparison group was 29.0 (95% CI, 13.8 to 60.6; P < .0001). Mean cranial radiation therapy (CRT) dose of > or = 30 Gy was associated with an increased risk in both leukemia and brain tumor survivors in a dose-dependent fashion, with the highest risk after doses of > or = 50 Gy CRT. Survivors of childhood leukemia and brain tumors, particularly those with brain tumors treated with CRT at doses of greater than 30 Gy, are at an increased risk of stroke.

Physical function and fitness in long-term survivors of childhood leukaemia

To evaluate the physical function and fitness in survivors of childhood leukaemia 5-6 years after cessation of chemotherapy. Thirteen children (six boys and seven girls; mean age 15.5 years) who were treated for leukaemia were studied 5-6 years after cessation of therapy. Physical function and fitness were determined by anthropometry, motor performance, muscle strength, anaerobic and aerobic exercise capacity. On motor performance, seven of the 13 patients showed significant problems in the hand-eye co-ordination domain. Muscle strength only showed a significantly lower value in the mean strength of the knee extensors. The aerobic and the anaerobic capacity were both significantly reduced compared to reference values. Even 5-6 years after cessation of childhood leukaemia treatment, there are still clear late effects on motor performance and physical fitness. Chemotherapy-induced neuropathy and muscle atrophies are probably the prominent cause for these reduced test results. Physical training might be indicated for patients surviving leukaemia to improve fitness levels and muscle strength.

Prevalence and Correlates of Fatigue in Long-Term Survivors of Childhood Leukemia

To estimate the prevalence of fatigue, identify the factors associated with fatigue, and to explore the relationship between fatigue and quality of life (QOL) in long-term survivors of childhood acute lymphoblastic leukemia (ALL). One hundred sixty-one ALL survivors diagnosed at Childrens Hospital Los Angeles (Los Angeles, CA) before age 18 years and between January 1, 1975 and December 31, 1995, participated in a structured telephone interview. Participants were aged 18 to 41 years and off treatment for an average of 14 years. Four measures of fatigue, including the Revised-Piper Fatigue Scale, were used to assess fatigue; depression was assessed using the Center for Epidemiological Studies Depression Scale. Multivariate logistic regression models were developed to identify factors associated with fatigue and depression. Prevalence of fatigue (30%) fell within the general population normal limits. Fatigue and depression were highly correlated (Pearson r = 0.75). Fatigue was associated with marriage (OR = 0.11; 95% CI, 0.02 to 0.50), having children (OR = 5.80; 95% CI, 1.30 to 25.82), sleep disturbances (OR = 6.15; 95% CI, 2.33 to 16.22), pain (OR = 5.56; 95% CI, 2.13 to 14.48), obesity (OR = 3.80; 95% CI, 1.41 to 10.26), cognitive impairment (OR = 2.56; 95% CI, 1.02 to 6.38), and exercise-induced symptoms (OR = 2.98; 95% CI, 1.11 to 8.02). Four factors associated with fatigue were also associated with depression: sleep disturbances, pain, obesity, and cognitive impairment. Fatigue was inversely related to QOL. Some survivors of childhood ALL experience fatigue many years after treatment. Fatigued survivors represent a high-risk subgroup as they report more depression and poorer QOL than non-fatigued survivors and their peers.

Psychological Outcomes in Long-Term Survivors of Childhood Leukemia, Hodgkin’s Disease, and Non-Hodgkin’s Lymphoma: A Report From the Childhood Cancer Survivor Study

To evaluate and compare psychological outcomes in long-term survivors of pediatric leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma and sibling controls. Adult survivors of childhood leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma (N = 5736) and sibling controls (N = 2565) were administered a long-term follow-up questionnaire allowing assessment of symptoms associated with depression and somatic distress. The majority of respondents in this study did not demonstrate symptomatology indicative of depression or somatic distress. Survivors, however, were significantly more likely than sibling controls to report symptoms of depression and somatic distress. Women were significantly more likely to indicate symptoms of depression and somatic distress than were men; however, this difference did not vary by survivor/sibling status. Similarly, socioeconomic (SES) variables predicted symptomatic levels of depression and somatic distress for both survivors and siblings, and these effects did not vary by survivor/sibling status. Among leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma survivors, in addition to gender and SES, the only treatment variable that predicted scores indicating depressive symptomatology was exposure to intensive chemotherapy. Exposure to intensive chemotherapy also predicted scores indicative of somatic distress symptoms. No other medical variables, including diagnostic category, age at diagnosis, time since diagnosis, and duration of treatment, predicted symptomatic scores for depression and somatic distress. This large, sibling-controlled, multisite study of young adult survivors of childhood leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma found that survivors had significant increased risk for reporting symptoms of depression and somatic distress and that intensive chemotherapy added to this risk. However, being a cancer survivor did not compound the effects of gender and SES variables on the 2 outcomes measured. The ability of SES, gender, and treatment-related variables to predict psychological symptoms in this cohort of childhood survivors and sibling controls calls for future research into varied biological and psychosocial pathways by which cancer influences future psychosocial functioning.

Hyperleptinaemia in young adults following cranial irradiation in childhood: growth hormone deficiency or leptin insensitivity?

In order to explore the mechanism of obesity in long-term survivors of childhood leukaemia, fat mass, lean body mass and serum leptin were assessed in a cohort of 32 (17 males) adults who had received cranial irradiation (XRT) in childhood as part of their treatment for acute lymphobiastic leukaemia (ALL), and compared with 35 age and body mass index (BMI) matched young adults (18 male). Thirty-one patients and 18 controls had fat mass and lean body mass assessed by dual x-ray absorptiometry (DEXA), using a lunar DPX-L scanner. Serum leptin concentrations were also measured in 27 patients and all controls. Growth hormone status had previously been determined using an insulin tolerance test and arginine stimulation test. Nine patients were classified as severe growth hormone (GH) deficient (group 1), 12 patients as GH insufficient (group 2) and 11 patients as normal (group 3). BMI and absolute fat mass were not significantly different between the patients and controls regardless of their gender (P = 0.1 and P = 0.14 respectively). In contrast, absolute lean mass was significantly reduced (P < 0.01) and leptin concentrations were significantly increased (P < 0.001) in patients compared with controls. BMI, fat mass and leptin concentrations but not lean mass were significantly different between the three GH status groups (P < 0.01, P < 0.01, P = 0.004, and P = 0.67 respectively). When leptin concentrations were expressed per unit of fat mass, they were increased in the patients compared with the controls (P = 0.03) with significant differences between the GH status groups (P = 0.004), being significantly higher in the severe GH deficient group. Young adults who receive cranial irradiation in childhood are prone to GH deficiency and hyperleptinaemia. The pathophysiological significance of the hyperleptinaemia remains to be established but it has occurred either as a consequence of radiation induced hypothalamic damage or GH deficiency.