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BACKGROUND The primary objective of this study was to test the hypothesis that survivors of childhood acute lymphoblastic leukemia (ALL) have deficits in neurocognitive performance, and smaller white-matter volumes are associated with these deficits. METHODS The patients studied included 112 ALL survivors (84 patients who had received chemotherapy only, 28 patients who had received chemotherapy and irradiation; 63 males, 49 females; mean age ± standard deviation, 4.1 yrs ± 2.6 yrs at diagnosis; mean ± standard deviation yrs since diagnosis, 6.0 ± 3.5 yrs), and 33 healthy siblings who participated as a control group. Neurocognitive tests of attention, intelligence, and academic achievement were performed; and magnetic resonance images were obtained and subsequently were segmented to yield tissue volume measurements. Comparisons of neurocognitive measures and tissue volumes between groups were performed, and the correlations between volumes and neurocognitive performance measures were assessed. RESULTS Most performance measures demonstrated statistically significant differences from the normative test scores, but only attention measures exceeded 1.0 standard deviation from normal. Patients who had received chemotherapy alone had significantly larger volumes of white matter than patients who had received treatment that also included cranial irradiation, but their volumes remained significantly smaller than the volumes in the control group. Smaller white-matter volumes were associated significantly with larger deficits in attention, intelligence, and academic achievement. CONCLUSIONS Survivors of childhood ALL had significant deficits in attention and smaller white-matter volumes that were associated directly with impaired neurocognitive performance. Cranial irradiation exacerbated these deficits. Cancer 2006. © 2006 American Cancer Society.

Although previous studies have documented a significant risk of intellectual loss after treatment for childhood medulloblastoma (MED), the pathophysiology underlying this process is poorly understood. The purpose of this study was to test the hypotheses that (1) patients treated for MED in childhood have reduced volumes of normal white matter (NWM) related to their treatment with craniospinal irradiation with or without chemotherapy, and (2) deficits in NWM among patients surviving MED can at least partially explain deficits in their intellectual performance. Eighteen pediatric patients previously treated for MED were matched on the basis of age at the time of evaluation to 18 patients previously treated for low-grade posterior fossa tumors with surgery alone (mean difference, 3.7 months). Evaluations were conducted with age-appropriate neurocognitive testing and quantitative magnetic resonance imaging by using a novel automated segmentation and classification algorithm constructed from a hybrid neural network. Patients treated for MED had significantly less NWM (p < 0.01) and significantly lower Full-Scale IQ values than those treated for low-grade tumors (mean, 82.1 vs 92.9). In addition, NWM had a positive and statistically significant association with Full-Scale IQ among the patients treated for MED. We conclude that irradiation- or chemotherapy-induced destruction of NWM can at least partially explain intellectual and academic achievement deficits among MED survivors.

Our objective was to test a hypothesis that subtle brain abnormality can be present in pediatric sickle cell disease (SCD) patients who are clinically free of stroke. We prospectively compared 50 patients with 52 healthy age-similar controls, using quantitative magnetic resonance imaging. A previously validated precise and accurate inversion-recovery method was used to measure T1 in a slice at the basal ganglia. We also used the Wechsler test to measure intelligence quotient (IQ) in a randomly selected subset of 27 patients. Brain T1 was significantly lower in patients in every gray matter structure evaluated but in none of the white matter structures. Regression suggests that T1 in caudate, nucleus pulvinares, and cerebral cortex was abnormal by age 4 years. Psychometric testing showed that 33% of patients were functioning in the range of mild mental deficiency (IQ, 50-70), compared with a published prevalence of 1.45% in inner-city black children. Thus, in our patients, SCD was associated with a 23-fold increase in the risk of mild mental deficiency. Full-scale IQ of SCD patients was a function of hematocrit (Hct), and when Hct was used to stratify patients, those with an Hct of less than 27% had significantly lower psychometric test scores, and significantly lower gray matter T1, than those with an Hct of 27 or more. Both cognitive deficits and subtle T1 abnormalities were associated with a low Hct, and both could be present when conventional magnetic resonance imaging findings were normal. Our findings suggest that chronic hypoxia of brain tissue can occur in SCD patients free of clinical stroke.

We have examined the influence of selected factors (gender, marital status, socio-economic status, co-morbid conditions, access to medical care, age at diagnosis, intensity of therapy and time since diagnosis) on subsequent health status and health-related quality of life (HRQL) of long-term survivors of pediatric solid tumors. Two hundred and twenty individuals who had survived a pediatric solid tumor 15 years or longer completed telephone and written assessments of their current status. Health status was assessed using the Late Effects of Normal Tissues toxicity scale. HRQL was investigated using the Ferrans and Powers Quality of Life Index–Cancer (QLIC) and the EORTC Quality of Life Questionnaire C30 (QLQ-C30). Results indicated that health status and HRQL were better in survivors treated with low-intensity therapy. One hundred and thirty respondents (59.1%) reported at least 1 serious toxicity. Dyspnea and fatigue were commonly reported in survivors of Hodgkin's disease. Correlational analyses showed that predictors of health status included socio-economic status, marital status and the presence of co-morbid factors. Mean HRQL scores for the 4 domains of the Ferrans and Powers QLIC and the functional scales of the EORTC QLQ-C30 indicated that most of the survivors were experiencing moderately good to excellent HRQL. One-third of survivors reported that their history of cancer had an adverse impact on their current financial status. Prediction models constructed for 3 of the domains from the 2 HRQL instruments are presented (health and functioning, global HRQL and financial impact). Within these 3 models, consistent predictors of HRQL outcomes included health status, presence of dyspnea or pain, marital status and socio-economic status. Int. J. Cancer Suppl. 12:25–31, 1999. ©1999 Wiley-Liss, Inc.

Children surviving medulloblastoma have a high risk for chronic, treatment-related neurocognitive deficits. Neuropsychological testing provides important data regarding the comparative toxicities of various therapeutic approaches. However, such testing can be expensive and logistically difficult, especially if a consulting psychologist is not readily available at the treating institution. Our purpose was to investigate the usefulness of a health-related quality of life inventory that does not require a psychologist for completion. We assessed the concurrent validity of traditional intelligence (IQ) testing and levels on the Cognition attribute of the multi-attribute Health Utilities Index Mark 2 (HUI 2) in estimating academic achievement scores of 22 patients treated for medulloblastoma with craniospinal irradiation following surgical resection. The results demonstrated that the Cognition utility scores were significantly lower than scores from the other components of the HUI 2 (Sensation, Mobility, Emotion, Self-Care, Pain). Cognition scores were also significantly positively correlated with IQ and achievement scores. Furthermore, Cognition scores were significantly lower among children who had received special educational services when compared with those who had not received such services. Our results provide preliminary evidence of the potential usefulness of the HUI 2 Cognition attribute in estimating IQ, achievement and the likelihood of the need for special educational services among children treated for medulloblastoma.

Conventional MRI (cMRI) has shown that brain abnormalities without clinical stroke can manifest in patients with sickle cell disease (SCD). We used quantitative MRI (qMRI) and psychometric testing to determine whether brain abnormalities can also be present in patients with SCD who appear normal on cMRI. Patients 4 years of age and older with no clinical evidence of stroke were stratified by cMRI as normal (n = 17) or abnormal (n = 13). Spin-lattice relaxation time (T1) of gray and white matter structures was measured by the precise and accurate inversion recovery (PAIR) qMRI method. Patient cognitive ability was assessed with a standard psychometric instrument (WISC-III or WISC-R). In all 30 patients with SCD, qMRI T1 was lower than in 24 age- and race-matched controls, in cortical gray matter (P < .0006) and caudate (P < .0009), as well as in the ratio of gray-to-white matter T1 (P < .008). In the 17 patients who were shown to be normal by cMRI, qMRI T1 was still lower than in controls, in both cortical gray matter (P < .02) and caudate (P < .004). Histograms of voxel T1 show that the proportion of voxels with T1 values intermediate between gray and white matter (ie, consistent with encephalomalacia) was 9% higher than controls in patients shown to be normal by cMRI (P < .05) and 15% higher than controls in patients shown to be abnormal by cMRI (P < .0005). The full scale intelligence quotient (FSIQ) of all patients with SCD was 75, compared to the FSIQ of 88 in a historical control group of patient siblings (P < .001). The FSIQ of patients shown to be normal by cMRI was 79, significantly lower than the FSIQ of patient siblings (P < .04). The FSIQ of 71 in patients shown to be abnormal by cMRI was significantly lower than both the patient siblings (P < .005) and the patients shown to be normal by cMRI (P < .04). Patients shown to be abnormal by cMRI scored lower than patients shown to be normal by cMRI, specifically on the subtests of vocabulary (P = .003) and information (P = .03). Cognitive impairment is thus significant, even in patients with SCD who were shown to be normal by cMRI, suggesting that cMRI may be insensitive to subtle neurologic damage that can be detected by qMRI. Because cognitive impairment can occur in children normal by cMRI, our findings imply that prophylactic therapy may be needed earlier in the course of SCD to mitigate neurologic damage.

Objective To assess the psychological functioning of adolescent and young adult survivors of pediatric malignancy, and identify risk factors for maladjustment. Design Patients age ≥ 14.5 years (N = 161) receiving surveillance follow-up at a major pediatric cancer center completed the SCL-90-R, a self-report measure of psychological symptomatology. Comparisons were made with the normative standardization sample, and the relationship of selected demographic and medical variables with psychological distress was explored using logistic regression analyses. Results Survivors mean scores on all SCL-90-R subscales were lower than those of the standardization sample, and the distribution of scores on the Anxiety, Psychoticism, Global severity Index, and Positive Symptom Total scales were significantly below normative values. No SCL-90-R subscale displayed an excessive frequency of clinically elevated scores. For patients who displayed clinical elevations on the SCL-90-R, three factors were identified which were associated with increased risk of maladjustment; older patient age at follow-up, more frequent disease relapse, and more severe functional impairment. Conclusions This cohort of childhood cancer survivors is characterized by very low levels of psychological distress and significantly better psychological health than would be expected according to normative data. These findings contrast with those of another study from the same institution in which a fourfold increase in social and behavioral problems was found amongst younger survivors, in the age range 7–15. The use of self-report vs. parent-report, and the potential influence of repressive adaptation on the self-reports of pediatric cancer survivors, are raised as possible explanations for these findings. Med. Pediatr. Oncol. 29:582–588, 1997. © 1997 Wiley-Liss, Inc.

Objective This seven-site study examined the overall health status, healthcare utilization, somatization, and health-risk behaviors of siblings of children with cancer compared to these factors in matched controls or normative data. The study also examined whether informants (i.e., siblings, parents, physicians) differed in their assessments of the above health domains. Design Subjects were 254 siblings of children with cancer from seven different pediatric oncology treatment centers that participated in the Sibling Adaptation to Childhood Cancer Collaborative study group. Predictors of the siblings' health status, healthcare utilization, somatization, and health-risk behaviors were identified, and the relationship between these health domains and the siblings' resiliency vs. dysfunctionality were explored via interviews. Results Overall, siblings were found to be moderately healthy, although siblings report significant problems with sleeping and eating. Healthcare utilization appears to be reduced for siblings. Most importantly, the parents of these siblings are less likely to seek medical help for a variety of conditions for which parents of control children would bring their children to a doctor. A pattern emerged of parental underreporting of sibling health variables when compared to what the siblings themselves reported. When the relationship between health outcomes and the siblings' adaptation to their sick sibling's illness was examined, the resilient and dysfunctional groups significantly differed from each other. It appears that health outcomes are related to sibling adaptation to the changes brought about by their sick sibling's cancer diagnosis and treatment. Conclusions The focus of care for families of children with cancer is often limited to the child with cancer. As indicated in this study, the “healthy” siblings may be overlooked in the process. While parents appear to recognize that their “healthy” children are complaining more about aches and pains, they may have little energy or time to attend to the needs of these other family members. It is the intent of this study to document what clinicians may expect and to highlight the need for evaluation of this otherwise neglected group. © 1996 Wiley-Liss, Inc.

Nutritional problems often result from malignancies and aggressive multimodal treatment. Early identification of reliable risk factors associated with malnutrition and need for nutritional support is necessary for development of preventative approaches. Nutritional and treatment-related characteristics were examined for 173 pediatric oncology patients referred for nutritional support and a comparison sample of 43 patients matched on treatment protocol and/or diagnosis who had never been referred for nutritional support. Abnormally low serum albumin levels, poor oral intake, mucositis, prior radiation therapy, and increased gastrointestinal toxicity were significantly more frequent among referred than non-referred patients. A discriminant function analysis indicated that poor oral intake was the single best predictor of need for nutritional support. Patients with solid tumors were more nutritionally depleted at the time of referral; all bone marrow transplant patients received nutritional support. Patients with central nervous system (CNS) tumors required nutritional support for longer time periods. We conclude that routine documentation of poor oral intake (i.e., observation of change in a child's eating patterns) is the most reliable indicator of children who eventually require nutritional support and who may benefit from interventions that could delay or prevent nutritional problems. Prophylactic interventions should be tailored to meet the specific needs of individual diagnostic groups.

The health-related beliefs and behaviors of long-term survivors of childhood cancer are important because of vulnerability to adverse late effects from their primary malignancy and its therapy. A health behavior survey was completed by 110 parents of long-term survivors ranging in age from 11-17 years, and by 40 adult long-term survivors of childhood cancer ranging in age from 18-29 years. The survey included questions on the former patient's frequency of alcohol and tobacco use, as well as diet, exercise, sleep, dental, and seatbelt habits. The reported prevalence of tobacco and alcohol use was less than 10% among those less than 18 years old. Among the adults, tobacco (17.5%) and alcohol (72.5%) use was greater, but problem drinking was infrequently reported. In order to assess their perceived vulnerability, we asked the parents and the young adult patients to rate the strength of their belief that it is more important for the patient to keep healthy compared to most other children or young adults. Contrary to our expectation, demographic factors such as the patient's gender, socioeconomic level, or time elapsed since completion of therapy exerted minimal influence on their responses. Over 80% of parents and 60% of young adult survivors believed that it was more important for the former patient to remain healthy compared to most other people. However, this shared belief in increased vulnerability was inconsistently expressed in the patient's health behaviors. These results suggest that specific changes are needed in the health assessment and education of long-term survivors of childhood cancer.

Twelve consecutively diagnosed children with brain tumors, ages 7 to 27 months, were treated by a combined-modality approach featuring aggressive surgical resection followed by chemotherapy and delayed irradiation. Patients received multiple clinical neurologic examinations and psychological evaluations, as well as diagnostic imaging studies, to monitor the efficacy of chemotherapy and toxic effects of therapy. Six of the eight children with residual tumor evident postoperatively on computed tomography scans had objective responses to chemotherapy. The efficacy of chemotherapy was further demonstrated by the lack of disease progression for 7 months or longer in eight children, seven of whom remain free of tumor 19 to 57 months (median, 28 months) from the date of diagnosis. The neurologic status of ten patients improved during treatment. Developmental progress was normal in two, low average in three, and frankly deficient in four of ten children formally evaluated. These results indicate that postoperative chemotherapy, added to a regimen of surgical resection and delayed irradiation, prolong survival with only minimal short term neurotoxicity in the majority of very young children with malignant brain tumors.

The adjustment of parents whose children had died from cancer 6 to 8 years earlier was assessed using structured interviews and standardized inventories. Forty parents had participated in a home hospice program during the terminal phase of their child's illness whereas 22 were parents of children who died in the hospital. Home care parents reported significantly stronger relationships with spouse and remaining children, firmer religious convictions, more adequate coping abilities, and less residual guilt than non-home care parents. On the Minnesota Multiphasic Personality Inventory (MMPI), non-home care parents exhibited more frequent indications of maladjustment including somatization, depression, and interpersonal problems. The results confirm that the more optimal adjustment of home care parents which was first reported 5 years earlier has been maintained. Support and expansion of pediatric home hospice programs are strongly encouraged in light of the positive results of our longitudinal studies.