Health-related quality of life in long-term survivors of acute lymphoblastic leukemia in childhood and adolescence.

PURPOSE: Children with acute lymphoblastic leukemia (ALL), the commonest form of cancer in this age group, suffer considerable morbidity during treatment, with the majority returning to good health soon after therapy has been completed, as reflected in health-related quality of life (HRQL). However, survivors are at risk of many adverse health outcomes later, including obesity, measured by body mass index (BMI), that is compounded by limited physical activity. This study examined the HRQL of long-term survivors of ALL and its relationship to BMI and physical activity. METHODS: A cohort of 75 subjects who were more than 10 years from diagnosis was assessed for BMI (weight in kg/height in m2) and completed two questionnaires. HRQL was measured by the multi-attribute, preference-based Health Utilities Index (HUI) instrument HUI23S4.15Q designed for self-report, and physical activity was quantified by the Habitual Activity Estimation Scale. RESULTS: The mean utility scores for overall HRQL (HUI2 = 0.88, HUI3 = 0.83) were similar to those in the Canadian and US general population segments of equivalent age (HUI2 = 0.86, HUI3 = 0.85). However, the minimum scores (HUI2 = 0.23, HUI3 = -0.09) revealed a group of survivors with notable disabilities in the attributes of hearing, emotion, cognition, and pain. There were no statistically significant correlations between HRQL and BMI or between HRQL and physical activity, except for deafness and inactivity on weekdays. CONCLUSIONS: Overall, long-term survivors of ALL in childhood enjoy good HRQL but some experience appreciable disability, though this is not associated with BMI or, in the main, with physical activity.

Measurement of socio-economic status in families of children with cancer in Guatemala.

The prospects for survival of children in low and middle income countries are linked to their families socio-economic status (SES), of which income is only one component. Developing a comprehensive measure of SES is required. Informed by clinical experience, a 15-item instrument was designed in Guatemala to categorize SES by five levels in each item. Almost 75% of families attending the Unidad Nacional de Oncología Pediátrica were in the lowest three of six categories, providing a framework for stratified financial and nutritional support. The measure of SES offers an opportunity for examining associations with health outcomes throughout Latin America.

A national study of the provision of oncology sperm banking services among Canadian fertility clinics.

The purpose of this study was to survey the current state of oncology sperm banking services provided by fertility clinics across Canada. A total of 78 Canadian fertility facilities were invited to complete a questionnaire related to the availability, accessibility, affordability and utilisation of sperm banking services for cancer patients. The total response rate was 59%, with 20 (69%) in vitro fertilisation clinics and 26 (53%) other fertility centres returning the survey. A total of 24 responding facilities accepted oncology sperm banking referrals. The time frame to book the first banking appointment for 19 (79%) facilities was within 2 days. Inconsistent practice was found regarding the consent process for cancer patients who are of minority age. Eight (33%) facilities did not provide any subsidy and charged a standard banking fee regardless of patients' financial situations. Overall, the utilisation of oncology sperm banking services was low despite its availability and established efficacy, suggesting that Canadian cancer patients are notably underserved. The study has highlighted some important issues for further consideration in improving access to sperm banking services for cancer patients, especially for adolescents. Better collaboration between oncology and reproductive medicine to target healthcare providers would help to improve sperm banking rates.

Accounting for body size deviations when reporting bone mineral density variables in children.

UNLABELLED: In a child, bone mineral density (BMD) may differ from an age-expected normal value, not only because of the presence of disease, but also because of deviations of height or weight from population averages. Appropriate adjustment for body size deviations simplifies interpretation of BMD measurements. INTRODUCTION: For children, a bone mineral density (BMD) measurement is normally expressed as a Z score. Interpretation is complicated when weight or height distinctly differ from age-matched children. We develop a procedure to allow for the influence of body size deviations upon measured BMD. METHODS: We examined the relation between body size deviation and spine, hip and whole body BMD deviation in 179 normal children (91 girls). Expressions were developed that allowed derivation of an expected BMD based on age, gender and body size deviation. The difference between measured and expected BMD was expressed as a HAW score (Height-, Age-, Weight-adjusted score). RESULTS: In a second independent sample of 26 normal children (14 girls), measured spine, total femur and whole body BMD all fell within the same single normal range after accounting for age, gender and body size deviations. When traditional Z scores and HAW scores were compared in 154 children, 17.5% showed differences of more than 1 unit and such differences were associated with height and weight deviations. CONCLUSION: For almost 1 in 5 children, body size deviations influence BMD to an extent that could alter clinical management.

Hemopoietic stem cells in human peripheral blood.

A population of lymphocytes, separable from the great majority by virtue of their larger size and their failure to exhibit the rosetting characteristics of thymus-dependent lymphocytes and bursa-equivalent cells, possess true pluripotentiality. On culture in vivo they proliferate and differentiate into erythrocytic, granulocytic, and megakaryocytic progeny. This may be the first clear demonstration of the primitive progenitor blood cell in man.

Soft-tissue necrosis induced by extravasated cancer chemotherapeutic agents.

The inadvertent extravasation of anticancer drugs in clinical use may result in the development of indolent lesions at the site of injection. Investigation of this phenomenon in Hartley guinea pigs showed that the pathogenesis was based on direct tissue toxicity and not on sensitization. The risk of a serious reaction appeared to be related to the localization of the injurious agent within the dermis rather than at the subcutaneous site.

A comprehensive multiattribute system for classifying the health status of survivors of childhood cancer.

PURPOSE: A multiattribute health status classification system was devised to describe comprehensively the health status of survivors of childhood cancer. METHODS: The system consists of seven attributes: sensation, mobility, emotion, cognition, self-care, pain, and fertility. Three to five levels of functioning are defined for each attribute. Any specific combination of seven attribute levels constitutes a health state. In the first survey, the system was used to classify the health status of 20 children currently undergoing therapy for high-risk acute lymphoblastic leukemia (ALL), Wilms' tumor, or neuroblastoma, and eight who had completed treatment. A second survey consisted of 13 children with brain tumors on active treatment. RESULTS: In general, independent ratings by clinicians were in agreement, and consensus was readily achieved in 1 to 2 minutes per patient. Children on therapy experienced a higher burden of morbidity than those off treatment. Brain tumor patients experienced more morbidity than patients in the first survey. CONCLUSION: The multiattribute system provides a compact but comprehensive tool for long-term follow-up of survivors of childhood cancer. It captures both multiple sequelae and varying levels of severity. By using a mathematical utility function, a single summary score of health-related quality of life may be assigned to each health state. Additional studies to establish reproducibility, validity, responsiveness, and generalizability are indicated.

Health-related quality of life in survivors of Wilms' tumor and advanced neuroblastoma: aA cross-sectional study.

PURPOSE: In pediatric oncology, Wilms' tumor and advanced neuroblastoma represent opposite ends of the spectra of survival probability and therapeutic intensity. Consequently, it was envisaged that survivors of Wilms' tumor would enjoy better health status and health-related quality of life (HRQL) than survivors of advanced neuroblastoma. PATIENTS AND METHODS: Health status questionnaires were sent to the parents of all eligible children and to the children themselves if they were > or = 8 years of age. Responses were received from 84% of 93 eligible families. Responses were converted by established algorithms into levels of two multiattribute health status classification systems known as Health Utilities Index Mark 2 and Mark 3. These systems are linked to measures of preference, in the form of multiattribute utility functions, which provide scores of morbidity for single-attribute levels and of global HRQL for comprehensive health states. RESULTS: A greater burden of morbidity was identified in the survivors of advanced neuroblastoma than in survivors of Wilms' tumor based on the assessments of the parents of these children. In particular, survivors of advanced neuroblastoma exhibited deficits in hearing and speech. It is possible that this morbidity burden reflects the prevalent use of platinum compounds (causing ototoxicity) in this group. Within parent-child dyads there was a high level of percentage agreement on responses in all attributes except cognition. CONCLUSION: Extension of this study to a larger sample size of patients will provide clarification of these observations.

Use of paediatric versus adult oncology treatment centres by adolescents 15-19 years old: the Canadian Childhood Cancer Surveillance and Control Program.

The aim of this study was to evaluate the treatment patterns of adolescents with cancer in Canada to ensure this population is receiving the most appropriate care. The Treatment and Outcome Surveillance (TOS) system was compared with the Canadian Cancer Registry (CCR) to estimate the proportion of adolescents (15-19 years) treated in Canadian paediatric oncology centres from 1995 to 2000 inclusive. Using TOS, the demographic, disease, and clinical characteristics of adolescents treated in paediatric versus adult centres in the Prairies were compared and differences were tested statistically. Approximately 30% of Canadian adolescents with cancer were treated in a paediatric centre. Adolescents treated in an adult centre were older at diagnosis and more likely to have carcinoma or germ cell tumours. The time between symptom onset and first treatment was longer for these adolescents, primarily due to the time between first health-care contact and assessment by a treating oncologist or surgeon. They were less likely to be enrolled in a clinical trial. These results suggest that care for adolescents with cancer in Canada is less satisfactory than for younger children, and can be improved.

Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995).

The Dana-Farber Cancer Institute (DFCI) ALL consortium has been conducting clinical trials in childhood acute lymphoblastic leukemia (ALL) since 1981. The treatment backbone has included intensive, multi-agent remission induction, early intensification with weekly, high-dose asparaginase, cranial radiation for the majority of patients, frequent vincristine/ corticosteroid pulses during post-remission therapy, and for high-risk patients, doxorubicin during intensification. Between 1981 and 1995, 1,255 children with newly diagnosed ALL were evaluated on four consecutive protocols: 81-01 (1981-1985), 85-01 (1985-1987), 87-01 (1987-1991) and 91-01 (1991-1995). The 5-year event-free survival (EFS) rates (+/- standard error) for all patients by protocol were as follows: 74 +/- 3% (81-01), 78 +/- 3% (85-01), 77 +/- 2% (87-01) and 83 +/- 2% (91-01). The 5-year EFS rates ranged from 78 to 85% for patients with B-progenitor phenotype retrospectively classified as NCI standard-risk, 63-82% for NCI high-risk B-progenitor patients, and 70-79% for patients with T cell phenotype. Results of randomized studies revealed that neither high-dose methotrexate during induction (protocol 87-01) nor high-dose 6-mercaptopurine during intensification (protocol 91-01) were associated with improvement in EFS compared with standard doses. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities.

Nutritional status in children with cancer: Before, during and after therapy.

CONTEXT: Malnutrition is prevalent in children with cancer at diagnosis, especially in low- and middle-income countries (LMIC) where the great majority of children live. It is associated with an added burden of morbidity and mortality. AIMS: Answers were sought to the best measure of nutritional status in LMIC, the impact of anti-neoplastic therapy, effective interventions to achieve normal nutritional status and the impact of these on clinical outcomes. RESULTS: Arm anthropometry offers reasonable estimates of fat mass and lean body mass that are both impacted adversely by treatment. Nutritional supplementation, including the use of simple local resources, is beneficial and can improve survival. Long-term survivors may continue to exhibit perturbed nutritional status. CONCLUSIONS: The prevalence and severity of malnutrition in children with cancer in LMIC demand attention. Opportunities exist to conduct studies in India to examine the effects of nutritional interventions, including on the overall well-being of survivors.

Altered mineral metabolism and bone mass in children during treatment for acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) often develop bone pain, abnormal gait, and unusual fractures while in remission and receiving continuing chemotherapy. A prospective longitudinal cohort study was undertaken of bone mass and biochemical mineral status in 40 consecutive children (27 male, 13 female, aged 0.3-17.0 years) receiving therapy on the Dana-Farber Cancer Institute protocol 87-01. Radiography, lumbar spine dual-photon absorptiometry, and biochemical measurements of mineral status were performed at diagnosis and at 6-month intervals throughout 24 months of chemotherapy. Eleven patients were not completely evaluated (4 deaths and 7 off study). Radiographic evidence of osteopenia was observed in 10, 64, and 76% at diagnosis, 12 and 24 months, respectively. Fractures occurred in 39% of children during treatment. Reduction in bone mineral content (BMC), as measured by Z scores, occurred in 64% of patients and was most severe in those greater than 11 years of age at diagnosis. Reduction in BMC during the first 6 months of therapy had a positive predictive value of 64%, while an increase in BMC had a negative predictive value of 82% for subsequent fracture. By 6 months of therapy, 31/37 (84%) children were hypomagnesemic, of whom 16 (52%) were hypermagnesuric. Plasma osteocalcin was subnormal at diagnosis in 29/40 (73%) but increased to normal by 6 months of treatment. Vitamin D status was normal throughout, but plasma 1,25-dihydroxyvitamin D remained subnormal in greater than 70% of children. Urinary cross-link N-telopeptide was normal at diagnosis and became elevated in 58% of children by the end of therapy. Suppressed bone mineralization is evident at diagnosis in a minority of children with ALL. Skeletal morbidity and a reduction in bone mineral mass become more prevalent during treatment, with increased bone resorption, perhaps mainly as a consequence of corticosteroid administration.

Health-related quality of life in survivors of tumours of the central nervous system in childhood--a preference-based approach to measurement in a cross-sectional study.

There is an evident need to measure the comprehensive burden of morbidity experienced by survivors of brain tumours in childhood. To this end, a questionnaire based on the Health Utilities Index mark 2 (HUI2) and mark 3 (HUI3) systems was completed independently for a cohort of such children by their parents, by a nurse, by physicians and by a selected group of the children themselves. Each of the HUI2 and HUI3 systems consists of a multi-attribute health status classification scheme linked to a preference function which provides utility scores for levels within single attributes (domains of health) and for global health states. All eligible families (n = 44) participated. Even cognitively impaired children of at least 9.5 years of age could complete the questionnaire. The greatest burden of morbidity, occurring in two-thirds of children, was in the attribute of cognition. Surprisingly, almost one-third of children experienced pain. Global health status was lowest in children who underwent radiotherapy before the age of 5 years and the corresponding utility scores were related inversely to the volume irradiated. Children with demonstrable disease had lower scores than those in whom disease was not evident. There was a high level of agreement (intraclass correlation coefficients > 0.5) on formal assessment of inter-rater reliability for global health-related quality of life utility scores. The usefulness of measures of health status and health-related quality of life, in children surviving brain tumours, has been demonstrated by this study.

Osteopenia in children surviving brain tumours.

Osteopenia has been reported in children surviving acute lymphoblastic leukaemia, apparently as a consequence of therapy. It has been suggested that cranial irradiation may play a crucial role in this disorder. To explore that possibility, survivors of brain tumours in childhood, all of whom had received radiotherapy, were examined for evidence of bone mineral loss. 19 children were assessed, on average at 7 years after treatment. Measurements of growth velocities, plain radiography of the skeleton, bone densitometry, health-related quality of life and physical activity were undertaken. Growth hormone (GH) deficiency had been detected in 6 children and 5 had received GH replacement, for a minimum of more than 3 years. 9 children were radiographically osteopenic (including the 5 who had received GH). Z scores for bone mineral density (BMD) were negative in the majority of children. Health-related quality of life was less and pain more frequent in those with low BMD scores. Pain was correlated negatively with both free-time activity and seasonal activity (P < 0.01). Osteopenia is a common sequel of therapy in children with brain tumours. Those with osteopenia have more pain and more compromised, health-related quality of life than those who are not osteopenic, and pain significantly limits physical activity. The pathogenesis of osteopenia in these children is still uncertain, but is likely to be multifactorial.

Applicability of the Health Utilities Index to a population of childhood survivors of central nervous system tumours in the U.K.

This paper describes the application of a multi-attribute, preference-linked health status and health-related quality of life measurement system--the Health Utilities Index (developed in Canada)--to a group of subjects in the U.K. Children who had survived tumours of the central nervous system (n = 30, age 6-16 years) formed the study group. Respondents (children, parents, physicians and physiotherapists) found the activity (completion of a 15-item questionnaire) to be acceptable and not burdensome (it was accomplished easily by all children > or = 10 years of age). Instrumental reliability was established by acceptable intra- and interobserver agreement and construct validity was supported by strong similarities between the results obtained in this study and those reported from a similar group of children in Canada. The greatest burden of morbidity was reported for the attributes of emotion and cognition (each affected in > 50% of the children). Pain was surprisingly prevalent (affected in approximately one-third of children). The finding of a large number of unique health states emphasises the complex morbidity burden experienced by these children who self-reported poorer overall health (as reflected in utility scores) than did the proxy respondents. The information obtained from this study is readily interpretable and clinically useful. The results of this study also illustrate that extreme caution must be exercised in undertaking linguistic modifications to established instruments for, in this instance, these resulted in a loss of the ability to detect the most severe emotional morbidity and reduced the comparability of results between studies. With this provision, the Health Utilities Index is evidently applicable in the U.K. and the original version has been recommended for use in brain tumour studies by the U.K. CCSG (the U.K. Children's Cancer Study Group).

Detection of circulating 'terminal transferase-positive' cells does not predict relapse in acute lymphoblastic leukemia.

Serial samples of peripheral blood were obtained from 35 children with ALL over a period of 18 months. The mononuclear cells were examined for TdT by indirect immunofluorescence using an unpurified anti-calf thymus TdT as the primary antibody. This analysis failed to distinguish those children who were destined to relapse (n = 9) from those who remained in continuous complete remission. Rather, the exhibition of fluorescence was linked to the co-existence of infection, with a negative predictive value of 0.91. Putative 'TdT-positive' cells were concentrated in the T-lymphocyte fraction and the very process of E-rosette formation seemed to contribute to this phenomenon. It appears as if the anti-TdT reagent recognizes not only TdT but also a variety of antigens which are expressed on or in immature and activated lymphocytes.

Demonstration of terminal deoxynucleotidyl transferase in single cells by indirect immunofluorescence--a methodological reappraisal.

The optimal conditions for assaying terminal transferase by indirect immunofluorescence with commercially available reagents have been explored. Target tissues examined included fresh, stored and cultured human acute lymphoblastic leukemia cells; normal human peripheral blood and bone marrow; and calf thymus. Brief, cold fixation in glutaraldehyde/ethanol or omission of fixation proved to be satisfactory. The most suitable primary antibody was an unfractionated rabbit serum with specificity for anti-calf thymus TdT which cross-reacted with human material and was neutralized in high dilution by purified enzyme. Inferior reagents and techniques gave false negative results. Identification of TdT appears to be feasible even in tissue samples stored for several months and enumeration of cells is facilitated by ethidium bromide counterstaining.

Interactions of lithium and hydrocortisone in vitro on normal human hematopoiesis.

Lithium salts and glucocorticosteroid hormones stimulate hematopoiesis in vitro and in vivo. In the former circumstance, the impact is demonstrable with concentrations of these substances which reflect physiological and pharmacological conditions. The evident therapeutic benefit of these effects, in patients who experience myelosuppression and pancytopenia with the use of cytotoxic chemotherapy for malignant disease, could be enhanced if the influences of lithium and steroids on blood cell formation were at least additive. However, the observations in this study suggest that these substances can be mutually inhibitory, with respect to hematopoiesis, and do not support the use of lithium and steroids in combination to alleviate iatrogenic reduction in bone marrow function.

Hydrocortisone promotes clonal granulopoiesis in cultures of normal human bone marrow--a "nutritional" advantage or true stimulation of growth?

The generation of normal human hemopoietic clones is promoted, in tissue culture, by physiological as well as pharmacological concentrations of hydrocortisone. In part this may reflect a facilitative, nutritional effect of the hormone which may be more evident in particular culture media. However, the findings, in liquid suspension cultures, of an increase in the absolute number of cells and a rise in the mitotic index in the presence of hydrocortisone, point to a real stimulation of cellular proliferation. Measurements of the number of clones early in culture, and the size of clones after longer intervals, indicate respectively that the hormone influences both recruitment of clonogenic cells into cytokinesis and amplification of established clones. The target cell in both processes may be the same, namely a morphologically recognizable entity, in the granulocyte lineage, having limited proliferative potential. Evidence in support of this interpretation includes the high cloning efficiency, small mean clonal size and brief clonal lifespan. These features suggest that members of the myeloblast-promyelocyte-myelocyte hierarchy are likely candidates, but whether the action of hydrocortisone is exerted directly on these cells, or on a more mature accessory population, remains to be determined.