Irradiation-induced progenitor cell death in the developing brain is resistant to erythropoietin treatment and caspase inhibition.

One hemisphere of postnatal day 8 (P8) rats or P10 mice was irradiated with a single dose of 4-12 Gy, and animals were killed from 2 h to 8 weeks after irradiation (IR). In the subventricular zone (SVZ) and the granular cell layer (GCL) of the dentate gyrus, harboring neural and other progenitor cells, nitrosylation and p53 peaked 2-12 h after IR, followed by markers for active caspase-3, apoptosis-inducing factor and TUNEL (6-24 h). Ki67-positive (proliferating) cells had disappeared by 12 h and partly reappeared by 7 days post-IR. The SVZ and GCL areas decreased approximately 50% 7 days after IR. The development of white matter was hampered, resulting in 50-70% less myelin basic protein staining. Pretreatment with erythropoietin did not confer protection against IR. Caspase inhibition by overexpression of XIAP prevented caspase-9 and caspase-3 activation but not cell death, presumably because of increased caspase-independent cell death.

Staff attitudes before and after the inception of a pediatric oncology unit.

A special pediatric unit was started for patients with cancer. All staff had experience in caring for chronically ill children, but there were great individual variations in training. Positive expectations of the new unit expressed by staff were (1) feeling needed, (2) having a common goal, and (3) seeing results. Negative expectations expressed were fear of the suffering and dying of the children. One year later the positive expectations were found to be fulfilled. The fears were not found to be confirmed. The existing relationships among the nursing staff were criticized at the opening of the unit. Relationships had improved 1 year later. The prevailing organization at the opening of the unit was criticized. The RNs had too little time for primary nursing of the patients. Conditions had improved 1 year later, but the RN staff was considered too small and more physical space was needed. The parents' presence at the ward was considered positive by all staff when the unit opened. One year later some negative aspects were also pointed out.

Brain tumors in childhood and adolescence in west Sweden 1970-1984. Epidemiology and survival.

A population-based series of 198 children, aged 0 to 16.9 years, with primary brain tumors, diagnosed from 1970 to 1984, was retrieved from the Swedish Cancer Registry. After review of slides and reclassification of histology according to the American Cancer Society, the average annual incidence rate was estimated to be 34.9 per million, which is a very high incidence compared to other countries. The age distribution was not uniform as age group 0 to 4 included more children than age groups 5 to 9 and 10 to 14. The largest subgroups were astrocytomas (25%) and primitive neuroectodermal tumor (PNET)/medulloblastomas (MB) (21%). Associated diseases were neurofibromatosis and Rubinstein-Taybi syndrome. The overall male to female ratio was 1.08:1, the same as in the population at risk; but for PNET/MB, it was 1.8:1. The 5-year survival for all tumors was 54%, and the 15-year survival, 49%, with great variation between tumor subgroups.

Immunoglobulin levels and lymphocyte response to mitogenic stimulation in children with malignant disease during treatment and follow-up.

Intensification of chemotherapeutic regimens has improved survival in childhood malignant disease. To characterize the impact of this intensified therapy on some aspects of the immune system, we have, in an unselected material of 220 children with malignant disease, investigated serum immunoglobulin levels and lymphocyte response at diagnosis and then subsequently during and up to 4 years after cessation of therapy. In leukemia and Hodgkin's disease, all immunoglobulin isotypes decreased during therapy. A profound depression of immunoglobulin M levels, lasting well after completion of therapy, was seen in all tumor types. The mitogenic response was attenuated in patients with leukemia at diagnosis but was rapidly restored after institution of therapy. Patients with solid tumors, particularly Hodgkin's disease, had a reduced mitogenic response during therapy. Thus these patients exhibit multiple immunological disturbances. The basis of the pronounced immunoglobulin M deficiency remains unclear.

A longitudinal study of growth in children with acute lymphoblastic leukemia.

Growth in terms of both height and weight was studied in a longitudinal sample consisting of ten children who all experienced the onset of acute leukemia between 18 months and 7 years of age. In spite of the lack of deviation in body size at birth, these children had somewhat higher values for attained size than the reference group one year before diagnosis. The information from this study showing a decrease in growth rate before the start of treatment, could suggest that the disease causes the growth failure. Growth rate for height increased with time from the first year of treatment, which could be correlated to a positive effect of medical treatment of the disease. These results indicate a very stable regulation of growth between 18 months and 12 years of age. The children dropped temporarily in mean one standard deviation (SD) corresponding to about 4 cm, from one year before the start of treatment to the end of the three years of treatment. It seems, however, that it is possible for the body to repair such a temporary growth inhibition as is seen in the catch-up growth during the following two years. Height measured in SD for the group two years after discontinuing treatment was practically the same as height at the time of the start of treatment. Children with leukemia during the first years of life and during the pubertal period may not show a similar growth pattern.

Long-term sequelae after pediatric brain tumors: their effect on disability and quality of life.

In an unselected series of pediatric brain tumors, 56 of 60 long-term survivors--craniopharyngiomas and pituitary tumors excluded--were investigated and interviewed mean X = 10 (5-16) years after diagnosis. After this time, sequelae were stable and included cognitive (38%), motor (25%), visual (20%), hormonal (20%), and psychological-emotional (14%) dysfunction. Memory dysfunction was found in 22% of patients with normal intelligence. Moderate or severe disability, from combinations of these impairments, was found in 34%. Sixty-six percent had no or mild disability compatible with active life and employment. However, these patients less often were married or had children compared with a control group of healthy subjects. Moderate and severe disability was found in 48% of supra- and in 21% of infratentorial tumors, after radiotherapy (RT) in 55% vs. without RT in 18%. RT before 6 years of age caused subnormal IQ in all cases. The self-reported quality of life was not related to degree of disability. Patients with psychological-emotional sequelae self-evaluated their quality of life lower than did patients with other types of long-term sequelae.

Long-term use of central venous catheters in paediatric oncology treatment.

During a 26-month period, 158 central venous catheters were inserted in 114 children (median age: 4.5 years) with malignant diseases. Polyurethane catheters were used, inserted either using a cut-down procedure or percutaneously in the external or internal jugular vein. All catheters were tunnelled from the point of insertion to the midpoint of the manubrium or upper sternum. The catheter tip reached the superior caval vein or the right atrium in 94% of the cases. The catheters were used for all infusions, including total parenteral nutrition, and for blood sampling. The median catheter duration was 104 days (range 5-835 days). Sixty-eight (43%) of the catheters were removed as they were no longer needed, and 31 (20%) were removed due to local infection or septicaemia. During a total of 23,486 catheter days (64.4 years), 110 episodes of septicaemia occurred. This represents one episode per 214 catheter days. In 43 of the 110 episodes of septicaemia, blood cultures showed growth of bacteria of the kind usually found in the gastrointestinal and respiratory tracts. All septicaemias were treated with intravenous broad-spectrum antibiotics and in 21 cases the catheters were removed due to septicaemia. Thirty-four (22%) catheters were removed accidentally. There were two cases of subclavian vein thrombosis.

Longitudinal growth in children with non-Hodgkin's lymphoma and children with acute lymphoblastic leukemia: comparison between unirradiated and irradiated patients.

Longitudinal growth was studied in children treated for non-Hodgkin's lymphoma (NHL). The aim of the study was to compare these children's growth velocity with findings in a previous study we performed on age-matched children with acute lymphoblastic leukemia (ALL) who received cranial irradiation. Nine children with NHL with an onset time of treatment between 4 and 9 years of age (mean 6.5 years) were studied with annual body measurements taken from the time of the diagnosis and thereafter annually during the following 4 years. None of the children received cranial irradiation. During the first treatment year a significantly low mean height velocity was observed (-1.4 standard deviation score [SDS]) for the NHL group. The consecutive two 1 year periods showed a normalization of the mean height velocity. For the group of children with ALL, there was a more prominent negative effect on height during the first 2 years of treatment than for the NHL group in the present study. After the cessation of therapy, the children with NHL showed a reduced catch-up growth compared with the children with ALL. The explanation offered is that cranial irradiation has a heavier impact on growth than chemotherapy during the first 2 years of treatment, but an intense chemotherapy during the maintenance period could have a considerable impact in blunting growth.

A longitudinal study of growth and growth hormone secretion in children during treatment for acute lymphoblastic leukemia.

Diminished growth rate during treatment for acute lymphoblastic leukemia (ALL) is of the multifactorial etiology. Effects on GH secretion have been shown after discontinuation of treatment including prophylactic CNS irradiation. Seventeen children treated for ALL with three different CNS preventive schedules were followed longitudinally with repeated estimations of the spontaneous GH secretion during a 24-month period. No difference was found in GH secretion during this time between patients who had received no radiotherapy and those who had received 18 or 24 Gy as CNS prophylaxis. During dexamethasone treatment the GH secretion was completely suppressed, which can be a mediator for the diminished growth rate during the first 2 years of ALL treatment. We conclude that there is no clinical reason to perform GH analysis within the first 24 months of treatment for ALL.

Growth hormone secretion and response to growth hormone therapy after treatment for brain tumour.

Children irradiated for brain tumours constitute an increasing group of patients who will require GH therapy. High-dose cranial irradiation is necessary for cure, but inevitably causes GH deficiency within a few years. In 19 patients investigated between 2 and 9 years after irradiation, the spontaneous 24-hour GH secretion was markedly reduced. The secretory pattern indicated loss of regulating hypothalamic hormones. After exogenous GHRH was administered, the pituitary was able to respond with a prompt GH release, showing that pituitary function was unaffected. Ten prepubertal children growing at 3.8 +/- 0.3 cm/year were treated with GH, 0.1 IU/kg/day s.c. Their growth rate increased to 8.2 +/- 0.4 cm in the first year. An increased growth rate was also maintained in the second year.

Echocardiographic findings in children treated for malignancy with chemotherapy including adriamycin.

Thirty-seven children receiving chemotherapy including adriamycin were studied with echocardiography. Abnormal left ventricular function assessed by systolic time intervals (STI) and/or left ventricular shortening fraction (delta LVID) was present in 30%, and dilated left ventricle was in 45% of the case, often accompanied by thinning the left ventricular wall. Three patients developed congestive heart failure, one with fatal outcome. Two of these patients had received chest irradiation along with the chemotherapeutic treatment. These three patients with overt heart failure had gross abnormalities in several echocardiographic variables of which delta LVID seemed most specific.

Studies of cerebral blood flow in children with acute lymphoblastic leukemia: case reports of six children treated with methotrexate examined by single photon emission computed tomography.

PURPOSE: Cranial irradiation has been widely used in order to prevent central nervous system (CNS) relapse of acute lymphoblastic leukemia (ALL) in childhood. Owing to the risk of late side effects, the Nordic Society for Pediatric Hematology and Oncology (NOPHO) replaced CNS irradiation with systemic high-dose methotrexate (HDMTX) in 1992. A prospective study of the effects of HDMTX and intrathecal MTX on CNS function is in progress at our center. PATIENTS AND METHODS: Six ALL patients underwent (99m)Tc-HMPAO single-photon emission computed tomography (SPECT) examination of regional cerebral blood flow (rCBF): three owing to neurological symptoms during treatment for ALL and the other three as part of the study. RESULTS: All the patients had various degrees of disturbed rCBF, which was more pronounced in the patients with neurological symptoms. One patient had severe symptoms and impaired rCBF after three intrathecal injections of MTX but before administration of HDMTX. CONCLUSIONS: Impaired cerebral perfusion was found in patients with and without neurological symptoms during treatment for ALL. The impact of these findings is still unknown, from both the long- and the short-term perspective. The possibility that intrathecal MTX alone or in combination with HDMTX may affect rCBF through vascular damage should be further investigated, in terms of both mechanisms and clinical significance.

Growth and growth hormone secretion after treatment for childhood non-Hodgkin's lymphoma.

The aim of this study was to evaluate the growth and growth hormone (GH) secretion, as assessed by the rate and pattern of secretion, in patients in remission from non-Hodgkin's lymphoma (NHL) who had been treated with corticosteroids and intense chemotherapy. None of the patients had received cranial irradiation. Twelve children were investigated yearly by taking 24-hour GH profiles starting 1 year from the time of diagnosis. The mean age at onset of the disease was 7.5 years. Another 12 young adults were studied in a cross-sectional manner 4.1-21.3 years (mean, 9.0 years) after diagnosis of NHL. The mean age at onset of the disease was 10.7 years. The median height velocity was significantly decreased during the 1st year following diagnosis (standard deviation scores [SDS] -0.15, P < .001), especially during the first 3 months (SDS -0.75, P < .001) when the most intense treatment was given. During the 2nd year height velocity was still somewhat reduced (SDS -0.13, P < .001). However, there was no reduction in final attained height. Spontaneous GH secretion, in terms of both secretory rate and pulsatile pattern, was evaluated by measuring integrated GH concentrations in 20-minute blood samples collected over a 24-hour period. The plasma GH concentrations were transformed into GH secretion rates by means of a deconvolution technique. Fourier time series analysis was applied to determine possible disturbances of rhythmicity of the GH secretion. The GH secretion rate and the pulsatile pattern of secretion in the NHL patients were similar to those of the reference population of pubertal matched healthy controls. There was no influence of the age at diagnosis or of the time from diagnosis of NHL on the GH secretion rate. Growth impairment in children with a malignant disease treated only with steroids and chemotherapy is therefore probably not caused by disturbed GH secretion, but rather by direct interference with bone growth of the cytotoxic drugs used. There was no significant influence on weight gain during the treatment period so an indirect effect of chemotherapy on bone growth through interference with adequate nutrition seems unlikely. However, GH secretion was not evaluated during the period of growth retardation, and therefore a transient deficiency was not excluded.

Prophylactic cranial irradiation increases the risk of testicular damage in adult males surviving ALL in childhood.

By combining three series of Scandinavian patients, we were able to compare the late testicular sequelae in 41 adult males whose therapy had included chemotherapy alone or chemotherapy with cranial irradiation without other radiotherapy for ALL in childhood. In multivariate analysis, cranial irradiation was associated with a decrease of 5.7 (95% confidence limits 1.5-9.9) cm (P = 0.010) in height, and a decrease of 4.8 (0.3-9.2) ml (P = 0.036) in testicle size. Cyclophosphamide was associated with increases of 8.2 (-0.5-16.9) (P = 0.065) and 3.9 (0.3-7.4) U/L (P = 0.036) in serum FSH and LH concentrations, respectively. Of the 12 patients who had received both cranial irradiation and cyclophosphamide therapy, 4 (33%) had delayed pubertal development as compared with 1 (3.5%) of the other 29 patients (P = 0.008). Patients 12-16 years of age at diagnosis had larger testicles (P = 0.051) and higher testosterone concentrations (P = 0.026) than others. Neither sexual activity nor semen findings correlated with the preceding treatment. Our data indicate that prophylactic cranial irradiation may be associated with impaired growth and pubertal development in boys with ALL.

Growth in children treated for acute lymphoblastic leukemia with and without prophylactic cranial irradiation.

Growth and weight gain were studied longitudinally over a period of four years in thirty-nine children treated for acute lymphoblastic leukemia. The children were divided into two groups according to treatment. Twenty-eight children were given prophylactic cranial irradiation and eleven children were treated without such irradiation. The duration of cytostatic treatment was three years in all cases. Average growth during the first two years was similar in the two groups, and the standard deviation scores (SDS) were below average. The rate of growth (in height) during the fourth year was significantly higher among those children who had not received cranial irradiation (p less than 0.01). After four years the average attained height had declined 0.5 SD for children treated with cranial irradiation and 0.2 SD for children without such treatment. Weight velocity was significantly greater than the expected mean in the non-irradiated group during the first year and in the irradiated group during the fourth year of the study. Attained weight after four years had increased 0.4 SD more among those children who had not received irradiation. The results suggest that prophylactic cranial irradiation is responsible for the greater part of the prepubertal growth inhibition in these children.

Reduced growth hormone secretion with maintained periodicity following cranial irradiation in children with acute lymphoblastic leukaemia.

OBJECTIVE: Low dose cranial irradiation in children with acute lymphoblastic leukaemia (ALL) has been reported to reduce GH secretion in puberty. A recent study also reported a disturbed periodicity of GH secretion during puberty. We have focused on the different stages of puberty in studying these two parameters of GH secretion and have also compared the effects of 18 vs 24 Gy radiation dose. PATIENTS AND MEASUREMENTS: Thirty-four children previously treated for ALL were compared with a control group of 208 healthy normally growing children. GH secretion was measured as 24-hour profiles. RESULTS: In children treated for ALL, GH secretion rate and GH peak amplitude were below the median values for controls, both before puberty and during all stages of puberty. The difference between patients and controls was most pronounced in late puberty. Radiation with 18 or 24 Gy gave similar results. However, time sequence analysis showed a similar periodicity of GH secretion in both patient and control groups before, as well as during, puberty. Thus, before puberty a broad range of cycles per 24 hours was seen. These synchronized during puberty to a predominant GH peak frequency of one every 3-4 hours. CONCLUSIONS: After low dose cranial irradiation with 18 or 24 Gy, the total amount of GH secreted is reduced both before and during puberty. We could not confirm previous findings of impaired periodicity of GH secretion in these children.

A longitudinal study on growth and spontaneous growth hormone (GH) secretion in children with irradiated brain tumors.

Longitudinal growth was studied in 27 children after radiotherapy for a brain tumor. Growth deviation (greater than or equal to 1 SD) was found in 56% of the children after 2 years and was most profound in prepubertal children aged between 3 and 8 years at the time of irradiation. In this group growth velocity was markedly reduced and no catch up was seen. In all children studied growth hormone (GH) secretion, measured as the spontaneous secretion over 24 hours, was found to be severely disturbed. Our conclusion is that all children with a growth deviation greater than or equal to 1 SD after radiotherapy (greater than or equal to 40 Gy) to the hypothalamo-hypophyseal region should be considered GH deficient. In such children GH treatment can be initiated without further testing.