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.

Regional cerebral blood flow and neuron-specific enolase in cerebrospinal fluid in children with acute lymphoblastic leukemia during induction treatment.

PURPOSE: To investigate possible side effects on the central nervous system from intrathecal methotrexate given during induction treatment for acute lymphoblastic leukemia in childhood. PATIENTS AND METHODS: Twenty-five children with acute lymphoblastic leukemia were examined by cerebral single photon emission computed tomography at the beginning of treatment (16 untreated, 9 during the first week) and after 4 weeks of treatment. Cerebrospinal fluid was sampled for analyses of neuron-specific enolase on four occasions in 54 patients. RESULTS: Regional cerebral blood flow became impaired during treatment in all patients. The single photon emission computed tomography score for nonhomogeneous perfusion increased from 6.4/50 to 16.6/50. Hypoperfusion was global without any clear preference for any lobe. The cerebellum was not affected. Neuron-specific enolase increased significantly during treatment, with a peak after 1 week, followed by a gradual decrease, but it was still significantly elevated after 4 weeks. CONCLUSIONS: Nonhomogeneous cerebral hypoperfusion was found in all patients during induction treatment, including repeated intrathecal administration of methotrexate, but before systemic high-dose methotrexate. Signs of neuronal injury, in the form of a moderate increase in neuron-specific enolase in the cerebrospinal fluid, were found early in the treatment. Follow-up is needed to evaluate the long-term impact of these findings.

Non-Hodgkin lymphoma in children: a 20-year population-based epidemiologic study in western Sweden.

PURPOSE: The aim of this study was to investigate incidence, clinicopathologic features, prognostic risk factors, and long-term survival in non-Hodgkin lymphoma (NHL) in a 20-year population-based study of children using Swedish health care organizations and their central registry for childhood malignancies. PATIENTS AND METHODS: The hospital registry, the Cause of Death Registry, and the two established Swedish registries for malignancy (the Swedish Cancer Registry and the National Registry for Solid Tumours in Childhood) were searched for children in western Sweden with NHL diagnosed from 1975 to 1994. The clinical files of all children with NHL were collected and abstracted for information regarding age at diagnosis, gender, disease characteristics, treatment, and outcome of treatment. All sections from paraffin-embedded blocks of tumors with a diagnosis of malignant lymphoma were collected and reexamined histopathologically and immunohistochemically. To guarantee that no patients with NHL were misdiagnosed, a reexamination of other childhood malignancies collected from these registries was also performed. Median follow-up duration of surviving patients is 10 years. RESULTS: The annual incidence of NHL in children younger than 15 years of age was 9/million children, representing 6% of all childhood malignancies during the investigation time. The male-female ratio was 4.1:1.0. Immunologic marker studies were available for 64 of the 77 NHLs: 41 patients had B-cell, 17 had T-cell, and 6 had Ki-1-positive anaplastic large cell lymphoma (ALCL). Two patients with Ki-1-positive ALCL were originally thought to have malignant histiocytosis and Langerhans cell histiocytosis (LCH), respectively. Treatment was the most significant prognostic factor; event-free survival (EFS) was 19% in the preprotocol era (1975 to 1979) and 74% from 1980 to 1994. Other than treatment, stage was the most significant prognostic factor; EFS was 86% for patients (1980 to 1994) with stage I or II disease and 64% for patients with stage III or IV disease, with a dismal prognosis for children with initial involvement of the bone marrow or central nervous system (EFS was 38% and 20%, respectively). Bulky disease and performance state at diagnosis were independent prognostic factors. The patterns of relapse, including early recurrence of the B-cell lymphomas, are in accordance with previous experience. CONCLUSION: The incidence of NHL was found to be somewhat higher than reported in our previous Nordic study. The higher incidence found in this study might be the result of the thorough data collection (based on hospital registry and cross-checked with all registries for malignant diseases in Sweden) or because reexamination of the tissue material was performed. A more pronounced male predominance than found in previous investigations was observed. The immunophenotypic distribution and the stage distribution is in accordance with earlier investigations. Treatment was the most important factor affecting outcome. A dramatic improvement of survival was seen with the introduction of intensive therapy; treatment success can be expected in 86% of children with localized disease and 64% of children with extensive disease. The absence of improvement in survival despite further treatment stratification with the introduction of the BFM protocol for B-cell-NHL is surprising. LSA2L2-like protocols seem to be as effective. Future studies on treatment of NHL must also concentrate on reducing the intensity of therapy in patients with lower risk disease to minimize late toxic effects.

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.

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.

Childhood non-Hodgkin's lymphoma in the five Nordic countries. A five-year population-based study from the Nordic Society of Pediatric Hematology and Oncology.

PURPOSE: The comparable health-care organizations and common Cancer Registry for childhood malignancies in the five Nordic countries offered an opportunity to conduct an epidemiological study on a reasonable number of childhood non-Hodgkin's lymphoma (NHL) cases collected in a population-based manner. MATERIAL AND METHODS: All childhood cases (0-14.9 years at diagnosis) reported during the 5-year period of 1985-1989 to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) Cancer Registry for childhood malignancies were reviewed and analyzed according to age, Murphy's stage, gender, site, and survival. RESULTS: The annual incidence of NHL is 0.7 per 100,000 children in the five Nordic countries, constituting 5% of all childhood malignancies. Age distribution was even; the male/female ratio was 3:1. Age and stage were shown by Cox regression analysis to be independent prognostic factors. Older age and lower stage affected outcome favorably. The stage and site distribution was similar to previous reports. Survival data were in accordance with those expected with modern treatment protocols. CONCLUSIONS: The incidence and relative frequency of NHL in childhood in the five Nordic countries is in agreement with previously reported data, but the even distribution of cases throughout childhood is a new finding. Older age at onset and stage of disease affect outcome favorably, whereas male gender contrary to acute lymphoblastic leukemia was not found to affect outcome.

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.

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.

Cerebral irradiation causes blunted pubertal growth in girls treated for acute leukemia.

The improved treatment of childhood leukemia is a major achievement. The late effects of the treatment need further investigation. Growth inhibition has been demonstrated in earlier studies. Growth and the timing of puberty were studied in 179 girls who had been treated for acute lymphoblastic leukemia (ALL) in Denmark, Finland, Norway, and Sweden. The patients were divided into two groups according to mode of CNS prophylaxis: with or without cerebral irradiation. Longitudinal analysis of 103 patients showed no difference in prepubertal growth in irradiated and nonirradiated girls. Growth during puberty was normal in girls without irradiation and below normal in irradiated girls. There was no difference in growth between girls after 24 Gy or 20 Gy of cerebral irradiation. Irradiated girls had a final height which was one SD less than expected before puberty and menarche occurred one year earlier than in the nonirradiated girls. Prophylactic cerebral irradiation is the most important factor for subnormal growth after treatment for ALL. There is no short-term influence on growth but the effects of irradiation become apparent several years after therapy when girls enter puberty somewhat early and have a subnormal pubertal growth. Growth and growth hormone (GH) levels should be evaluated several years after CNS irradiation, and treatment with GH and/or luteinizing hormone releasing hormone (LHRH) analogues may be considered.

SIOP Working Committee on Psychosocial Issues in Pediatric Oncology.

Recognizing the importance of psychosocial issues in the care and cure of the child with cancer, the board of the International Society of Pediatric Oncology (SIOP) in 1991 constituted a Working Committee on Psychosocial Issues in Pediatric Oncology, with Giuseppe Masera as chair and John Spinetta as co-chair. This committee met for the first time in Rhodes, Greece, in October 1991. The committee discussed various psychosocial issues and developed a document on Aims and Recommendations, summarizing the experiences of major centers. This document was approved by the SIOP board, which recommended diffusion of the document to the pediatric oncology community.

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.

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.

Reproduction following treatment for childhood leukemia: a population-based prospective cohort study of fertility and offspring.

Of all children diagnosed with leukemia in Denmark, Finland, Iceland, Norway, and Sweden, 981 had discontinued therapy before 1985 and had been followed up annually after cessation of therapy. Progeny was registered and fertility evaluated among survivors who passed age 18 years without a relapse (n = 299). By April 1989, 48 offspring were registered, one of whom had congenital anomalies. This was no more than expected from the incidence of birth defects in the general population. No childhood malignancies or genetic diseases have so far been diagnosed in the progeny. In the study group, none of the 19 female and 8 male survivors of myeloid leukemias had become parents, and only 4 fathers were reported among the 131 male survivors of acute lymphoblastic leukemia (ALL). However, 23 of the 149 females treated for ALL had delivered 41 children. Fertility was measured as cumulative rates of first birth by maternal age. In a Cox regression analysis, cases who had received prophylactic radiation of the central nervous system (CNS) had a lower first birth rate than those without radiation (rate ratio 0.39, 95% CI 0.15-1.00), indicating that doses of 18-24 Gy to the brain may possibly be a risk factor. By using the Norwegian birth cohort of 1966 as a control group, matching the median year of birth for the study subjects, the group of female ALL survivors as a whole was as likely as the general female population to have given birth up to the age of 23. The first generation of females successfully treated for childhood ALL seems to have a nearly normal reproductive pattern during young adulthood, without increased risk of congenital anomalies in the offspring. However, cranial radiation as CNS prophylaxis may possibly impair subsequent reproduction.

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.

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.

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.

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.