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Background The surgical treatment of Ewing's sarcoma family tumours (ESFTs) is challenging especially with axial tumours. The aim of the study was to analyse surgical treatment and outcome in a nationwide, population-based material consisting of surgically treated axial and peripheral ESFTs of bone and soft tissue. Methods The data were collected from the Finnish National Cancer Registry and the medical records of patients diagnosed during 1990–2009. Fifty-seven patients with surgically treated ESFTs were included, 22 with an axial and 35 with a peripheral primary tumours. The surgical treatment, its complications, survival and prognostic factors were analysed. Results Fifty-four patients underwent surgery with a curative intent and three underwent de-bulking operations. Bone reconstruction was performed in six patients with an axial and 15 with a peripheral tumour. Positive resection margins were associated with a worse five-year local relapse-free survival (33% vs. 84% for those with resection margins free of tumour cells, p = 0.003). The five-year sarcoma-specific survival was affected only by an axial location of the primary (61% vs. 89% for those with a peripheral tumour, p = 0.031). The late complications were mainly associated with bone reconstruction and more frequent among patients with a peripheral compared to an axial tumour (p = 0.031). Conclusions In the treatment of ESFTs, achieving adequate resection margins is crucial to avoid local relapses. Surgical complications are common particularly with bone reconstruction.

Background High-dose methotrexate (HD-MTX) is commonly used in treatment of pediatric leukemias and lymphomas. Transient deterioration in renal function is frequently noted during HD-MTX treatment, but possible long-term changes are less well known. In this study we aimed to study long-term renal prognosis after HD-MTX treatment, and to find possible underlying risk factors for reduced renal function. Procedure Medical records of pediatric cancer patients treated with HD-MTX were reviewed retrospectively after follow-up of 1–10 years. Renal function before and after chemotherapy was investigated in a total of 28 patients. Assessment of glomerular and tubular function was prospectively evaluated in each case. Glomerular function was evaluated by either 51Cr-EDTA or 99mTc-DTPA clearance methods, and by urinary albumin excretion. Tubular function was assessed by measuring blood electrolyte levels and urinary α1- or β2-microglobulin. Results A decrease in glomerular filtration rate (GFR) was statistically significant as follow-up time increased (P = 0.02). Age at the time of diagnosis and exposure to potentially nephrotoxic antibiotics during cancer treatment had no influence on GFR. However, albuminuria was observed more often in patients treated with amphotericin B or gentamycin (P = 0.04). No changes in tubular function were observed. Conclusions Our results show that HD-MTX treatment significantly decreases GFR and may cause albuminuria in pediatric cancer patients several years after treatment. Long-term renal follow-up of these patients is therefore important. Pediatr Blood Cancer 2008;51:535–539. © 2008 Wiley-Liss, Inc.

In a multinational, population-based study from the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), 2648 children below 15 y of age were diagnosed with acute lymphoblastic leukaemia (ALL) in the years 1981-1996. The annual incidence was 3.9/100 000 children and was stable throughout the study period. The development from regional or national protocols to common Nordic treatment protocols for all risk groups was completed in 1992 through a successive intensification of therapy, based on multidrug chemotherapy including pulses of methotrexate in high doses and avoidance of cranial irradiation in most children. For children with non-B-cell ALL (n o 2602), the event-free survival (p-EFS) increased from 0.53 6 0.02 (diagnosed 7/81-6/86) to 0.67 6 0.02 (7/86-12/91) to 0.78 6 0.02 (1/92-12/96). The corresponding p-EFS values at 5 y were 0.57, 0.70 and 0.78, respectively. The main improvements were seen in the group of children with non-high risk leukaemia, with 5-y p-EFS values increasing from 0.60 to 0.76 and 0.85 for the three periods. In high-risk patients, progress has been moderate, especially in children with high white blood cell values at diagnosis. During the last 5-y period, only 10% of the patients received cranial irradiation in first remission while 90% of the patients received high doses of cytostatic infusions (methotrexate isolated or combined with cytarabinoside) and multiple intrathecal injections of methotrexate as CNS-adjusted treatment without any indication of an increased CNS relapse rate. ' Childhood acute lymphoblastic leukaemia, incidence, prognosis in childhood acute lymphoblastic leukaemia, prognostic factors, treatment results

The prognosis in childhood non-Hodgkin lymphoma (NHL) has improved dramatically during recent decades. The authors report the results from a 6-year population-based study of clinical characteristics and treatment results of NHL from the five Nordic countries.All children younger than 15 years of age at diagnosis with NHL diagnosed from 1995 to 2000 were stratified and treated according to immunophenotypic classification and stage of disease.A total of 230 patients were diagnosed with primary NHL, which gives an annual incidence of 0.9/100.000 children, with a median age of 8 years. Seven percent of the children were below 3 years of age at diagnosis. The male/female ratio was 2.3 and was unrelated to age. Patients with pre-B and T-cell NHL constituted 33%, B-cell NHL 53%, and anaplastic large cell lymphoma (ALCL) 14%. According to Murphy's classification, 14% had stage 1, 17% stage 2, 50% stage 3, and 19% stage 4 disease, 12 of whom (28%) had central nervous involvement (CNS) at diagnosis. By January 1, 2003, four children had died during induction, three children died in remission (2, 6, and 26 months from diagnosis), and 24 children experienced a relapse. At 5 years, the probability of event-free survival (p-EFS) was 86+/-2% for all children. The 5-year p-EFS values for stages 1 through 4 were 94%, 97%, 83%, and 79%, respectively. The 5-year p-EFS values were 91% for B-cell, 87% for pre-B, 81% for ALCL, and 79% for T-cell NHL. The 12 patients with CNS involvement at diagnosis had a significantly poorer outcome than stage 4 patients with CNS involvement (p-EFS = 50% vs. 90%, P0.01). The 218 patients without CNS disease at diagnosis had a 5-year p-EFS of 88%.With modern intensive chemotherapy, more than 85% of NHL patients will achieve long-lasting first remission. In the future, preventing death during induction and remission and improving therapy for patients with CNS disease would have a major impact on the overall p-EFS.

Purpose: To evaluate cardiac function by means of conventional and three-dimensional echocardiography (3DE) and measurement of natriuretic peptides in children and adolescents previously treated for childhood malignancy using individual follow-up data and matched control children as reference criteria. Patients and Methods: Thirty-nine survivors of childhood malignancy were examined in 1994 and 1998. The mean time from the diagnosis was 8.6 (3.9 to 16.8) years and between cardiac evaluations was 4.1 (3.3 to 5.1) years. Patients were divided into two groups according to therapies given (group I (n = 30): no cardiac irradiation, median cumulative anthracycline dose 210 mg/m2; group II (n = 9): irradiation in the cardiac region, median cumulative anthracycline dose 180 mg/m2). Results: Fractional shortening (FS) in 1994 was higher than in 1998 (32.5 ± 4.3 vs. 30.3% ± 3.3%, P = .009). 33% of patients in group I and 56% in group II in 1994 and 30% of patients in group I and 67% in group II in 1998 had N-terminal of the propeptide-atrial natriuretic peptide (NT-proANP) levels exceeding the 90th percentile of controls. In 1998, both groups (I and II) had lower ejection fraction (EF) measured by 3DE than their matched controls (52.9 ± 5.2 vs. 58.8% ± 3.1%, P < .001 and 50.0 ± 6.6 vs. 60.8% ± 3.2%, P = .024, respectively). Left atrial maximum volumes/body surface area were smaller in the patients than in controls. B-Type natriuretic peptide values did not differ significantly in either group. Conclusion: Left ventricular contractility decreases slowly even years after cardiotoxic cancer therapy in children. 3DE and NT-proANP measurements are effective methods to evaluate the cardiac function in these patients.

Our purpose was to increase the dose intensity of chemotherapy and reduce the days with neutropenic fever in childhood high-risk (HR) acute lymphoblastic leukemia (ALL) by systematic use of granulocyte-macrophage colony-stimulating factor (GM-CSF).All children with HR-ALL in Finland during 1990-1996 were included. Two open-label study groups were formed: 1) 34 children diagnosed between January, 1992, and December, 1996, received seven or nine courses (depending on cranial RT or no cranial RT) of GM-CSF at 5 microg/kg s.c. daily until an absolute neutrophil count (ANC) of 1,000 x 10(6)/liter at scheduled places in the protocol and 2) 80 control children, those diagnosed between January, 1990, and December, 1991, plus all with significant coexpression of myeloid markers, did not receive GM-CSF.Dose intensity increased in patients who received regular GM-CSF support. The intensive phase of therapy, including induction, consolidation courses, and delayed intensification, was 33 days shorter (P0.001) in children with seven courses and 26 days shorter (P0.01) in those with nine courses of GM-CSF compared to controls. The number of infections during the whole ALL therapy was reduced by use of GM-CSF in children aged5 years (P0.001), but not in those aged5 years. The mean total duration of intravenous antibiotics per child was 39 days in the GM-CSF group and 48 days in the control group (P0. 001). Systematic use of GM-CSF was cost-effective.Systematic use of GM-CSF improved dose intensity by shortening the intensive treatment period by about 4 weeks. Use of GM-CSF reduced the days for inpatient antibiotics by about 1 week per child, which translates into reduced costs.

Some attempts have been made to reduce the costs incurred in the therapy of leukaemia, but no studies are available regarding costs of the entire treatment in children with acute lymphocytic leukaemia (ALL). We analysed all the direct costs of treatment of 11 children with ALL diagnosed and treated in Kuopio University Hospital. The follow-up continued from diagnosis until the end of treatment for each patient. Patient treatment on the ward lasted for 84-210 d and in the outpatient clinic for 24-66 d, depending on the risk group. From 11-54 of the inpatient days were required for the treatment of infections. Total mean cost of the entire treatment was US $103250 (US $55196-166039) per patient, 53% of which were basic hospital costs and 47% patient-specific costs. Laboratory tests and radiology accounted for 18% of all direct costs and cytostatic drugs for 13%, but blood products accounted for only 4% of the total. Infections were the most important extra cause of costs, accounting for 18% of the mean total costs per patient. The complete treatment of a child with ALL came to a total of US $103250. However, since 80% of children with ALL are long-term survivors, the cost must be regarded as a good investment.

Background The prophylactic use of hematopoietic growth factors has been shown to reduce the duration of neutropenia and related complications encountered after anticancer chemotherapy. However, the optimal timing for initiation of granulocyte colony-stimulating factor (G-CSF) has not been established. Procedure We evaluated the clinical parameters of the early versus delayed start (+1 day vs. +5 days postchemotherapy) of filgrastim (G-CSF; 5 μg/kg) after 36 courses of anticancer chemotherapy in 18 children with cancer in randomized fashion. Each child received two identical anticancer chemotherapeutic courses followed by one early (group 1) and one delayed (group 2) administration of G-CSF. Filgrastim was administered until absolute neutrophil count (ANC) exceeded 1.0 × 109/l. Results The mean duration of G-CSF therapy was 8.6 (range, 5–14) days in group 1 and 5.4 (range, 3–10) days in group 2 (P = 0.001). The mean duration of neutropenia (ANC < 1.0 × 109/l) did not differ between the study groups (7.8 vs. 8.2 days). Seven infection episodes occurred in group 1 and eight in group 2, respectively. The mean number of hospital days on broad-spectrum antibiotics was 2.3 (range, 0–8) in group 1 and 3.3 (range, 0–11) in group 2 (ns). Conclusions We conclude that the delayed start of filgrastim reduced the costs of this treatment, but was not followed by more prolonged neutropenia or febrile neutropenias. Med. Pediatr. Oncol. 32:326–330, 1999. © 1999 Wiley-Liss, Inc.

BACKGROUND The objective of this study was to assess the eligibility for and the course of compulsory military service of childhood cancer survivors. METHODS The medical, military recruitment, conscription, and military service data of male Finnish childhood cancer survivors were collected from manually filed records. Inclusion criteria were: survivors born 1977 or earlier, treated for a malignancy between birth and age 15 years, and followed by a pediatrician until at least age 18 years. The documents of 207 survivors from the Pediatric Clinics of Finnish University Hospitals were examined, and 130 of these survivors were considered eligible for military service. Demographic factors, the predictors of fitness for military service, factors associated with service interruption, the attained level of military training, and the health status of conscripts during service were evaluated. Comparisons were made with the Finnish male population of the same age and with conscripts serving at the corresponding time. RESULTS Approximately 60% of studied survivors were enlisted. Positive predictors of fitness for service were year of birth of 1973 or later (odds ratio [OR], 3.2), height at call-up age of 170–174.9 cm (OR, 3.6), and the man's own positive opinion of his fitness for service (OR, 62.3). Negative predictors were age at diagnosis ≥ 11 years (OR, 0.5), central nervous system radiotherapy (OR, 0.3), limb defects (OR, 0.02), and the group of sequelae concerning neurologic, cardiopulmonary, and gastrointestinal systems, or secondary malignancies (OR, 0.3). Survivors interrupted their service more often (20%) (P < 0.001). Leukemia survivors were less likely to interrupt their service (7%) compared with other survivors (P = 0.04). Factors associated with service interruption were: diagnosis (P = 0.04), the man's own opinion of his fitness for service (P = 0.013), surgery (P = 0.003), and height (P = 0.049), weight (P = 0.019), and body mass index (P = 0.035) at the beginning of military service. The attained level of military training was equal to that of controls. The survivors visited the garrison physician less frequently in total (mean, 5.9 times) (P < 0.001), visited because of infections as much as controls, and were off duty more (mean, 11.9 days) (P = 0.012) than controls. CONCLUSIONS The current study found that childhood cancer survivors were less likely to meet the requirements set for military service in Finland. The causes of rejection usually were obvious, but approximately 30% were rejected merely on the basis of a former cancer diagnosis. However, enlisted survivors coped well with military service if their treatment sequelae were taken into consideration carefully at the time of enlistment. Vocational opportunities within the armed forces might be an appropriate career option even for survivors of childhood malignancies. Cancer 1999;85:732–40. © 1999 American Cancer Society.

In a retrospective analysis we evaluated the occurrence of infections in 59 children with acute lymphoblastic leukemia (ALL) during the entire duration of their anticancer chemotherapy. We recorded a total of 245 infection episodes, 118 (50%) being during neutropenia and 119 (50%) during nonneutropenia. The infections most commonly detected during neutropenia were fevers of undetermined origin (36%), clinically or microbiologically defined focal infections (33%), and bacteremias (28%). During nonneutropenia, upper respiratory tract infections (55%) were the most common. Patients needed hospitalization for infections for a total of 1951 days (i.e., a mean of 33 days per patient) and the mean number of infection episodes was 4.2 per patient. Recurrent fever developed in 21% of the children with bacteremia. Mortality caused by bacteremias was 10%. Infections during the chemotherapy of ALL were a significant cause of morbidity in children, but mortality was low.

PURPOSE To evaluate the following prospectively in poor-risk neuroblastoma (NBL) patients: (1) the feasibility and efficacy of in vivo purging of bone marrow; and (2) the outcome after autologous bone marrow transplantation (ABMT) when immunologically tumor-free, unpurged autografts were used. PATIENTS AND METHODS Twenty-three children with poor-risk NBL were evaluated during induction chemotherapy by repeat bone marrow examinations, including aspirate, biopsy, and an immunofluorescence method using the anti-GD2 monoclonal antibody 3A7. Nineteen patients completed the program with surgery with or without local irradiation followed by ABMT. RESULTS Autologous bone marrow grafts, both immunologically and cytologically clean, were obtained and used in 19 of 23 children. The overall 4-year disease-free survival of the 19 grafted children was 53%, with a toxic death rate of 16% and a posttransplant relapse rate of 37%. According to the in vivo purging efficacy of the 18 children with initial marrow disease, the following three groups were formed: patients with (1) perfect in vivo purging (n = 5); (2) eventually successful in vivo purging (n = 8); and (3) unsuccesful in vivo purging (n = 5). The 4-year DFS was 100%, 67%, and 0%, respectively (P < 0.001). The five patients with unsuccessful in vivo purging failed because of resistant/progressive bulky disease. CONCLUSION In patients with poor-risk NBL, in vivo purging of bone marrow by conventional chemotherapy is feasible, can be monitored, and the purging efficacy during the first 3 months after diagnosis is a strong prognostic factor reflecting tumor responsiveness to therapy. Autografting with immunologically clean, unpurged marrows gives a DFS well comparable to previous studies using ex vivo purging.

Background Adjuvant chemotherapy has improved the outcome of childhood malignant brain tumors in large randomized trials. With increasing survival rates, treatment toxicity has become a matter of concern. Radiation therapy and cisplatinum are known to be ototoxic. Methods We evaluated the incidence and factors predisposing to ototoxicity in children treated with the “8 in 1” chemotherapy protocol in Finland during 1986–1993. Thirty-five of the 82 children survived for at least 1 year after diagnosis. Thirty of these children were old enough to have a audiogram. Results Seventeen of the 30 children had normal hearing, seven had hearing loss at high frequencies, and six (20%) had severe hearing loss in the speech range. The risk factors for severe hearing loss were young age, a high cumulative dose of cisplatinum, and deteriorating renal function. In the presence of these factors, the risk of severe hearing loss was over 50%. Hearing loss at high frequencies could occur after low cumulative doses of cisplatinum, but severe hearing loss correlated with high cumulative doses. Conclusions Cisplatinum-induced hearing loss at high frequencies is common, but hearing loss in the speech range also occurs, particularly in children with predisposing factors, and may progress insidiously and rapidly. Therefore a hearing test before each “8 in 1” course is important. © 1996 Wiley-Liss, Inc.

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.

The tolerability and kinetics of a solvent-detergent-treated 6% intravenous immunoglobulin (IVIG) preparation were studied in 15 hypogammaglobulinaemia patients during 3-4 regular substitution infusions of 9-48 g, the mean dose being 359 mg/kg. The infusions were well tolerated, and the trough serum IgG levels achieved were comparable to two commercial IVIG preparations. The stepwise increase of the infusion rate up to 5 mg/kg/min and the use of this IVIG as a 12% solution were possible without serious adverse events in all the 6 studied hypogammaglobulinaemia patients. This greatly reduced the time needed for the infusions.

Mitochondrial DNA (mtDNA) deletion is associated with a variety of clinical entities. In addition to progressive external ophthalmoplegia and Kearns-Sayre syndrome, mtDNA deletions have been demonstrated in Pearson's syndrome. We report an mtDNA deletion in an infant with a variant of Pearson's syndrome. Not only does she have congenital anemia, severe tubulopathy, and exocrine pancreas insufficiency, but she also has diabetes and cerebral atrophy. However, there are no signs of gut or liver involvement. Bone marrow improved while new tissues were involved, thus showing variability in progression of the disease. Decreased respiratory chain enzyme activities were demonstrated in muscle, and an mtDNA deletion was demonstrated in muscle, kidney, leukocytes, and fibroblasts.

Esthesioneuroblastoma is a rare tumor in children, and the correct diagnosis may be difficult, as is demonstrated in this case report. A 5-year-old girl was diagnosed with this tumor, which was incurable and behaved like a neuroblastoma, sending metastases to the bone marrow and invading the cranium and the spinal canal.

111 febrile episodes in 98 neutropenic children were randomly treated with either ceftazidime (CAZ) 150 mg/kg/day or with piperacillin (PIP) 200 mg/kg/day, both combined with flucloxacillin (FLUC) 50 mg/kg/day. A total of 37/47 (79%) eligible episodes in the CAZ group and 41/53 (77%) in the PIP group were cured without needing to stop the initial therapy. The success without modification of the treatment in the verified septicaemias in the CAZ group was 8/18 (44%) and in the PIP group 5/18 (28%). Of the bacteriologically documented infections, 13/24 (54%) in the CAZ group and 11/24 (46%) in the PIP group were cured without modification of the therapy. Similarly, 17/31 (55%) of all the isolated bacteria in the CAZ group and 14/33 (42%) in the PIP group were eradicated with the initial therapy. Overall there were 13 deaths of which 4 in the CAZ group and 5 in the PIP group occurred during the infection. An increasing granulocyte count exceeding 0.25 X 109/1 at the end of the therapy was a good prognostic si...

Background A cytogenetic study of 75 consecutive children with ALL revealed a normal karyotype, a low hyperdiploid karyotype (including 47–50 chromosomes), and a high hyperdiploid karyotype (including >50 chromosomes) in 10, 12, and 33 patients, respectively. An acquired extra X-chromosome was detected at diagnosis by conventional cytogenetics in 29 (88%) of 33 children with a high hyperdiploid karyotype and in 4 (33%) of 12 children with a low hyperdiploid karyotype. X-chromosome aneuploidy was retrospectively studied by fluorescence in situ hybridization (FISH) in eight and 20 patients with a normal and a hyperdiploid karyotype, respectively. Procedure A classical cytogenetic study was performed according to standard methods. FISH with the centromeric probe specific to X-chromosome was used to study interphase cells of bone marrow or blood samples. Results An extra X-chromosome was found by FISH in all 13 patients with a high hyperdiploid or tetraploid, in 6 of 7 patients with a low hyperdiploid, and in none with a normal karyotype. Two children with a normal karyotype displayed monosomy X. Altogether, 57.3% of newly diagnosed children displayed X-chromosome aneuploidy. Conclusions Our study indicates that X-chromosome aneuploidy may be the most common chromosome abnormality in childhood ALL. It can be detected in nearly all children with a high hyperdiploid karyotype and up to one-half of the patients with a low hyperdiploid karyotype. FISH with an X-chromosome centromeric probe is a rapid and simple tool to detect an abnormal clone at diagnosis in the majority of children with ALL and is useful in confirming remission in these patients. Med. Pediatr. Oncol. 32:360–365, 1999. © 1999 Wiley-Liss, Inc.

Background We studied serum N-terminal atrial natriuretic peptide (NT-ANP) in children during and after chemotherapy for cancer to determine its applicability in detecting cardiac dysfunction. Forty-three patients were receiving chemotherapy for malignancy. Forty-eight patients were off chemotherapy and survived between 0.9 and 13 (median 5) years after the diagnosis, receiving cumulative anthracycline doses between 0 and 600 (median 225) mg/m2. Procedure and Results. Cardiac evaluation of the patients included measurement of serum NT-ANP, recording of ECG, and assessment of systolic and diastolic function of the heart by echocardiography. During chemotherapy, serum NT-ANP levels were higher than in controls but varied markedly in the same individuals. Serum NT-ANP levels showed no consistent increase in the weeks following anthracycline administration. In late follow-up, serum NT-ANP levels were higher than in age-matched controls (median (range), 0.22 (0.06–0.47) vs. 0.14 (0.06–0.27) nmol/l, respectively, P < .001). The subgroup of patients with bone marrow transplantation and/or cardiac irradiation had the highest NT-ANP concentrations (0.30 (0.20–0.45) nmol/l). Conclusions. Thus, serum NT-ANP measurements seemed to represent a useful contribution in the long-term cardiac follow-up of children after cancer. This blood test can readily be included to laboratory follow-up, is reasonably inexpensive and may decrease the need for more laborious tests of cardiac function. When there is ongoing chemotherapy, NT-ANP levels are influenced by a variety of factors that invalidate its routine use during this period. Med. Pediatr. Oncol. 31:73–78, 1998. © 1998 Wiley-Liss, Inc.

Eighty-two children with malignant brain tumours were treated according to the “8 in 1” chemotherapy protocol in Finland during 1986 to 1993. Thirty-seven with brain tumours not involving the hypothalamic-pituitary region are still alive and tumour-free. The growth and response to growth hormone (GH) therapy in these children was analysed. Children who received craniospinal irradiation had the most severe loss of height SDS, being −1.07 within 3 years of the diagnosis. Even children with no irradiation to the hypothalamic-pituitary axis had a mean change in height SDS of −0.5 after 3 years. Fifteen of 23 children who received craniospinal irradiation and two out of eight children who received cranial irradiation have received GH therapy. A catch-up growth response to the daily GH therapy with the mean dose of 0.7 IU/kg per week was complete in 3 years (+1.87 SDS), irrespective of craniospinal irradiation, in children who were treated at prepubertal age but was seen in none of the children who had reached pubertal age. Conclusion Growth impairment and GH deficiency are common in children treated for malignant brain tumours. The response to GH therapy is good in prepubertal children in terms of increased growth velocity, although the final height is not yet known.

Sixty-four children with malignant brain tumours diagnosed at less than 3 years of age were reported to the Finnish Cancer Registry from 1975 to 1993. The survival rate has improved significantly: the 5-year survival rate was 26% for all children, 13% for children diagnosed during 1975-85 (n = 30) and 40% for those diagnosed during 1986-93 (n = 34). Of the surviving children in 1986-93, 43% were categorized in Bloom's group I or II and could lead active lives without major disabilities. The remaining children had severe neurologic late complications, such as hemiplegia, intractable seizures, and mental retardation.

Sixty-eight children with malignant brain tumors were treated with the "8 in 1" chemotherapy protocol from 1986 to 1993 in Finland. The overall 5-year survival rate was 43 %. Thirty-one children are still alive and tumor-free, and have been evaluated in the present study. Of these 31 children, 26 % had hemi- or tetraplegia, 13 % intractable seizures, and 30 % attend special schools. The mean full scale (FS) IQ was 85 (range 45-138), 24 % had an FSIQ value less than 70, and 36 % more than 90. One-half of the survivors were placed in BLOOM'S group I or II, are able to lead an active life, and have only mild neurologic disabilities. In the other, neurologic late complications accumulated and these children were relegated to BLOOM'S group III or IV, with major disabilities such as hemiplegia, intractable epilepsy, or mental retardation. The most important prognostic factors were severe perioperative complications, young age at diagnosis, and cranial irradiation.

We evaluated the outcome of 68 children with malignant brain tumors treated with the “8 in 1” chemotherapy protocol in Finland from 1986 to 1993, comparing 5-year survival rates with those for a historical control group (from 1975 to 1985). For all malignant brain tumors, overall survival was 43% (vs 28% in the control group; P< 0.05), and progression-free survival (PFS) was 43% (vs 23%; P< 0.05). For medulloblastoma and primitive neuroectodermal tumor, survival was 63% (vs 35%; P< 0.05), and the corresponding PFS was 59% (vs 35%; P = 0.15). For high-grade glioma, both the survival rate and the PFS were 27%. (vs 17%; P = MS). Thus the outcome was significantly better for our “8 in 1” –treated patients than for the historical controls, especially among the children with primitive neuroectodermal tumor and medulloblastoma. In contrast, those with high-grade gliomas and brain stem tumors seem to have received little benefit; different, more effective treatments are needed for these patients.

9590 Background: Classification of childhood solid tumors differs greatly from tumors diagnosed in adults. Thus establishment of childhood cancer registries is essential to monitor changes and progress in cancer care. Methods: All individuals born in the Nordic countries are allocated a unique ID number and have access to comprehensive health care services. Further, it is required by law that all new cases of cancer are reported to cancer registries. This makes it possible to achieve almost complete registration of all cancer cases and their status together with information regarding the cancer tumour and its treatment. Status registrations were made partly from national population registries and partly from death registries only, as conditions differ between countries. Crude survival was modelled using the Kaplan-Meier method stratified by selected diagnostic groups, age groups and diagnostic period. The crude estimates were compared with log-rank tests. Results: In total, 12,343 children

We evaluated serum C-reactive protein (CRP) level and serum sodium concentration as early indicators of bacteremia in neutropenic children in two different series in 1983-1984 (49 bacteremias) and 1989-1990 (29 bacteremias). During the earlier period, the goal was to avoid unnecessary antimicrobial therapy. Currently a neutropenic patient is placed on antimicrobial therapy at the first sign of fever. In 1983-1984 the serum CRP concentration was elevated in every case, whereas in 1989-1990 it was normal in 34% cases (P = .0001). Hyponatremia was detected on admission in 84% and 52% cases (P = .0001). The urinary sodium concentration was elevated in most cases. The mortality in bacteremia was 22% in 1983-1984 compared to 3% (P = .025) in 1989-1990. Prompt initiation of empirical antimicrobial therapy in children with fever and neutropenia invalidates the use of hyponatremia and an elevated CRP level as early indicators of sepsis.

Identical male twin infants who in 1987 presented with hepatoblastoma at the age of 7 months are reported. Twin B was admitted for investigation due to enlarged liver and spleen. He was found to have an inoperable hepatoblastoma of fetal type and was treated with chemotherapy and local irradiation. However, 7 months after the chemotherapy the tumor recurred. the asymptomatic twin A was examined because of the known familial cases, and he proved to have an identical tumor. He was successfully radically operated on and 2 years after the chemotherapy is still doing well with no evidence of tumor. As the mother and the maternal grandmother had polyps in the colon, quite probably the hepatoblastomas of the twins were associated with familial adenomatous polyposis.

A new therapeutic approach was adopted for 13 consecutive patients with stage IV neuroblastoma over 1 year of age admitted to the Children's Hospital, University of Helsinki, between October 1981 and August 1985. Treatment was based on induction, with aggressive, repeated early surgery and a relatively short course of chemotherapy with cisplatinum and etoposide, and on consolidation, with 140-180 mg/m2 of melphalan followed by autologous unpurged bone marrow. Induction therapy failed in only 2 of the 13 patients. One of the two was never autografted. So a total of 12 children underwent autologous marrow transplantations, 10 in primary and 1 in secondary remission, and one with residual disease. One patient died in septicemia during postmelphalan pancytopenia, and four patients relapsed 0.3-2.9 years after transplantation. Seven of the original 13 patients (54%) are well and living in continuous remission 2.3-4.1 (median 2.8) years after diagnosis.

Nine children with acute lymphoblastic leukemia in remission were studied at the end of their three years' maintenance therapy. In the jejunal biopsy specimens significantly fewer intraepithelial lymphocytes and IgA-cells were observed in the patients than in the controls. However, the crypts were deeper than normal, and the mitotic activity of the crypt cells was markedly increased in all of the patients. Three children presented with decreased epithelial disaccharidase activities. One had abnormal D-xylose test and two abnormal lactose tolerance test. Although weight gain did not differ from the normal, height increase was retarded in all but one of the patients. We conclude that leukemia treatment leads to changes in the intestinal mucosa that might in part contribute to impairment of growth in the patients and to suppression of mucosal immunity in their jejunum.

In a period of 6.5 years, acute leukaemia was diagnosed in 140 children at our hospital: 137 children had long bone radiographs and 45 patients had bone lesions. Eleven of the 115 patients who had skull radiographs had osteolytic lesions and another four had wide sutures. No patients had bone changes at relapse or at cessation of 3 years' successful therapy. In acute lymphoblastic leukemia, the frequency of osseous lesions tended to be higher in patients in sub-groups with a more favourable prognosis. The duration of remission and survival times were higher in patients with "leukemic" long bones than in those without them (p less than 0.10 and less than 0.05, respectively). Changes in the skull could not be related to the outcome. We found no abnormalities in the bones of the eight patients with acute non-lymphoblastic leukemia.

Seven late relapses of acute lymphoblastic leukemia occurring 5.5 to 12.3 years after cessation of therapy are reported in 986 patients who had discontinued treatment for leukemia acquired before the age of 15. The study covers patients from the five Nordic countries. Of the 434 patients with ALL who had passed 5 years of follow-up without recurrence, seven have subsequently relapsed so far; an estimated cumulative proportion of 6.9% within the 10 years. In addition, we report a girl 15.9 years old at diagnosis who relapsed 7.3 years after cessation of therapy. These findings confirm that "cure" of acute lymphoblastic leukemia treated in the 1970s cannot be considered definite, even 5 years after discontinuation of therapy.

A 3-year-old boy presented with a marked right exophthalmos of a few days duration. This was due to a retrobulbar granulocytic sarcoma that was subtotally removed at a lateral orbitotomy. Subsequent studies revealed acute myelogenous leukemia (AML) of FAB-type M2. The orbital tumor disappeared totally after local irradiation and cytostatic treatment. Another granulocytic sarcoma developed 3 months later in the left orbit. It disappeared also during repeated cytostatic induction therapy although only transient hematologic remission was achieved. After 1 month a recurrence of the tumor in the left orbit was noted. The disease progressed without response to treatment and the patient died 11 months after diagnosis.

The patient presented with a diabetes at the age of 3 years. At the age of 5 years she got persistent diarrhoea, lost weight and showed symptoms or arthritis and pericarditis. She was found to have total villous atrophy of the jejunum, which did not respond to dietary treatment, total parental nutrition, prednisone and cyclophosphamide medication. She had high titres of antinuclear antibodies and elevated serum IgG, but antibodies to DNA and to ribonuclearprotein were negative. A low titre of antibodies to human intestinal epithelial cells was found. The patient died of overwhelming fungal sepsis. We propose that the intestinal damage is part of the autoimmune disease. Careful study of jejunal biopsy specimens is helpful in distinguishing this type of patient from patients with coeliac disease.

Summary: In 46 intestinal specimens from infants 2 hr to 6 months old, the numbers of immunoglobulin-containing cells were counted by the direct immunofluorescent or direct immunoperoxidase technique. A restudy was made of biopsy specimens taken for diagnostic purposes, 34 from the rectum and 3 from the transverse colon of 30 infants at the Children's Hospital, Helsinki in 1971–1977, and in addition, of autopsy material recently collected from the intestines of 9 infants. Up to the age of 12 days, no immunoglobulin-containing cells were seen. A small number (1 to 2) of IgM-containing cells was seen in the lymph nodes of the 2 earlier specimens taken at the ages of 6 and 12 days. A rectal specimen from a 12-day-old infant showed 24 IgA- and 60 IgM-containing cells/mm2. In rectal specimens of infants less than 1 month old, the mean number of IgM-containing cells (26/mm2) was higher than that of IgA-containing cells (14/mm2), but older infants had a significantly higher mean number of IgA-containing cells (P < 0.01). The mean number of IgM-containing cells was the same in children 1 to 3 months (53 cells/mm2) and 3 to 6 months of age (59 cells/mm2), whereas the mean number of IgA-containing cells increased with age up to 6 months (112 and 163 cells/mm2). The youngest infant who had IgG-containing cells was 13 days old, although positive staining of intercellular spaces in the lamina propria and of the capillary endothelium by anti-IgG serum was observed in all specimens. The mean number of IgG-containing cells was low (5 cells/mm2) in all age groups. Sparse IgE-contain-ing cells (less than 12/mm2) were seen in 4 of the 46 specimens. In 5 patients, 2 or 3 consecutive specimens were available for the study; in these, the increase in the numbers of IgA- and IgM-containing cells was similar to the mean increase in cell numbers for the series as a whole. Speculation: There is a deficiency of immunoglobulin-containing cells in the gut of newborn infants up to the age of 12 days, and this is probably the reason for the high permeability of the neonatal intestine to foreign proteins.

Antigliadin antibodies in serum samples of 31 children with coeliac disease were measured by an enzyme-linked immunosorbent technique. In young patients (less than 2 years) tested before gluten withdrawal IgA antigliadin antibody levels were invariably above the levels of 36 controls. The titres fell rapidly when gluten was eliminated from the diet and rose on its reintroduction. The titres were not always greater than the control level in older untreated patients. IgA antigliadin antibodies seem to be a good marker of the immune reaction in the jejunum triggered by gluten. In 2 IgA-deficient patients gluten challenge caused an increase in IgM antigliadin antibodies, and at the same time the number of IgM-containing cells increased in the jejunal mucosa. Rising IgG antigliadin antibody levels after gluten elimination were seen in 6 patients, 5 of whom had very low complement C3 levels before gluten elimination.