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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

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.

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.

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.

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.

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.

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.