Methotrexate Concentration Levels in the Cerebrospinal Fluid During High-Dose Methotrexate Infusions: An Unreliable Prediction

In 25 children with lymphoid malignancies, 96 high-dose methotrexate infusions (3 g/m²) with a duration of 24 h have been administered as a part of the treatment schedule. A lumbar puncture was performed to apply methotrexate intrathecally. The moment of lumbar puncture during the infusion was chosen at different times. In 76 of the infusions the concentration of methotrexate in the cerebrospinal fluid and in plasma were determined just prior to the intrathecal administration. From the second to the eighth hour after the initiation of the infusion the concentration of methotrexate in the cerebrospinal fluid appeared to be significantly lower than 16 or 24 h after the initiation of the infusion. Of all samples during the infusions, the plasma concentration varied a tenfold (2-20 X 10^-5 mol/L), but the cerebrospinal fluid concentration of methotrexate varied about a 300-fold (3.5-900 X 10 mol/L). No correlation could be found between the plasma concentration of methotrexate and the cerebrospinal fluid concentration. It is concluded that the methotrexate concentration in the cerebrospinal fluid cannot be predicted by determining the plasma concentration. It lakes at least 8 h of infusion before a steady-state concentration of methotrexate is reached in the cerebrospinal fluid. In high-dose methotrexate infusions without intrathecal therapy, the dose of 3 g/m² is the minimum amount of methotrexate to reach the minimum therapeutic concentration 5 X 10⁷ mol/L) in the cerebrospinal fluid for the treatment of subclinical central nervous system invasion of malignant lymphoid cells. To maintain the minimum therapeutic concentration according to the CxT principle the duration of the infusion should be preferably longer than 24 h.     

Plasma and serum micronutrient concentrations in preschool children

Abstract The plasma concentrations of vitamin A, vitamin E, β-carotene and serum concentrations of zinc, retinol-binding protein and prealbumin were examined for a random cluster sample, stratified by socioeconomic status, of 467 healthy preschool children. Children were aged 9–62 months; 44% were females. The mean plasma values were: vitamin A, 1.29 µmol 1^-1; vitamin E, 18.9 µmol 1^-1; and β-carotene, 0.30 µmol 1^-1. The mean serum values were: zinc, 13.9 µmol 1^-1; retinol-binding protein, 25.5mg 1^-1; and prealbumin, 186.2 mg 1^-1. The mean molar ratio of vitamin A to retinol-binding protein for the study group was 1.10. There were no differences in the mean values of any of the measured micronutrients between the genders. The results of this survey do not indicate that the prevalence of micronutrient deficiency in this preschool population is of public health significance.     

Cerebrospinal Fluid and Plasma Methotrexate Levels Following High-Dose Regimen Given as a 3-Hour Intravenous Infusion in Children with Nonhodgkin's Lymphoma

In the French non Hodgkin's lymphoma protocols, central nervous system prophylaxis is provided by high-dose methotrexate (HD-MTX), given as a 3-hour IV infusion of 3 g/m² MTX along with intrathecal MTX injection. The incidence of CNS relapse is less than 3%. We designed a study to evaluate the MTX transfer across the blood brain barrier in terms of cytotoxic concentrations, during these short-term infusions. Cerebrospinal fluid and plasma MTX levels were measured during 61 courses in 29 children with non Hodgkin's lymphoma; none of them had central nervous system disease. Samples were obtained either 4, 12, 18, or 24 hours after the start of HD-MTX IV infusion. A potentially cytotoxic MTX level (10^-6 M) was reached in all courses at 4 hours (median: 2.3 × 10^-6 M) and remained available in 8/16 courses at 12 hours (median: 1.0 × 10^-6 M) and in only 2/17 courses at 18 hours (median: 0.29 × 10^-6 M). Twenty-four hours after the start of HD-MTX IV infusion, CSF MTX level was always less than 10^-6 M. The plasma MTX levels were 260, 1.3, 1.0, and 1.7 × 10^-6 M at 4, 12, 18, and 24 hours, respectively. There was no correlation between plasma and CSF MTX levels. These data show that potentially cytotoxic MTX concentrations can be reached in CSF after a 3-hour IV infusion of 3 g/m² in every patient and remain available for at least 8 hours in half of them.     

The captopril test in children with renovascular and renal hypertension

We used the captopril test (CT) in 32 children, 8 with renovascular hypertension (RVH), 17 with renal hypertension (RH) and 7 with normal blood pressure, in order to study the renin-angiotensin system activation (RASA). All children affected by RVH presented a positive CT: a post-captopril plasma renin activity (PRA) of 12 ng ml^-1 h ^-1 or more, an absolute PRA increase of 10 ng ml ^-1 h ^-1 or more and a 150% increase or more, or 400% or more if the baseline PRA was less than 3 ng ml^-1 h^-1. The CT may be useful for demonstrating the RASA in RVH.     

Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand

Benign intracranial hypertension (BIH) is reported in three children from Australia and one from New Zealand, who were being treated with recombinant human growth hormone (rhGH). Three males and one female, aged between 10.5 and 14.2 y, developed intracranial hypertension within 2 weeks to 3 months of starting treatment. A national database, OZGROW, has been prospectively collecting data on all 3332 children treated with rhGH in Australia and New Zealand from January 1986 to 1996. The incidence of BIH in children treated with growth hormone (GH) is small, 1.2 per 1000 cases overall, but appears to be greater with biochemical GHD (<10IUml ^-1), i.e. 6.5/1000 (3 in 465 cases), relative risk 18.4, 95% confidence interval 1.9-176.1, than in all other children on the database. The incidence in patients with Turner's syndrome was 2.3/1000 (1 in 428 cases). No cases in patients with partial GHD (10–20 IUml ^-1) or chronic renal failure were identified. Possible causative mechanisms are discussed. The authors'practice is now to start GH replacement at less than the usual recommended dose of 14IUm-² week^-1 in those children considered to be at high risk of developing BIH. Ophthalmological evaluation is recommended for children before and during the first few months following commencement of rhGH therapy and is mandatory in the event of peripheral or facial oedema, persistent headaches, vomiting or visual symptoms. The absence of papilledema does not exclude the diagnosis.     

Degradation and clearance of methotrexate in children with osteosarcoma receiving high-dose infusion

Plasma methotrexate (MTX) concentrations were quantitated in 34 patients after 127 high-dose (35–350 mg/kg) infusions with citrovorum factor rescue. Significant linear correlations have been obtained between methotrexate dosage and concentrations in plasma at 6 and 24 hours after the initiation of the therapy. However, similar trends have not been observed when 48- and 72-hour samples were analyzed. Clinical toxicity was not serious when the methotrexate level in plasma was < 4.5 × 10^?6 M at 48 hours after the start of a six-hour infusion in children. A minimal four-hour steady-state methotrexate plasma level can be maintained during a six-hour infusion. Children excrete methotrexate at a faster rate than adults; the half-life of MTX during the first phase of plasma clearance curve is one hour shorter in children. Urinary analyses have indicated that substantial methotrexate is metabolized. The chemical nature of these components has not been identified. Further, the urinary metabolic profiles varied among patients.     

Degradation and clearance of methotrexate in children with osteosarcoma receiving high-dose infusion.

Plasma methotrexate (MTX) concentrations were quantitated in 34 patients after 127 high-dose (35--350 mg/kg) infusions with citrovorum factor rescue. Significant linear correlations have been obtained between methotrexate dosage and concentrations in plasma at 6 and 24 hours after the initiation of the therapy. However, similar trends have not been observed when 48- and 72-hour samples were analyzed. Clinical toxicity was not serious when the methotrexate level in plasma was less than 4.5 X 10(-6) M at 48 hours after the start of a six-hour infusion in children. A minimal four-hour steady-state methotrexate plasma level can be maintained during a six-hour infusion. Children excrete methotrexate at a faster rate than adults; the half-life of MTX during the first phase of plasma clearance curve is one hour shorter in children. Urinary analyses have indicated that substantial methotrexate is metabolized. The chemical nature of these components has not been identified. Further, the urinary metabolic profiles varied among patients.     

The Risk of X-Ray Examinations of the Lungs in Neonates

ABSTRACT. X-ray examinations of the lungs is an important element in the evaluation of the neonates and their respiratory function. It is often necessary to perform a large number of X-ray examinations depending upon the infant's birthweight, gestational age and respiratory problems. To estimate the risk of X-ray examinations of the lungs the radiation dose to 18 infants at the Neonatal Intensive Care Unit, Hvidovre Hospital, was measured by means of a thermoluminescent dosimeter placed on the nipple of the infant. The radiation dose to various organs was estimated and the risk weighted whole body radiation dose calculated to 40 microsievert per examination (AP- and lateral). Using the latest increased risk factors this means an excess cancer mortality of 5 × 10^-1 for boys and 11 × 10^-5 for girls per millisievert, corresponding to 25 X-ray examinations (AP- and lateral) of the lungs. It is concluded, that even using the latest increased risk factors, the radiation risk of repeated X-ray examinations of the chest in prematures will be very low considering the benefit for the infant.     

Randomized trial comparing intravenous immunoglobulin with methylprednisolone pulse therapy in acute idiopathic thrombocytopenic purpura

Forty-three children with newly diagnosed idiopathic thrombocytopenic purpura (ITP), platelet count (PC) below 20 × 10⁹ 1⁻¹, and either continued bleeding or failure to show a spontaneous rise in the PC after a 3 day observation period were randomized to treatment with either intravenous immunoglobulin (IVIG) infusions I gkg⁻¹ (n = 23) or intravenous methylprednisolone pulse therapy (MPPT) 30mgkg¹ (n = 20) on two consecutive days. After 72h, IVIG had induced greater platelet responses (mean PC 188 × 10⁹ versus 77 × 10⁹1⁻¹ 2p < 0.001) and raised the PC to a haemostatically safe level above 50 × 10⁹1⁻¹ more frequently (91 versus 50%, one-sided e×act p = 0.003). Children responding poorly were then given the alternative treatment in addition. After 6 days, a normal PC of over 150 × 10⁹1⁻¹ had been obtained more frequently in the group given first-line IVIG (70 versus 50%, p = 0.16). The relapse rates during 6 months of follow-up were not significantly different (26 versus 40%, p = 0.26). Cross-over treatment in 11 children with relapse confirmed the superior response to IVIG. The treatment given was restricted to the two initial infusions more often in the IVIG group (70 versus 35%, p = 0.05). These results indicate that IVIG may be preferable to MPPT as the initial treatment for ITP.     

Methotrexate-Induced Leukoencephalopathy is Treatable with High-Dose Folinic Acid: A Case Report and Analysis of the Literature

An episode of leukoencephalopathy is reported in a 13-year-old girl who, after standard radiotherapy for a posterior fossa medulloblastoma, received 8 treatments with a protocol containing a 4-hour infusion of 500 mg/m² methotrexate and 12 mg intrathecal methotrexate. The leukoencephalopathy, documented clinically and by CT and EEG, cleared after 2350 mg of leucovorin (citrovorum factor, folinic acid) was given in addition to the 135 mg given as part of the therapy. A review of the literature suggests that leukoencephalopathy may be prevented by high doses of leucovorin and can be treated by high doses, if lower doses were used initially. When high dose leucovorin was not used, residual neurological damage is not unusual.     

Vitamin D status does not influence the breast-milk calcium concentration of lactating mothers accustomed to a low calcium intake

Plasma 25-hydroxy-vitamin D and breast-milk calcium concentration were measured at 3 months of lactation in 60 Gambian mothers accustomed to a low calcium diet, of whom 30 were consuming a calcium supplement and 30 were receiving a placebo, and in 48 British mothers. The plasma 25-hydroxy-vitamin D concentration of the Gambian women was not affected by either calcium supplementation (supplemented, 64. 4 ± 2. 5 nmol 1^-1; placebo, 64. 9 ± 3. 5 nmol l^-1; mean ± SE) or season. The British average was lower (53. 9 ± 3. 0 nmol 1^-1, p = 0. 004), owing to marked seasonal effects. The breast-milk calcium concentration was lower in The Gambia (supplemented, 5. 38 ± 0. 13 mmol 1^-1; placebo, 5. 10 ± 0. 13mmol 1^-1; British, 6. 93 ± 0. 15 mmol 1^-1, p < 0. 0001). There was no relationship between plasma 25-hydroxy-vitamin D and breast-milk calcium concentration in any group. There was no trend towards lower breast-milk calcium concentration in women with vitamin D status towards the bottom of the normal range or in British women during the winter. This study provides no support for the hypothesis that breast-milk calcium concentration is influenced by vitamin D status or that lactating women with a low calcium intake are at particular risk of vitamin D deficiency.     

Short-course oral prednisone therapy in children presenting with acute immune thrombocytopenic purpura (ITP)

Immune thrombocytopenic purpura (ITP) is a disorder for which management remains controversial. The ongoing goal is to define the minimal therapy required for children with acute ITP. A pilot study of short-course oral prednisone (4 mg⁻¹ kg⁻¹ d⁻¹ for 4 d with no tapering) was undertaken in 25 consecutive children with acute ITP and platelet counts under 20 × 10⁹ 1⁻¹. Of the 25 children, 22 responded to the prednisone therapy by achieving a platelet count higher than 20 × 10⁹ 1⁻¹ within 1 week of commencing treatment. This regimen was found to be safe, inexpensive and effective in increasing the platelet count of children to a haemostatically safe level.     

High-Dose Methotrexate and Continuous Infusion Ara-C in Children's Non-Hodgkin's Lymphoma: Phase II Studies and Their Use in Further Protocols

Twenty-three children with refractory or relapsed non-Hodgkin's lymphoma (NHL) received high-dose methotrexate (HD-MTX), and 9 received Ara-C by continuous intravenous infusion, as phase II studies. They all had previously received a protocol including vincristine, adriamycin, cyclophosphamide, IV push Ara-C, asparaginase, intrathecal MTX, and cranial irradiation, and had failed to respond or had relapsed. HD-MTX was given at the dose of 6 g/m² or more with leucovorin rescue, Ara-C at the dose of 100 mg/m² /day by continuous infusion over 10 days. Among the 22 evaluable patients receiving HD-MTX, 10 responses (7 CR; 3 PR) were observed. Among the 9 patients receiving Ara-C, 4 responded (1 CR; 3 PR). Toxicity in those previously heavily treated patients was acceptable. These two drugs are now successfully included in childhood NHL treatment protocols.     

Hereditary Tyrosinemia of Chronic Course without Rickets and Renal Tubular Dysfunction

ABSTRACT. Three patients with hereditary tyrosinemia type 1, two brothers and one girl, studied at the age of 5, 12 and 15 years, respectively, had neither generalized hyperaminoaciduria, glucosuria nor clinical symptoms of rickets. Untreated the elder brother had only slightly elevated plasma tyrosine level (141 μmol/l, normal <80), and low excretion of p-hydroxyphenyllactate. He presented with pronounced thrombocytopenia (3 × 10⁹/1). At 13 years of age he contracted hepatocellular carcinoma. The younger brother presented with serum tyrosine of 318 μol/l and thrombocyte count 48 × 10⁹/1. Succinylacetone in urine was elevated in both, 30 and 79 μmol/mmol creatinine, respectively. The female patient was investigated for hepatomegaly in infancy, atypical tyrosinemia being considered, but afterwards developed normally without diet or any other treatment until she contracted hepatoma at the age of 15 years. Her plasma tyrosine level was 600-700 μmol/1, and she excreted large amounts of p-hydroxyphenyllactate. Succinylacetone in urine was low but elevated (8 μmol/mmol creatinine). The fumarylacetoacetase activity in fibroblasts from the brothers and in lymphocytes from the girl was less than 5% and 10% of control levels, respectively. In conclusion, the chronic form of hereditary tyrosinemia may occur without evidence of renal tubular dysfunction.     

Phenotypes of Peripheral Blood Lymphocytes during Acute Hepatitis A

ABSTRACT. We investigated peripheral blood lymphocyte phenotypes of 74 patients at weekly intervals during the course of acute hepatitis A. In the second week after onset of jaundice, a significant elevation of total lymphocytes was observed (4096 × 10⁶± 1003 × 10⁶/l vs. controls 3038 × 10⁶± 1208 × 10⁶/l, p < 0.005). However, no change in the relative percentages of B-cells (CD20+), T-cells (CD3+ or CD2+), or T-cell subpopulations (CD4+ helper cells and CD8+ suppressor cells) could be demonstrated during the course of the disease. Activated T-cells (CD3+DR+) were elevated during the first week (204 × 10⁶± 134 × 10⁶/l vs. normal 91 × 10⁶± 54 × 10⁶/l, p <0.005) and during the second week (202 × 10⁶± 82 × 10⁶/l, p < 0.0005) after onset of disease and returned to normal values until the third week. Cells expressing phenotypes of lymphocytes capable of exerting non-MHC-restricted cellular cytotoxicity, i.e. Natural Killer cell activity (CD57+, CD16+, and CD56+) were significantly elevated in percentage in the first week of disease, as compared to controls (CD57: 14.5 ± 7.0% vs. 9.3 ± 5.8%, p <0.05; CD16: 13.4 ± 7.3 vs. 9.5 ± 5.1%, p < 0.05; CD56: 10.5 ± 3.5% vs. 8.0 ± 1.5%, p < 0.005). Also the absolute numbers of these lymphocyte subpopulations were found to be elevated during the first and second week. The increase in NK cells in the initial phase of acute hepatitis A suggests an important role of these cells in the first line of defence in this disease.     

Simplified Immunoglobulin Treatment of Idiopathic Thrombocytopenic Purpura

ABSTRACT. The recommended dose of intravenous IgG for idiopathic thrombocytopenic purpura has been 0.4 g/kg on 5 consecutive days. A simplified approach, giving a single infusion of 0.8–1.0 g/kg over 8 hours, has been tried in a series of 11 children with newly diagnosed disease. In 8 cases the infusion produced a prompt platelet response culminating at 128–502×10⁹/1 after 3–13 days, and 4 of these cases required no further treatment while 2 needed a booster infusion due to an early relapse and 2 followed a chronic course. In 3 cases platelet responses were poor in spite of supplementary doses to a total of 1.4–2.0 g/kg: 2 infants failed to achieve normal platelet counts and 1 case with fulminant bleeding manifestations proved completely resistant. Significant side effects were not observed. These results indicate that IgG-therapy practically may be initiated with a single infusion, the resulting platelet response indicating the need for further infusions.     

INCREASED FRACTIONAL EXCRETION OF PHOSPHATE AND BETA2-MICROGLOBULIN IN UNILATERAL RENAL DISEASE

ABSTRACT. Following progressive nephron loss tubular reabsorption in the remaining nephrons will fall to preserve solute and electrolyte excretion. We have examined the fractional excretion (FE) of phosphate, sodium, beta₂-microglobulin (β²M)and tubular glucose reabsorption (T_glucose) in children with unilateral renal disease to find 1) the threshold for this response and 2) whether intrinsic renal mechanisms can elicit this response. Separate renal function studies were performed using unilateral ureteral compression. Total glomerular filtration rate (GFR) was 93.7 ± 2.99 ml/1.73(m²)^-1.min^-1, and 110.25 ± 5.40 in control children. GFR in the scarred kidney (SK) was 22.4 ± 2.46 and in the contralateral kidney (CIK) 67.2 ± 4.60 ml. 1.73 (m²)^-1. min^-1. The kidney area was reduced in proportion to GFR in SK. FE phosphate and β₂M were significantly higher in SK than in CIK (sign test), but absolute values for FE_phosphate and β₂M were not higher in SK than in control kidneys. FE_sodium and T_glucose were the same in SK and CIK. Conclusion: Following moderate unilateral reduction of GFR selective depression of tubular reabsorption can occur without extrarenal impulses.     

Effects of volume expansion on cardiac output in the preterm infant

Clinical and echocardiography haemodynamic evaluations of response to volume expansion are described in 12 preterm neonates aged < 7days presenting without cardiac dysfunction and with a low cardiac output. They received 10% albumin solution (20 ml kg^-1) for 3h. Measurements were made before infusion, at volumes 5, 12. 5 and 20 ml kg^-1 and 1 h later. All infants increased significantly their cardiac output (CO) (from a median of 177 to 283 ml kg^-1 min^-1). The rise of CO decreased with the volume infused. The index of systemic vascular resistance (SVR = ratio of mean arterial pressure to the CO) decreased for the six patients without PDA (from 272 to 193 mmHg 1^-1 kg^-1 min^-1, p < 0. 05) showing that the hypovolemic preterm infant is able to shut down peripherally in response to hypovolemia. The four hypotensive infants responded by increasing mean arterial blood pressure (from 29 to 44 mmHg). Cutaneous refilling time decreased during infusion (from 6. 7 to 3. 8 s, p < 0. 01). One infant had an haemodynamically significant ductus arteriosus revealed by volume expansion, another one developed myocardial dysfunction.     

Decreased ferritin levels, despite iron supplementation, during erythropoietin therapy in anaemia of prematurity

Erythropoietin (rHuEPO) therapy has been shown to be beneficial in preventing and treating anaemia of prematurity and to decrease the need for blood transfusions. There is, however, only scanty data on the effect of rHuEPO therapy on iron metabolism. We studied 29 preterm infants (age 34 ± 14 days) who were randomly assigned to receive either rHuEPO 900 U kg^-1 week^-1 with 6 mg kg^-1 day^-1 of iron for 4 weeks ( n= 15) or no therapy. The following parameters were evaluated and compared between and within groups at the beginning, during and at the end of the study: Haematocrit (SI), reticulocytes (10⁹μgl^-1), serum ferritin (μg1^-1) and iron (μmol 1^-1). The results were as follows. At the baseline, erythropoietin levels were similar in both groups: 7.2 ± 5.6 versus 6.2 ± 3.2 mU ml^-1 (NS). In the treated infants the haematocrit remained stable during the study and was significantly higher than in the control group by the end of the study: 0.34 ± 0.03 versus 0.28 ± 0.05 ( p = O.001). rHuEPO therapy increased the reticulocyte count from 130 ± 70 to 430 ± 200 ( p = 0.0002). However, rHuEPO therapy depleted both serum ferritin and it-on levels from 321 ± 191 to 76 ± 58 $uMgl^-1 ( p = 0.04) and from 18 ± 5 to 13 ± 4 μmoll^-1 ( p = 0.03), respectively. We conclude that rHuEPO therapy prevented anaemia and its sequelae; however, serum ferritin and iron levels were depleted. We suggest that the effect of rHuEPO may be further increased by higher iron supplementation.     

Medulloblastoma in Nordic Children. I

ABSTRACT. The average annual incidence of histologically verified medulloblastomas was 5.4×10^-6 among all 4.9 million Nordic children younger than 15 years from 1968 to 1977. The ratio between boys and girls was 2:1. The incidence had no clear seasonal variation and it peaked at 3 to 4 years of age at onset. The rate of survival after 5 years was 17.4%, equal for boys and girls, but highest in the older age groups. Tumor growth accounted for most deaths with lack of local control in 88% of 112 children autopsied. Metastases outside of the central nervous system occurred in only 6 % of the children. Thus, intensification of the treatment should be directed towards the central nervous system.