Antibiotic use during infectious episodes in the first 6 months of anticancer treatment-A Swedish cohort study of children aged 7-16 years.

BACKGROUND: Children undergoing cancer therapy are at risk for infectious complications that require hospitalization and antimicrobial therapy. Host factors such as age and underlying disease may predict the risk of severe infections in these children. To describe the increased morbidity due to infections in children with cancer, we characterized the antibiotic use during the infectious complications in a national cohort of children 7-16 years of age with cancer. PROCEDURE: Data on infectious complications were prospectively collected from the medical records of all newly diagnosed children with cancer, aged 7-16 years, in Sweden between 2004 and 2006. An episode of infection was defined as a period of time when oral or intravenous antimicrobial treatment was prescribed because of symptoms of infection. RESULTS: A total of 230 infectious episodes occurred in 80 of the 101 patients. Pathogens were isolated in 15% of the blood cultures that showed a predominance of Gram-positive bacteria. Intravenous broad-spectrum antibiotics with cephalosporins and carbapenems were mostly used as single drugs but also in combination with aminoglycosides and glycopeptide. The median treatment length varied between 6 and 11 days depending on cancer diagnosis. CONCLUSION: Our data demonstrate that infectious complications contribute significantly to morbidity in children with cancer aged 7-16 years. At the time of this survey, antibiotic prescription patterns varied and cephalosporins and carbapenems were mostly used. With increasing antibiotic resistance, a more stringent antibiotic stewardship with less use of cephalosporins and carbapenems should be encouraged for children with cancer. Data on prescription patterns should be incorporated as a quality measurement in pediatric cancer care.

Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders.

From 1990 to 1997, 113 eligible patients with classical osteosarcoma received neo-adjuvant chemotherapy consisting of high-dose methotrexate, cisplatin and doxorubicin. Good histological responders continued to receive the same therapy postoperatively, while poor responders received salvage therapy with an etoposide/ifosfamide combination. With a median follow-up of 83 months, the projected metastasis-free and overall survival rates at 5 years are 63 and 74%, respectively. Independent favourable prognostic factors for outcome were tumour volume < 190 ml, 24-h serum methotrexate > 4.5 microM and female gender. The etoposide/ifosfamide replacement combination did not improve outcome in the poor histological responders. In conclusion, this intensive multi-agent chemotherapy results in > 70% of patients with classical osteosarcoma surviving for 5 years. The data obtained from this non-randomised study do not support discontinuation and exchange of all drugs used preoperatively in histological poor responders. As observed in previous Scandinavian osteosarcoma studies, female gender appears to be a strong predictor of a favourable outcome.

High-dose methotrexate: on the relationship of methotrexate elimination time vs renal function and serum methotrexate levels in 1164 courses in 264 Swedish children with acute lymphoblastic leukaemia (ALL).

PURPOSE: The objectives of the present study were to determine the relationship between methotrexate (MTX) elimination time and various aspects of renal function and to evaluate the prognostic value of elevated serum MTX and creatinine for delayed MTX elimination. PATIENTS AND METHODS: The majority of the 264 children were being treated for ALL. According to the NOPHO-92 protocol, 5 or 8 g MTX/m(2) was administered over 24 h. Serum creatinine was assessed daily. In 11 patients from one centre, renal function was studied in more detail using serum cystatin C, iohexol clearance, and urinary albumin, IgG and protein HC. RESULTS: Increased serum creatinine correlated significantly with the elimination time of MTX, whereas no indications were found of tubular or barrier function damage. Of the 1164 courses, 44 had delayed elimination of MTX (>/=120 h). Serum MTX >150 microM at the end of infusion had a sensitivity of 0.27 and a specificity of 0.94 to predict delayed MTX elimination, and >/=50% increase in serum creatinine during the first treatment day (creatinine ratio) had a sensitivity of 0.32 and a specificity of 0.99. The corresponding risk ratios were 5 and 19 for MTX >150 micro M and creatinine ratio, respectively. In courses with a normal elimination time (<72 h), 99% of the courses had a rise in serum creatinine of less than 50%. CONCLUSIONS: Elevation of serum creatinine by more than 50% is a better predictor of delayed elimination than the level of serum MTX at the end of MTX infusion, especially if information on previous creatinine measurements is used to reduce the impact of an occasionally low serum creatinine value before the start of the MTX infusion.

Pharmacokinetics of doxorubicin in children with acute lymphoblastic leukemia: multi-institutional collaborative study.

BACKGROUND: In adults, it has been shown that the pharmacokinetics of doxorubicin are highly variable, despite standardization of the dose based on body surface area (BSA). The purpose of this study was to determine the plasma concentrations of doxorubicin and its active metabolite doxorubicinol in children treated for acute lymphoblastic leukemia (ALL). PROCEDURE: Children, 107 in number, aged 1.3-17.3 years, were studied at Day 1 of induction therapy according to the current Nordic protocol. Five infants, 3-9 months old, were also included. Plasma samples were drawn 23 hr after the start of a 24-hr infusion of doxorubicin 40 mg/m(2), and analyzed by reversed-phase liquid chromatography. RESULTS: There was a more than 10-fold difference between patients in dose normalized plasma concentration of doxorubicin, median 62.8 ng/ml, range 22.6-334 ng/ml. The doxorubicin concentrations differed significantly between age groups (P = 0.003). Children aged 4-6 years had the highest doxorubicin concentrations, median 77.9 ng/ml, followed by 2-4-year-old children, median 64.3 ng/ml. Both younger and older children had median values of about 50 ng/ml. Patients with white blood cell (WBC) count > 50 x 10(9)/L at diagnosis had significantly lower doxorubicin concentrations, median 55.3 ng/ml, than those with WBC count < 10 x 10(9)/L, median 64.4 ng/ml (P = 0.015). There was no difference in doxorubicin concentration between boys and girls. No correlation was found between doxorubicin levels and serum aminotransferases or serum creatinine. The concentration of doxorubicinol was 13% (median value) of that of doxorubicin. Four infants, 7-9 months old, had plasma clearance between 350-431 ml/min/m(2), which is in the same range as in older children. A 3-month-old infant had a clearance of 181 ml/min/m(2). CONCLUSIONS: The age groups who had the highest doxorubicin concentrations, (2-) 4-6-year-old children, are known to make up a large proportion of standard risk ALL cases with good prognosis. The correlation between doxorubicin plasma levels and clinical effect needs further study. The influence of age, body composition, and tumor burden on the pharmacokinetics of antineoplastic drugs should also be further explored, aiming at improvements in the current dosing regimen based on BSA.

Quantification of doxorubicin in plasma--a comparative study of capillary and venous blood sampling.

Doxorubicin, an anthraquinone glycoside, is currently one of the clinically most important antineoplastic drugs. The aim of the present study was to identify potential concentration differences of doxorubicin in plasma from capillary and venous blood samples. Sixteen patients (seven females and nine males; median age: 37 years, range: 1-77 years) were included. The quantitative analysis of doxorubicin was carried out by reversed-phase liquid chromatography with fluorometric detection. The concentration of doxorubicin in capillary and venous samples were closely correlated (r=0.98; p<0.0001). The median plasma concentration ratio capillary/venous was 1.13 (95% confidence interval: 1.06-1.20) and not affected either by plasma drug concentration, age or the body mass index of the patient. The concentration ratio was significantly higher in males (median: 1.18) than in females (median: 1.01). The observed concentration differences of doxorubicin in plasma from capillary and venous samples are of minor importance only. Capillary blood sampling is recommended for use in pharmacokinetic studies of doxorubicin, especially in pediatric patients, in order to avoid sometimes traumatic venous blood sampling.

[Cytostatic therapy reduces the immune defense. Children treated for leukemia have impaired immunity against measles and rubella]. / Cytostatikaterapi sänker immunförsvaret. Leukemibehandlade barn förlorar sin immunitet mot mässling och röda hund.

A study is summarized analyzing the levels of serum antibodies against vaccination antigens in 43 children treated for acute lymphoblastic leukemia. Two different therapeutical regimens were used. All children had been immunized against measles and rubella before being diagnosed with leukemia. Eight of the 24 children treated 1986-1991 lacked protective levels of antibodies against measles; four of the 24 children lacked antibodies against rubella. In the second cohort of children (n = 16) treated from 1992 and onwards, nine lacked protective levels of antibodies against measles, eight lacked antibodies against rubella.

A comparative pharmacokinetic study of doxorubicin and 4'-epi-doxorubicin in children with acute lymphocytic leukemia using a limited sampling procedure.

Antraquinone glycosides are an important class of antineoplastic drugs, frequently used for treatment of a variety of malignancies in children. Doxorubicin (Dox) is the most frequently used drug within this class of antineoplastics. 4'-epi-doxorubicin (Epi), a Dox isomer, was developed with the aim of reducing risks for fatal heart toxicity observed with Dox. The aim of the present study was to investigate the pharmacokinetics of Dox and Epi in children with acute lymphocytic leukemia. In total 31 patients (13 females and 18 males; median age 5.4 years; range 0.73-15.3 years) were studied using a simplified sampling procedure. The pharmacokinetic differences of the two drugs were established by their simultaneous administration. The plasma pharmacokinetics of neither Dox nor Epi correlated with the age of the patients. There were no gender differences in dose-normalized maximum concentrations of neither Dox nor of Epi. The inter-patient variation of the dose-normalized maximum concentrations of Dox and Epi is larger among females than among males. The Cmax ratio Dox/Epi was 1.39+/-0.19 (mean +/- SD). The pharmacokinetic differences of Dox and Epi in children, although less pronounced than in adults, are still of a magnitude that might be of clinical importance.

Five-year results in Ewing's sarcoma. The Scandinavian Sarcoma Group experience with the SSG IX protocol.

The first Scandinavian protocol for Ewing's sarcoma, SSG IV, resulted in a local control rate of 74% and 5-year metastasis-free survival (MFS) of 43%. The second protocol, SSG IX, was started in order to improve upon these results. It featured four chemotherapy cycles, each consisting of two courses of VAI (vincristine, doxorubicin, ifosfamide) alternating with one course of PAI (cisplatin, doxorubicin, ifosfamide) at 3-weekly intervals. Total treatment time was 35 weeks. Local therapy was given at week 9. Inoperable or non-radically operated patients received hyperfractionated accelerated radiotherapy 1.5 Gy twice daily between chemotherapy courses to a total dose of 42-60 Gy, depending on surgical radicality and tumour localisation. 88 patients were included (58 male, 30 female, mean age 20 years; range 5-65 years). The tumour (73 M0 and 15 M1) was located centrally in 31 patients (35%), in the extremities in 34 (39%) and other sites in 23 (26%) of cases. The median size of tumour was 10 cm (range 2-23), soft tissue was invaded in 87%. Surgery was the local therapy for 60 (68%) patients: amputation in 8 and local excision in 52. The surgical margins were wide in 35 patients, marginal in 14 and intralesional in 3. Radiotherapy was given to 17 non-radically operated patients postoperatively and to 28 patients with inoperable tumours primarily. Histological responses were evaluated in 52 patients. 9 local recurrences were observed (10%). Distant metastases developed in 24 M0 patients (33%). The estimated 5-year MFS was 58% and overall survival (OS) 70% for M0 and 27% and 28% for M1 patients, respectively. Survival was favourable in patients with non-metastatic extremity tumours (90%) and tumours operated with wide margins (90%). Patients with a total necrosis after chemotherapy had a better OS than those with a partial or poor response (P=0.003). The toxicity (World Health Organisation) was acceptable (gastrointestinal G1-2; haematological G3-4). The SSG IX protocol gave better local control and survival rates than the SSG IV. Whether this is due to a higher therapeutic efficacy of the present protocol cannot be ascertained in this comparison with a historical control.

The clinical use of fine needle aspiration cytology for diagnosis and management of children with neuroblastic tumours.

This study presents the results of fine needle aspiration cytology in a series of 26 consecutive children with neuroblastic tumours. The cytological spectrum varied from undifferentiated small tumour cells to mature ganglion cells in a fibrillar background. In 24 children with neuroblastic tumours at onset the cytological diagnosis was correct in 21 cases, whereas two aspirates yielded nondiagnostic necrotic material and a fibrillar material without tumour cells, respectively. One necrotic lymph node aspirate was initially incorrectly diagnosed as lymphoma, but the diagnosis was later revised to neuroblastoma. Suspected signs of disease progression or relapses were confirmed (n = 9) or ruled out (n = 1) using aspiration cytology. The diagnostic accuracy in the complete series was 97% (31/32) in cases with adequate smears. Immunocytochemistry confirmed the cytological diagnosis in 14 of 15 cases and was decisive in one. Elevated catecholamine metabolites in urine was detected in all children with a cytological diagnosis of neuroblastoma. General anaesthesia was only performed when coincidental invasive investigations (n = 13) were to be carried out or if the aspiration was intrathoracic (n = 6). It is concluded that aspiration cytology in conjunction with immunocytochemistry offers a safe, rapid and accurate diagnostic method which may be useful, together with analyses of catecholamine metabolites in urine, in the clinical management of children with neuroblastic tumours.

Impact of morning versus evening schedule for oral methotrexate and 6-mercaptopurine on relapse risk for children with acute lymphoblastic leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO).

PURPOSE: To study the risk of non-B-cell acute lymphoblastic leukemia (ALL) relapse in relation to the routines of administration of oral methotrexate (MTX) and 6-mercaptopurine (6MP) and to the erythrocyte (E) levels of the intracellular cytotoxic metabolites, that is, MTX polyglutamates and 6-thioguanine nucleotides (E-MTX and E-6TGN). PATIENTS AND METHODS: E-MTX and E-6TGN levels were measured at least three times (medians, eight and nine) in 294 children with non-B-cell ALL during oral MTX and 6MP therapy. For each patient, we registered (a) the individual circadian schedule of drug administration and (b) the coadministration of food, and (c) calculated a mean (m) of all E-MTX and E-6TGN measurements and (d) the product of mE-MTX and mE-6TGN (mE-MTX*6TGN), due to their synergistic action. RESULTS: A total of 42 patients were on a morning schedule, 219 were on an evening schedule, and 33 had miscellaneous routines. A total of 149 patients took the drugs with meals, 106 took the drugs between meals, and 39 had varying routines. With a median follow-up of 78 months, ALL has recurred in 66 patients. The patients on an evening schedule had a superior outcome [probability of event-free survival (pEFS) = 0.82 +/- 0.03 vs. 0.57 +/- 0.08; p = 0.0002], whereas the coadministration of food did not significantly influence outcome. Patients with a mE-MTX*6TGN < 813 [product of median mE-MTX (4.7 nmol/mmol Hb) and mE-6TGN (173 nmol/mmol Hb)] had an inferior outcome (pEFS = 0.70 +/- 0.04 vs. 0.85 +/- 0.03; p = 0.003), even if only patients on an evening schedule were analyzed. Thus, 109 patients on the MTX/6MP evening schedule with an mE-MTX*6TGN < or = 813 (nmol/mmol Hb)2 had a pEFS of 0.89 +/- 0.03 and a probability of continuous hematopoietic remission of 0.91 +/- 0.03. CONCLUSIONS: An evening schedule should be recommended for oral MTX/6MP maintenance therapy. The value of individual dose adjustments by E-MTX and E-6TGN remains to be determined in prospective randomized trials.

Intralesional steroids in Langerhans cell histiocytosis of bone.

Langerhans cell histiocytosis may involve single or multiple organ systems. Bone involvement is the most common feature. We have examined retrospectively the effects of 20 intralesional injections of steroids into bone in seven patients seen at our department from 1988 to 1993. Most of these injections (75%) relieved the symptoms, and no side-effects were observed. However, injections into the jaw were seldom effective. Our results suggest that the dose of the steroids administered is of importance.

Disturbances in the oral cavity in pediatric long-term survivors after different forms of antineoplastic therapy.

Oral health and disturbances in dental development were studied in long-term survivors after antineoplastic therapy. Fifty-seven children treated with combination chemotherapy and 19 children treated with total body irradiation (TBI) prior to bone marrow transplantation (BMT) were examined. The variables studied were dental caries, salivary flow, salivary microbial counts, enamel disturbances, and disturbances in dental development. The results showed no increased caries experience in children treated with BMT or chemotherapy compared with controls. Children treated with BMT had a significantly lower salivary secretion rate of 0.7 +/- 0.4 ml/min, compared with 1.1 +/- 0.5 in the chemotherapy group, and 1.3 +/- 0.6 in the control group (P < 0.05). The clinical examination showed equal numbers of teeth affected by disturbances in enamel mineralization in the BMT and chemotherapy groups. A mean 15.9 +/- 8.2 teeth were affected by disturbances in root development in the BMT group compared with 1.2 +/- 1.6 in the chemotherapy group (P < 0.001). The results show that children who are long-term survivors of pediatric malignant diseases exhibit a wide range of disturbances in the oral cavity. In this study the most severe disturbances are found in children treated with total body irradiation prior to BMT.

Plasma neuropeptide Y in healthy children: influence of age, anaesthesia and the establishment of an age-adjusted reference interval.

Plasma concentrations of neuropeptide Y, analysed in 112 healthy children, decreased significantly with age, while sex, discomfort induced by the sampling procedure or induction of general anaesthesia did not have a significant influence. An age-adjusted upper reference limit was established and proved to be useful when tested prospectively in 56 children with tumours. Two of 18 children with preliminary diagnosis of rhabdomyosarcoma had elevated plasma neuropeptide Y; both showed malignant ectomesenchymoma (p < 0.01), a mixed tumour with neural crest features. Among 38 children with neural crest derived tumours, all 7 with benign ganglioneuromas had plasma neuropeptide Y concentrations below the reference limit, while 13 of 31 with neuroblastoma had elevated concentrations (p < 0.05). Only neuroblastoma patients with elevated plasma neuropeptide Y had a poor outcome; 10 of 13 died, whereas all with normal concentrations are alive after 3-74 months of follow-up (p < 0.001).

Trk mRNA and low affinity nerve growth factor receptor mRNA expression and triploid DNA content in favorable neuroblastoma tumors.

Nerve growth factor (NGF) is suggested to play a role in spontaneous differentiation or regression of neuroblastoma. Expression of mRNAs for trk protooncogene and NGF low affinity receptor gene (LNGFR) were analyzed in 45 neuroblastomas with Northern Blot. Trk and LNGFR expression correlated with young age, localized tumors or IV-S disease, absence of N-myc amplification, triploid DNA content, spontaneous tumor regression and favorable prognosis. Regardless of other factors, trk and LNGFR mRNAs distinguished three prognostic subsets: one favorable (trk+, LNGFR+, n = 19, 100% survival probability), one intermediate (trk+, LNGFR-, n = 11, 62%) and one poor (trk-, n = 15, 0%). An algorithm based on the combined analysis of trk and LNGFR mRNAs and DNA ploidy divided the material in two groups with 96 and 0% survival probability respectively (p < 0.001), and predicted outcome accurately in 43 of 45 children. It is hypothesized that loss of functional NGF-receptors constitutes an early critical step in the evolution of unfavorable neuroblastomas prone to progression in spite of current therapy.

Expression of nerve growth factor receptor mRNAs and clinical response to retinoic acid in neuroblastoma.

Four children with advanced or relapsed neuroblastoma were treated with oral 13-cis-retinoic acid 0.75 mg/kg/day. Clinical response to retinoic acid was noted only in the two children with tumors coexpressing trk protooncogene mRNA, encoding an essential part of the nerve growth factor (NGF) high affinity receptor, and low affinity NGF receptor gene (LNGFR) mRNA. Clinical stage or age, plasma neuropeptide Y, tumor DNA ploidy and N-myc amplification did not as accurately predict response to retinoic acid as NGF receptor mRNAs. In vitro data have shown that retinoic acid up regulates LNGFR expression and NGF sensitivity via interaction with specific regulatory elements in the LNGFR gene promoter. We hypothesize that part of the therapeutic effect of retinoic acid in neuroblastoma in vivo may be exerted via increased NGF receptor expression and NGF sensitivity. Analysis of trk and LNGFR mRNA may be useful to predict clinical response to retinoic acid in these children.

Plasma and urine levels of methotrexate and 7-hydroxymethotrexate in children with ALL during maintenance therapy with weekly oral methotrexate.

A new high-performance liquid chromatographic assay was used to determine methotrexate (MTX) and its main metabolite, 7-hydroxymethotrexate (7-OH-MTX), in the plasma (n = 17) and urine (n = 14) of children (age 3-12 years) on maintenance therapy for acute lymphocytic leukemia (n = 14) or non-Hodgkin's lymphoma (n = 3). Each child received oral doses of weekly MTX (4.0-29 mg/m2) and daily 6-mercaptopurine (40-111 mg/m2). Plasma samples were collected daily from two children during the 1-week dose interval. A limited sampling strategy was designed, whereby 2 days of blood sampling were used in the other 15 patients. Morning urine samples were collected daily for 1 week following MTX intake from 14 of the children. MTX was detectable in all plasma and urine samples for the entire dose interval. The main metabolite, 7-OH-MTX, could be detected in plasma and urine from all patients on the first day after dose intake but only in a few patients during the whole dose interval. Interpatient variability of MTX and 7-OH-MTX levels was high at all points during the week. Significant correlation were found between the urinary MTX levels on days 2 and 7 and plasma MTX levels on day 2 after intake. No significant correlation was found between drug levels in plasma or urine and liver function tests in the children showing signs of mild liver injury. This assay provides a tool for further studies on the role of pharmacokinetics for the clinical effects of weekly oral low-dose MTX given alone or in combination with 6-mercaptopurine.

Neuropeptide Y in neuroblastoma: increased concentration in metastasis, release during surgery, and characterization of plasma and tumor extracts.

Five children with neural crest tumors (two ganglioneuromas, one ganglioneuroblastoma, and two neuroblastomas) were investigated regarding neuropeptide Y-like immunoreactivity (NPY-LI) in tumor tissue and plasma at diagnosis and during surgery. Radioimmunoassay of extracted plasma revealed higher NPY-LI at diagnosis of neuroblastoma (640 and 230 pmol/L resp) than ganglioneuroblastoma or ganglioneuroma (74, 45, and 26 pmol/L resp). During surgery of neuroblastoma plasma NPY-LI increased two- to four-fold while no peroperative increase was seen in the other children. NPY-LI was considerably higher in neuroblastoma tissue (220 pmol/g and 144 pmol/g) than in ganglioneuroblastoma (40.2 pmol/g), ganglioneuroma (0.6 and 4.4 pmol/g), or healthy adrenal tissue (5.5 pmol/g). The highest NPY-LI concentration was found in neuroblastoma metastasis, 3,091 pmol/g. Gel-permeation chromatography of a neuroblastoma tumor showed that a majority of NPY-LI was representing intact NPY (NPY 1-36) while metastasis and plasma from the same child mainly contained smaller immunoreactive fragments. High concentrations of systemic NPY in neuroblastoma patients are of tumoral origin. Plasma levels of NPY and its fragments can be useful in diagnosing and monitoring neuroblastoma, and for early detection of relapse or metastatic disease. A possible involvement of NPY in neuroblastoma tumor growth and spread deserves further investigation.

Neuropeptide Y (NPY) synthesis in lymphoblasts and increased plasma NPY in pediatric B-cell precursor leukemia.

Neuropeptide Y (NPY), a regulatory peptide in both the central and peripheral nervous systems, has recently been found in neuroendocrine tumors as well as in the bone marrow of rat and certain autoimmune mice, but not in human bone marrow. To investigate a possible role for NPY in the human hematopoietic system, we have prospectively studied NPY-like immunoreactivity in plasma (P-NPY-LI) and NPY mRNA in bone marrow from children with acute leukemia. Northern blot showed high levels of NPY mRNA in bone marrow and peripheral lymphoblasts from children with B-cell precursor leukemia. In situ hybridization showed NPY mRNA in malignant B-cell precursor lymphoblasts. No NPY mRNA was detected in the bone marrow of children with T-cell leukemia. P-NPY-LI was higher (P less than .001) in 51 children with leukemia (200:50 to 385 pmol/L, median:interquartile range) compared to 51 age-matched healthy controls (37:20 to 52 pmol/L). P-NPY-LI was higher (P less than .001) in those with favorable clinical risk classification. Elevated P-NPY-LI, compared with the upper age-adjusted reference limit, was only found in children with B-cell precursor leukemia (31 of 40), whereas all children with B-cell, T-cell, or myeloid leukemia (n = 11) had normal P-NPY-LI (P less than .001). During the 2- to 46-month follow-up, children with elevated P-NPY-LI had better (P less than .001) outcome compared to those with normal P-NPY-LI (79.4% v 34.6% probability for event-free survival).