Neuroblastoma represents distinct clinical-biologic entities: a review and perspective from the Quebec Neuroblastoma Screening Project.

Data are presented suggesting that neuroblastoma represents at least two distinct clinical-biologic entities. One, favorable neuroblastoma, is associated with young age and early stage at diagnosis, triploid karyotypes, no 1p abnormalities or N-myc gene amplification, more mature catecholamine synthesis and excretion, and excellent clinical outcome despite no or minimal therapy. The other, unfavorable neuroblastoma, is associated with older age and advanced stage, pseudodiploid karyotypes and 1p deletions, N-myc oncogene amplification, less mature catecholamine synthesis and excretion, and poor outcome despite aggressive multimodality therapy including bone marrow transplantation. Favorable neuroblastomas rarely, if ever, evolve into unfavorable disease. Unresolved issues regarding this hypothesis and implications for the efficacy of preclinical detection through mass screening are discussed.     

Screening for neuroblastoma at 3 weeks of age: methods and preliminary results from the Quebec Neuroblastoma Screening Project

A large neuroblastoma screening study was recently started in the province of Quebec, Canada. This project, a collaboration between the Quebec Network for Genetic Medicine and the University of Minnesota, is studying the impact of screening infants for the preclinical detection of neuroblastoma on the population-based mortality caused by this tumor. All infants born in Quebec during a 5-year period will be screened twice, at 3 weeks and at 6 months. Urinary homovanillic acid and vanillylmandelic acid determination from dried filter paper samples is used for screening. Initial qualitative screening is done by means of thin-layer chromatography with confirmatory quantitative screening by gas chromatography-mass spectrometry (GC-MS). During the initial 6 months of 3-week screening, 41,673 neonates (92% compliance rate) were screened and 10.6% of them were tested also by GC-MS. Nine of these neonates had positive results on two GC-MS tests and were referred for evaluation to rule out the presence of neuroblastoma. Four had the tumor, 1 had a calcified adrenal gland, and 4 had no tumor detected. Three additional neonates had clinical diagnosis of neuroblastoma before they reached the screening age of 3 weeks. A neuroblastoma that did not secrete homovanillic acid or vanillylmandelic acid was diagnosed clinically in 1 additional patient who tested negative by screening.     

Screening Infants for Neuroblastoma: The Parents' Perspective in False-Positive Cases

The objective of this study was to ascertain the reactions and experiences of parents whose children were defined as false-positive cases in a research program of screening 6-month-old babies for neuroblastoma. Parents of seven of the eight infants falling into this category participated in the study. Parents of five children described themselves as worried/very worried at the positive result, some contemplating the treatment involved and the possibility that their child could die. Parents waited a maximum of 3 days before the clinical investigations took place. The mother of one child was dissatisfied with the handling of the investigations, reporting a luck of information and little opportunity to discuss questions; she was subsequently more anxious about her child. Parents of two children reported lasting “concern” that they attributed to neuroblastoma screening.     

The impact of cystic fibrosis on neonatal intestinal obstruction: the need for prenatal/neonatal screening

To determine the incidence of cystic fibrosis (CF) in neonates with intestinal obstruction (NIO) secondary to meconium ileus (MI), jejunoileal atresia (JA), meconium plug syndrome (MPS), volvulus (V), and meconium peritonitis (MP) and analyze the correlation of ultrasonographic (US) signs with CF in NIO with a prenatal diagnosis of intestinal anomaly, a prospective analysis of different types of NIO from 1990 to 1998 was undertaken. Immunoreactive trypsin measurement, genetic studies, and sweat tests were performed to confirm or rule out CF. Cases with prenatal diagnosis were analyzed for gestational age, dilated bowel, ascites, hyperechoic bowel, and calcifications. Of 80 neonates, 19 (24%) had CF: 2/33 (6%) JA, 6/14 (43%) MPS, 1/14 (7.1%) MP, 10/10 (100%) MI, and 0/9 V. Thirty (37.5%) had a prenatal diagnosis of an intestinal anomaly. The overall incidence of CF in NIO with a prenatal diagnosis of intestinal anomaly was 4/30 (13%), or 333 times the estimated risk of CF in the general population. A hyperechoic pattern with dilated bowel was associated with higher specificity for CF: 3/3 cases (100%), followed by hyperechoic bowel with ascites: 3/4 cases (75%). All babies with any type of NIO should thus be screened for CF. Prenatal screening for CF should be indicated in all pregnancies with US patterns of specific intestinal disorders.     

Late relapse and prognosis for neuroblastoma patients surviving 5 years or more: a report from the European Neuroblastoma Study Group "Survey"

BACKGROUND AND PROCEDURE: Most deaths from neuroblastoma occur within 2 years of diagnosis but there have been several anecdotal reports of relapse and death after much longer periods of follow up. In order to investigate and quantify the risk of late events we analysed data for patients registered with the European Neuroblastoma Study Group between 1982 and 1990. Out of a total of 1,277 children registered, 427 were alive with follow-up beyond 5 years from diagnosis (median follow-up of 8.8 years, range 5-14 years). Of these 406 were in remission with no prior recurrence, 16 were in remission having experienced a relapse prior to 5 years, and 5 were alive with progressive disease. RESULTS: For the 406 patients in remission with no prior relapse the 10 year progression free survival (PFS) was 96% (CI 94-98). For those aged over 1 year with stage 4 disease at diagnosis 10 year PFS was 88% (CI 79-96) compared to 98% (CI 97-99) for other patients combined, P< 0.001. In a multivariate analysis of all 422 patients in remission at 5 years, significant risk factors for subsequent relapse were age > 1 yr with stage 4 disease at diagnosis (relative risk 10.5, P < 0.001) and prior relapse (RR 4.2, P= 0.01). CONCLUSIONS: The results of this study emphasise the importance of longterm follow-up of patients and the need for late monitoring of clinical trials in children with neuroblastoma. They also provide a baseline for comparison with future and hopefully more effective treatment programmes.     

Breastfeeding and hepatitis C virus (HCV): the need for a careful appraisal]

We review the available data on the possible role of breast-feeding in hepatitis C virus (HCV) transmission to infants of HCV-RNA-positive mothers. Current knowledge about HCV excretion through breast milk, HCV infection of breast-fed infants by mothers contaminated after delivery, and vertical transmission risk to infants breast-fed by chronic HCV viremic mothers are presented. Vertical transmission risk by breast-feeding HCV-RNA-positive mothers is unclear: no study has been performed with the aim and the required methodology to evaluate HCV transmission risk related to breast-feeding duration. Recommendations to HCV-RNA-positive mothers who wish to breast-feed their infant are discussed in light of present knowledge about HCV secretion in breast milk, mother-to-infant HCV transmission, and historical records on vertical transmission of other viruses to infants breast-fed by their viremic mothers.     

The transplanted child: New immunosuppressive agents and the need for pharmacokinetic monitoring

BACKGROUND:

Pharmacokinetic monitoring has been insufficiently studied in paediatric solid organ transplantation, especially because some agents are relatively new to paediatric use, are of new formulation modification or are being used in combinations not previously well studied. The choice of immunosuppressive drugs after paediatric renal transplantation is increasing. Cyclosporine A (CyA), tacrolimus and mycophenolate mofetil (MMF) use has become routine. While pharmacokinetic monitoring of CyA and tacrolimus is routine, few paediatric data on tacrolimus pharmacokinetics exist, and, for MMF, pharmacokinetic monitoring is performed in only a few Canadian centres. The aim of the present article is to provide guidelines for the use of these three drugs by using a large number of full pharmacokinetic profiles in children.

METHODS:

One hundred forty-nine full pharmacokinetic 10-point profiles on cyclosporine microemulsion, 103 on the classic cyclosporine, 118 on tacrolimus and 114 on MMF were retrospectively analyzed. All pharmacokinetic profiles were obtained from paediatric renal transplant patients in steady state.

RESULTS:

For pharmacokinetic monitoring of the classic cyclosporine formulation, evaluation of the trough levels suffices to estimate the area under the curve (AUC). For microemulsified cyclosporine, the trough levels do not provide a useful tool, and blood concentrations at 2 or 3 h (C2 or C3) after intake should be measured instead. Tacrolimus trough levels sufficiently estimate the AUC, but measuring the C4 yields the best prediction of the AUC. Nonetheless, C2 also provides a superior tool than the trough levels. Tacrolimus and CyA AUCs change substantially over time after renal transplantation. There is only a poor correlation between the trough level and the AUC for mycophenolic acid (MPA). No single time point provides a surrogate marker of the AUC. At least three time points are required to accurately estimate the AUC, and C1, C2 and C6 serve as the best markers. The article also describes the interaction between MPA and differing concomitant immunosuppression, as well as the variation of the MPA AUC with differing concentrations of cyclosporine.

CONCLUSIONS:

Pharmacokinetic monitoring of these three drugs is mandatory in paediatric renal transplantation because it is impossible to predict the drug interactions and blood levels from a given dose. Target AUCs for a given time point after transplantation remain to be established.     

The need for vigilance: the case of a false-negative newborn screen for cystic fibrosis

Cystic fibrosis (CF) is the most common life-limiting recessive genetic disorder in the white population. CF is caused by abnormalities in the gene that codes for the cystic fibrosis transmembrane conductance regulator protein (CFTR) and may result in severe chronic lung disease, poor growth, and malnutrition. Physicians often do not consider CF in the differential diagnosis of an infant with failure to thrive in the presence of a negative newborn screening (NBS) result. In Minnesota, newborn infants are screened for CF by immunoreactive trypsinogen (IRT) testing followed by DNA analysis if the IRT screen result is abnormal. All positive NBS results are followed by confirmatory sweat-testing by pilocarpine iontophoresis. We present here the case of a 1-month-old white boy with failure to thrive, chronic diarrhea, and severe malnutrition. Minnesota state CF NBS results were negative at birth (IRT: 43 ng/mL [96% cutoff value: 52 ng/mL]). Clinical symptoms resulted in sweat-testing by Gibson-Cooke pilocarpine iontophoresis at 1 month of age, and the result was positive (102 mmol Cl(-)/L [normal: ≤30 mmol Cl(-)/L]). CFTR mutation analysis confirmed a homozygous f508del genotype, and stool pancreatic elastase testing revealed severe exocrine pancreatic insufficiency. This case represents the first known false-negative result in Minnesota since the initiation of NBS for CF in 2006, which illustrates the importance of considering CF in the evaluation of an infant with failure to thrive and symptoms of malabsorption, regardless of NBS results.     

The need for nutrition support teams in pediatric units: a commentary by the ESPGHAN committee on nutrition

The reported prevalence of malnutrition in pediatric hospitals ranges from 15% to 30% of patients, with an impact on growth, morbidity and mortality. Major deficits in nutrition care have been highlighted in European hospitals, and the implementation of nutrition support teams (NSTs) has been suggested as a means to improve malnutrition diagnosis and nutrition care for hospitalized patients.This comment by the ESPGHAN Committee on Nutrition reviews disease related-mechanisms causing malnutrition and consequences of malnutrition and suggests a framework for implementation of NSTs in pediatric units. The recommendations by the Committee on Nutrition include: 1) Implementation of NSTs in hospitals is recommended to improve nutritional management of sick children; 2) The main tasks of the NST should include screening for nutritional risk, identification of patients who require nutritional support, provision of adequate nutritional management, education and training of hospital staff and audit of practice; 3) The NST should be multidisciplinary, with expertise in all aspects of clinical nutrition care; 4) The funds needed to support NSTs should be raised from the health care system; and 5) Further research is needed to evaluate the effects of NSTs in prevention and management of pediatric nutritional disorders, including cost effectiveness in different settings.