Scott C. Denne

Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial

BACKGROUNDnPlexiform neurofibromas are slow-growing chemoradiotherapy-resistant tumours arising in patients with neurofibromatosis type 1 (NF1). Currently, there are no viable therapeutic options for patients with plexiform neurofibromas that cannot be surgically removed because of their proximity to vital body structures. We undertook an open-label phase 2 trial to test whether treatment with imatinib mesylate can decrease the volume burden of clinically significant plexiform neurofibromas in patients with NF1.nnnMETHODSnEligible patients had to be aged 3-65 years, and to have NF1 and a clinically significant plexiform neurofibroma. Patients were treated with daily oral imatinib mesylate at 220 mg/m(2) twice a day for children and 400 mg twice a day for adults for 6 months. The primary endpoint was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data were analysed on an intention-to-treat basis; a secondary analysis was also done for those patients able to take imatinib mesylate for 6 months. This trial is registered with ClinicalTrials.gov, number NCT01673009.nnnFINDINGSnSix of 36 patients (17%, 95% CI 6-33), enrolled on an intention-to-treat basis, had an objective response to imatinib mesylate, with a 20% or more decrease in tumour volume. Of the 23 patients who received imatinib mesylate for at least 6 months, six (26%, 95% CI 10-48) had a 20% or more decrease in volume of one or more plexiform tumours. The most common adverse events were skin rash (five patients) and oedema with weight gain (six). More serious adverse events included reversible grade 3 neutropenia (two), grade 4 hyperglycaemia (one), and grade 4 increases in aminotransferase concentrations (one).nnnINTERPRETATIONnImatinib mesylate could be used to treat plexiform neurofibromas in patients with NF1. A multi-institutional clinical trial is warranted to confirm these results.nnnFUNDINGnNovartis Pharmaceuticals, the Indiana University Simon Cancer Centre, and the Indiana University Herman B Wells Center for Pediatric Research.

ENERGY EXPENDITURE IN THE EXTREMELY LOW-BIRTH WEIGHT INFANT

Information about energy requirements of extremely low-birth weight infants is sparse, despite the rapidly improving survival rates of this population. Metabolizable energy intake can be estimated from energy balance studies and the percentage of caloric intake that is actually absorbed by these infants is approximately 87%. Data on energy expenditure in extremely premature infants is limited; however, energy expenditure has been shown to increase with postnatal age. Because both intake and expenditure are affected by multiple factors, there is significant variability in estimates of the energy requirements in extremely low-birth weight infants. At present, no valid recommendations can be made regarding optimal energy requirements for the extremely low-birth weight infant, except that their requirements probably exceed those of stable, growing very low-birth weight infants, currently estimated at 105 to 135 kcal.kg-1d-1.

Energy Requirements, Protein-Energy Metabolism and Balance, and Carbohydrates in Preterm Infants

Energy is necessary for all vital functions of the body at molecular, cellular, organ, and systemic levels. Preterm infants have minimum energy requirements for basal metabolism and growth, but also have requirements for unique physiology and metabolism that influence energy expenditure. These include body size, postnatal age, physical activity, dietary intake, environmental temperatures, energy losses in the stool and urine, and clinical conditions and diseases, as well as changes in body composition. Both energy and protein are necessary to produce normal rates of growth. Carbohydrates (primarily glucose) are principle sources of energy for the brain and heart until lipid oxidation develops over several days to weeks after birth. A higher protein/energy ratio is necessary in most preterm infants to approximate normal intrauterine growth rates. Lean tissue is predominantly produced during early gestation, which continues through to term. During later gestation, fat accretion in adipose tissue adds increasingly large caloric requirements to the lean tissue growth. Once protein intake is sufficient to promote net lean body accretion, additional energy primarily produces more body fat, which increases almost linearly at energy intakes >80-90 kcal/kg/day in normal, healthy preterm infants. Rapid gains in adiposity have the potential to produce later life obesity, an increasingly recognized risk of excessive energy intake. In addition to fundamental requirements for glucose, protein, and fat, a variety of non-glucose carbohydrates found in human milk may have important roles in promoting growth and development, as well as production of a gut microbiome that could protect against necrotizing enterocolitis.

Protein and energy metabolism response to the initial dose of infliximab in Children with Crohn's disease

Background Tumor necrosis factor‐&agr; (TNF‐&agr;) may contribute to the alterations in protein and energy metabolism present in children with Crohns disease (CD), who frequently suffer from growth disturbance. We hypothesized that anti‐TNF‐&agr; therapy would reduce protein losses, due to decreased proteolysis and increased protein synthesis, and that anti‐TNF‐&agr; therapy would decrease resting energy expenditure. Methods Children with active CD underwent metabolic assessment immediately before and 2 weeks following initial infliximab infusion. Using the stable isotopes [d5] phenylalanine and [1–13C] leucine, 2 independent measures of protein metabolism were determined during fasting and in response to parenteral nutrition. Energy expenditure, determined by indirect calorimetry, was measured in fasting and parenterally fed states. Results Fifteen children completed the study. Following infliximab therapy, significant reductions in proteolysis (P < 0.05) were noted in the fasting state (8%–11%) and during parenteral nutrition infusion (10%–12%). Phenylalanine utilization for protein synthesis decreased significantly (8%–13%) following infliximab (P < 0.05). Protein balance was not significantly altered. No significant changes in energy expenditure were observed following infliximab in fasting or parenterally fed states. Supplementation with parenteral nutrition resulted in significantly decreased proteolysis (8%–21%; P < 0.05), increased protein synthesis (37%–45%; P < 0.01), and improved protein balance (P < 0.01) compared to the fasting state. Conclusions Following the initial infliximab infusion in children with CD, proteolysis and protein synthesis were significantly reduced in the fasting and parenterally fed states. Supplementation with parenteral nutrition resulted in significant improvements in protein metabolism compared to the fasting state both before and after infliximab therapy. (Inflamm Bowel Dis 2007)

Energy expenditure in extremely low birth weight infants near time of hospital discharge.

OBJECTIVEnTo test the hypothesis that total energy expenditure is significantly higher in extremely low birth weight (ELBW) infants compared with healthy term infants near the time of discharge.nnnSTUDY DESIGNnThis study was designed to determine total energy expenditure and body composition in a group of ELBW infants nearing discharge receiving full-volume enteral feedings of fortified breast milk or postdischarge formula (Neosure) (n = 10; mean birth weight, 0.8 +/- 0.1 kg; mean gestational age, 26 +/- 0.8 weeks; mean age at study, 68 +/- 9 days; mean postconceptional age, 36 +/- 1 weeks) and compare them with healthy term newborns all receiving breast milk (n = 14; mean birth weight, 3.5 +/- 0.5 kg; mean gestational age, 39.0 +/- 1.4 weeks; mean age at study, 2.3 +/- 1 days). Body composition and total energy expenditure were measured using the doubly labeled water method over a 7-day period.nnnRESULTSnMean total energy expenditure was significantly higher in the ELBW infants compared with the term infants (89 +/- 22 kcal/kg/day vs 58 +/- 19 kcal/kg/day; P <or= .001). Total energy expenditure normalized to fat-free mass was also significantly greater in the ELBW infants (98 +/- 3 kcal/kg/day vs 73 +/- 20 kcal/kg/day; P <or= .01).nnnCONCLUSIONSnThe rate of total energy expenditure is greater in ELBW infants nearing discharge compared with normal healthy term infants. In the ELBW infants, higher energy intake compensates for their higher total energy expenditure.

Effect of rhIGF-I infusion on whole fetal and fetal skeletal muscle protein metabolism in sheep

Insulin-like growth factor I (IGF-I) has been shown to have significant anabolic effects in the regulation of fetal protein metabolism. To investigate the tissue-specific effects of IGF-I on fetal skeletal muscle metabolism, we infused recombinant human (rh) IGF-I directly into the hindlimb of nine chronically catheterized, late-gestation fetal sheep. Substrate balance and amino acid kinetics were measured across the hindlimb and were compared with the effects at the whole body level before and during a 3-h infusion of rhIGF-I into the external iliac artery at 150 μg/h. Infusion of rhIGF-I resulted in increases in IGF-I concentrations by 2- to 5.75-fold in the ipsilateral iliac vein and by nearly 3-fold in the abdominal aorta. In the study limb, IGF-I had no effect on protein synthesis (phenylalanine rate of disposal 0.88 ± 0.13 before vs. 0.73 ± 0.19 μmol/min during IGF-I) or breakdown (phenylalanine rate of appearance 0.67 ± 0.13 before vs. 0.60 ± 0.17 μmol/min during IGF-I) and did not alter net phenylalanine balance. IGF-I also did not affect hindlimb oxygen or glucose uptake. In contrast, at the whole body level, the rate of appearance of leucine, indicative of fetal protein breakdown, decreased during IGF-I infusion (rate of appearance of leucine 41.1 ± 3.3 to 37.6 ± 2.7 μmol/min) as did fetal leucine oxidation (8.4 ± 0.8 to 6.8 ± 0.6 μmol/min). There was no change in the umbilical uptake of leucine, and although not statistically significant, fetal leucine accretion increased 2.4-fold. These results provide further evidence that IGF-I promotes fetal protein accretion; however, its site of action is in tissues other than skeletal muscle.Insulin-like growth factor I (IGF-I) has been shown to have significant anabolic effects in the regulation of fetal protein metabolism. To investigate the tissue-specific effects of IGF-I on fetal skeletal muscle metabolism, we infused recombinant human (rh) IGF-I directly into the hindlimb of nine chronically catheterized, late-gestation fetal sheep. Substrate balance and amino acid kinetics were measured across the hindlimb and were compared with the effects at the whole body level before and during a 3-h infusion of rhIGF-I into the external iliac artery at 150 microgram/h. Infusion of rhIGF-I resulted in increases in IGF-I concentrations by 2- to 5. 75-fold in the ipsilateral iliac vein and by nearly 3-fold in the abdominal aorta. In the study limb, IGF-I had no effect on protein synthesis (phenylalanine rate of disposal 0.88 +/- 0.13 before vs. 0. 73 +/- 0.19 micromol/min during IGF-I) or breakdown (phenylalanine rate of appearance 0.67 +/- 0.13 before vs. 0.60 +/- 0.17 micromol/min during IGF-I) and did not alter net phenylalanine balance. IGF-I also did not affect hindlimb oxygen or glucose uptake. In contrast, at the whole body level, the rate of appearance of leucine, indicative of fetal protein breakdown, decreased during IGF-I infusion (rate of appearance of leucine 41.1 +/- 3.3 to 37.6 +/- 2.7 micromol/min) as did fetal leucine oxidation (8.4 +/- 0.8 to 6.8 +/- 0.6 micromol/min). There was no change in the umbilical uptake of leucine, and although not statistically significant, fetal leucine accretion increased 2.4-fold. These results provide further evidence that IGF-I promotes fetal protein accretion; however, its site of action is in tissues other than skeletal muscle.

Glucose and amino acid kinetic response to graded infusion of rhIGF-I in the late gestation ovine fetus

Insulin-like growth factor I (IGF-I) has anabolic effects and is thought to be important in fetal development. The present study was designed to determine the dose response of recombinant human (rh) IGF-I on ovine fetal glucose and amino acid kinetics. Chronically catheterized fetal lambs were studied at 122-127 days gestation. The kinetics of leucine, phenylalanine, and glucose were measured before and during the infusion of rhIGF-I. rhIGF-I was infused into the fetal inferior vena cava at low, medium, or high rates (9.9, 20.1, or 40.2 nmol/h, respectively). A stepwise increase in serum IGF-I was achieved (164 +/- 3, 222 +/- 7, and 275 +/- 5 ng/ml). Insulin concentrations were decreased at the medium and high rhIGF doses. The rate of appearance (Ra) of leucine and phenylalanine and leucine oxidation decreased. Phenylalanine appearance from protein breakdown was decreased, with a maximal suppression of 30% observed at the highest rate of infusion. Glucose Ra was increased at the medium and high doses; other aspects of glucose metabolism were unchanged. The change in both glucose Ra and suppression of proteolysis was significantly correlated to the rhIGF-I infusion rate. It is concluded that rhIGF-I exerts dose-related effects in the ovine fetus, increasing fetoplacental glucose turnover and causing significant suppression of both proteolysis and amino acid oxidation.Insulin-like growth factor I (IGF-I) has anabolic effects and is thought to be important in fetal development. The present study was designed to determine the dose response of recombinant human (rh) IGF-I on ovine fetal glucose and amino acid kinetics. Chronically catheterized fetal lambs were studied at 122-127 days gestation. The kinetics of leucine, phenylalanine, and glucose were measured before and during the infusion of rhIGF-I. rhIGF-I was infused into the fetal inferior vena cava at low, medium, or high rates (9.9, 20.1, or 40.2 nmol/h, respectively). A stepwise increase in serum IGF-I was achieved (164 ± 3, 222 ± 7, and 275 ± 5 ng/ml). Insulin concentrations were decreased at the medium and high rhIGF doses. The rate of appearance (Ra) of leucine and phenylalanine and leucine oxidation decreased. Phenylalanine appearance from protein breakdown was decreased, with a maximal suppression of 30% observed at the highest rate of infusion. Glucose Ra was increased at the medium and high doses; other aspects of glucose metabolism were unchanged. The change in both glucose Ra and suppression of proteolysis was significantly correlated to the rhIGF-I infusion rate. It is concluded that rhIGF-I exerts dose-related effects in the ovine fetus, increasing fetoplacental glucose turnover and causing significant suppression of both proteolysis and amino acid oxidation.

Regulation of Fetal Amino Acid Metabolism: Substrate or Hormonal Regulation?

Insulin is regarded as the primary fetal growth-promoting hormone, but direct in vivo experimental data supporting this conjecture are sparse. Data obtained from studies in in vivo, chronically catheterized fetal lambs under a variety of experimental circumstances demonstrate that glucose availability is the primary modulator of fetal protein accretion, via its ability to diminish amino acid catabolism. The ovine fetus is shown to be resistant to insulin-induced suppression of proteolysis, relative to the adult. Data from studies in the human premature infant show that the findings in the ovine fetus are similar to those in the ex utero premature human.

Evaluation of adequacy of protein and energy

Growth assessment is the most common measure of nutritional adequacy in pediatrics, especially when evaluating nutrition of preterm neonates. The American Academy of Pediatrics defines postnatal nutrient intake to promote growth as one that approximates the rate of growth...for a normal fetus of the same post-menstrual age. It is known that in the fetus, fat and lean body mass are accreted progressively as gestation progresses, whereas postnatal growth and observed accretion of fat and lean body mass differ. This review discusses anthropometric measures used to assess growth, biochemical markers used to monitor nutritional sufficiency, and the effect of growth trajectory in preterm infants on health outcomes later in life.

Seven great achievements in pediatric research in the past 40 y

Over the last 40 y there have been dramatic decreases in global mortality and improvements in quality of life. The pace and scope of research progress has been incredible with its roots in basic science and epidemiologic discoveries leading to efficacy and effectiveness trials. Changes in clinical and public health practice and policy have improved health of populations originating from research discovery. Despite the evident successes, there are current threats to continuing the investment necessary to support critical research. Although the importance of biomedical research was unquestioned for decades, this has changed in the recent times. Historically, the United States has been the global leader in spending on medical research; however, funding has flattened. As an example although the compound annual growth rate for research was >6% from 1994 to 2004, in the last decade this growth has been <1% and in the most recent years has actually declined (1). In addition, Gitterman et al. have noted that the National Institutes of Health investment in pediatric research has been flat even during the growth years (2). These funding trends threaten continued progress. This article highlights seven great achievements in pediatric research of the last 40 y (Table 1). Because of research in these areas, children are healthier and safer today and will become healthier adults. As part of a strategic planning effort in 2013, the American Academy of Pediatrics (AAP) Committee on Pediatric Research conducted an open-ended survey of the board members of pediatric professional organizations on the greatest successes in pediatric research and future opportunities. Although there were many achievements to consider, seven achievements were selected (Table 1) demonstrating how pediatric research investment has paid off in extending and saving lives. The Pediatric Policy Council, which comprised representatives from the Academic Pediatric Association, the American Pediatric Society, the Association of Medical School Pediatric Department Chairs, and the Society for Pediatric Research has been involved in disseminating information on these achievements.