Clinical effects and pharmacokinetics of the fusion protein PIXY321 in children receiving myelosuppressive chemotherapy

A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited, and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels. Purpose: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with myelosuppressive chemotherapy. Methods: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered once or twice daily by subcutaneous injection in total doses of 500 to 1000 μg/m² per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule only). Results: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose studied (1000 μg/m² per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m² (range 77–1804 ml/min per m²) and the median half-life was 3.7 h (range 2.1–20.8 h). On day 14, clearance increased in all patients studied (median increase 63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were <1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent activity in vitro. Conclusions: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients. Received: 29 January 1997 / Accepted: 9 May 1997     

Clinical, electrophysiological, and molecular genetic studies in a new family with paramyotonia congenita

OBJECTIVES: To characterise the clinical and electrophysiological features and to determine the molecular genetic basis of pure paramyotonia congenita in a previously unreported large Irish kindred. METHODS: Clinical and neurophysiological examination was performed on three of the five affected family members. Five unaffected and three affected members of the family were available for genetic testing. Direct sequence analysis of the SCN4A gene on chromosome 17q, was performed on the proband's DNA. Restriction fragment length polymorphism (RFLP) analysis was used to screen other family members and control chromosomes for the SCN4A mutation identified. RESULTS: Each affected member had clinical and examination features consistent with pure paramyotonia congenita. Electrophysiological studies disclosed a 78% drop in compound muscle action potential (CMAP) amplitude on cooling to 20 degrees C. DNA sequence analysis identified a heterozygous point mutation G4367A in exon 24 of the SCN4A gene which segregated with paramyotonia and was absent in 200 control chromosomes. The mutation is predicted to result in a radical amino acid substitution at a highly conserved position within the voltage sensing fourth transmembrane segment of the fourth repeated domain of the sodium channel. CONCLUSIONS: The G4367A mutation is likely to be pathogenic and it associates with a pure paramyotonia phenotype. In keeping with other paramyotonia mutations in this region of the skeletal muscle sodium channel, it is predicted that this mutation will impair voltage sensing or sodium channel fast inactivation in a temperature dependent fashion. This study provides further evidence that exon 24 in SCN4A is a hot spot for paramyotonia mutations and this has implications for a DNA based diagnostic service.     

Physical activity combined with massage improves bone mineralization in premature infants: a randomized trial.

BACKGROUND: Osteopenia of prematurity is a known source for morbidity in preterm infants. Premature infants have shown favorable outcomes in response to massage and physical activity. Whether such intervention can stimulate bone formation or decrease bone resorption is yet to be determined. OBJECTIVE: To test the hypothesis that massage combined with physical activity can stimulate bone formation and ameliorate bone resorption in premature infants. DESIGN/METHODS: A prospective double-blinded randomized trial was conducted at the Neonatal Intensive Care Unit of Ain Shams University in Cairo, Egypt. Thirty preterm infants (28 to 35 weeks' gestation) were randomly assigned to either control group (Group I, n=15) or intervention group (Group II, n=15). Infants in the intervention group received a daily protocol of combined massage and physical activity. Serum type I collagen C-terminal propeptide (PICP) and urinary pyridinoline crosslinks of collagen (Pyd) were used as indices for bone formation and resorption, respectively. PICP and Pyd were measured at enrollment and at discharge for all subjects. t-Test, ANOVA and linear regression analysis were used for statistical analyses. RESULTS: There was no difference between groups I and II in gestational age (32.1+/-1.8 vs 31.5+/-1.4 weeks) or birth weight (1.429+/-0.148 vs 1.467+/-0.132 g). In the control group, serum PICP decreased over time from 82.3+/-8.5 to 68.78+/-14.6 (p<0.01), while urinary Pyd increased from 447.7+/-282.8 to 744.9+/-373.6 (p<0.01) indicating decreased bone formation and increased bone resorption, respectively. In the intervention group, serum PICP increased over time from 62.5+/-13.8 to 73.84+/-12.9 (p<0.01). Urinary Pyd also increased over time from 445.7+/-266.5 to 716.8+/-301.8 (p<0.01). In a linear regression model including gestational age and intervention, serum PICP increased significantly in the intervention group (regression coefficient 18.8+/-4.6, p=0.0001) while urinary Pyd did not differ between groups (regression coefficient=5.6+/-114.3, p=0.961). CONCLUSIONS: A combined massage and physical activity protocol improved bone formation (PICP) but did not affect bone resorption (Pyd). Pyd increased over time in both groups, possibly due to continuous bone resorption and Ca mobilization.     

The impact of geographic unit of analysis on socioeconomic inequalities in cancer survival and distant summary stage – a population‐based study

Objective: When using area‐level disadvantage measures, size of geographic unit can have major effects on recorded socioeconomic cancer disparities. This study examined the extent of changes in recorded socioeconomic inequalities in cancer survival and distant stage when the measure of socioeconomic disadvantage was based on smaller Census Collection Districts (CDs) instead of Statistical Local Areas (SLAs). Methods: Population‐based New South Wales Cancer Registry data were used to identify cases diagnosed with primary invasive cancer in 2000–2008 (n=264,236). Logistic regression and competing risk regression modelling were performed to examine socioeconomic differences in odds of distant stage and hazard of cancer death for all sites combined and separately for breast, prostate, colorectal and lung cancers. Results: For all sites collectively, associations between socioeconomic disadvantage and cancer survival and distant stage were stronger when the CD‐based socioeconomic disadvantage measure was used compared with the SLA‐based measure. The CD‐based measure showed a more consistent socioeconomic gradient with a linear upward trend of risk of cancer death/distant stage with increasing socioeconomic disadvantage. Site‐specific analyses provided similar findings for the risk of death but less consistent results for the likelihood of distant stage. Conclusions: The use of socioeconomic disadvantage measure based on the smallest available spatial unit should be encouraged in the future. Implications for public health: Disadvantage measures based on small spatial units can more accurately identify socioeconomic cancer disparities to inform priority settings in service planning.     

Radiation exposure from head computed tomography scans in pediatric trauma

Background

We have previously reported that children receive significantly less radiation exposure after abdominal and/or pelvis computed tomography (CT) scanning for acute appendicitis when performed at our children's hospital (CH) rather than at outside hospitals (OH). In this study, we compare the amount of radiation children receive from head CTs for trauma done at OH versus those at our CH.

Methods

A retrospective chart review was performed on all children transferred to our hospital after receiving a head CT for trauma at an OH between July 2012 and December 2012. These children were then blindly case matched based on date, age, and gender to children at our CH.

Results

There were 50 children who underwent head CT scans for trauma at 28 OH. There were 21 females and 29 males in each group. Average age was 7.01 ± 0.5 y at the OH and 7.14 ± 6.07 at our CH (P = 0.92). Average weight was 30.81 ± 4.69 kg at the OH and 32.69 ± 27.21 kg at our CH (P = 0.81). Radiation measures included dose length product (671.21 ± 22.6 mGycm at OH versus 786.28 ± 246.3 mGycm at CH, P = 0.11) and CT dose index (53.4 ± 2.26 mGy at OH versus 49.2 ± 12.94 mGy at CH, P = 0.56).

Conclusions

There is no significant difference between radiation exposure secondary to head CTs for traumatic injuries performed at OH and those at a dedicated CH.     

Angiopoietin-2 as a biomarker of non-ST-segment elevation myocardial infarction in patients with or without type 2 diabetes

IntroductionAngiopoietin-2 (Ang-2) is a novel marker of coronary artery disease (CAD) and diabetes (DM). The aim was to evaluate Ang-2 as a potential new biomarker of non-ST elevation myocardial infarction (NSTEMI) in patients with or without type 2 DM (T2DM).Material and methodsThis was a multi-center, prospective study that included 138 (males: 91/66%) consecutive patients hospitalized due to NSTEMI, T2DM, or different cardiac disorders. The subjects were divided into four study groups: group A: 28 patients with NSTEMI and T2DM; group B: 47 patients with NSTEMI without T2DM; group C: 31 patients with T2DM, without a history of CAD; group D: 32 patients as a control group. Patients with NSTEMI underwent urgent coronarography. Clinical characteristics including biomarkers (hs-CRP, hsTnT, NT-proBNP, VEGF, HbA_1c), SYNTAX SCORE, type of intervention (PCI vs. CABG), and number of implanted stents were taken into account in the analysis.ResultsSerum Ang-2 concentrations were significantly higher in patients with NSTEMI (group A: 1769 pg/ml; group B: 1757 pg/ml) and patients with T2DM (group C: 1993 pg/ml) as compared to the patients without CAD and without T2DM (group D: 866.8 pg/ml; p < 0.05). The prognostic accuracy of Ang-2 in NSTEMI diagnosis was determined with the area under the ROC curve (area under curve (AUC) = 0.63).ConclusionsAngiopoietin-2 serum concentration is elevated in the presence of NSTEMI in patients with and without T2DM and does not correspond to the degree of myocardial injury and hemodynamic status. Ang-2 remains elevated also in patients with T2DM without a history of CAD.