Operating characteristics of two independent sample design in phase I trials in paediatric oncology

PurposeThe European medicines agency (EMEA) has stated that the degree of pre-treatment could modify the patient’s tolerance to new treatments in paediatric oncology. It is current practice to divide a phase I trial into two groups to identify the maximum tolerated dose (MTD) in each group separately. The aim of this study was to investigate the relevance of this approach.MethodsWe reanalysed a large phase I trial of Irinotecan that included 80 children (32 heavily pretreated patients and 48 less heavily pretreated). An extended simulation study was performed to investigate the robustness of the conclusions in the context of small sample sizes. Dose recommendations were studied according to scenarios with group differences, as measured by odds ratio (OR), ranging from 1 (no difference) to 10 (large difference) and sample sizes increasing from 20 × 2 to 60 × 2 patients.ResultsThis study shows a high risk of misidentification of the MTD in each of the two groups, regardless of the group difference. With a group difference corresponding to OR = 8 and balanced sample sizes (20 × 2 patients), the same MTD was identified in 11% of the simulations. Even with larger sample sizes (40 × 2 patients), this figure reached 24% for OR = 3. There is also a very high risk of identifying two different MTD (52% for 40 × 2 patients) although the risk is similar in both groups.ConclusionsTwo independent sample designs in paediatric phase I trials should be avoided or reserved to limited situations when there is a strong rationale possibly based on adult data.     

Treatment and long term outcome in West syndrome: The clinical reality. A multicentre follow up study

We systematically reviewed the files of 51 infants presenting with infantile spasms and hypsarrhythmia in order to study the initial treatment strategies and the long term outcome. 80% of the infants were classified as symptomatic. In the nine participating centres, different treatment protocols were used, but the large majority of the children received vigabatrin as first line treatment. Second line options included hormonal treatment, topiramate and valproate. The time to reach cessation of infantile spasms was significantly shorter in the cryptogenic group than in the symptomatic group (50% at 13 days versus 66 days respectively) and was irrespective of the treatment used. The late follow up data (>2 years) showed that 60% of the children had epilepsy and that 75% of the children had a delay in their psychomotor development. Again, outcome in the cryptogenic group was better than in the symptomatic group, but also in the cryptogenic group, 50% of the children had a clear developmental delay, even if spasms were controlled early in the course of the disease. Our retrospective study illustrates that not only the underlying brain dysfunction is the major determinant for later outcome in infantile spasms (symptomatic group) but also even a short period of infantile spasms can be responsible for later developmental delay (cryptogenic group).     

The effect of RGD density on osteoblast and endothelial cell behavior on RGD-grafted polyethylene terephthalate surfaces

Hybrid materials combining polyethylene terephthalate and different types of cells (endothelial and osteoblastic cells) have been developed thanks to the covalent grafting of different densities of RGD containing peptides onto the polymer surface. Biomimetic modifications were performed by means of a three-step reaction procedure: creation of COOH functions, coupling agent grafting and the immobilization of the RGDC peptides. High resolution μ-imager was used to evaluate RGD densities (varying between 0.6 and 2.4 pmol/mm²) and has exhibited the stability of the surface grafted peptides when treated in harsh conditions. The efficiency of this route for biomimetic modification of a PET surface was demonstrated by measuring the adhesion of MC3T3 and HSVEC cells and by focal adhesion observation. Results obtained prove that a minimal RGDC density of 1 pmol/mm² is required to improve MC3T3 and HSVEC cells responses. Indeed, cells seeded onto a RGDC-modified PET with a density higher than 1 pmol/mm² were able to establish focal adhesion as visualized by fluorescence microscope compared to cells immobilized onto unmodified PET and RGDC-modified PET with densities lower than 1 pmol/mm². Moreover, the number of focal contacts was enhanced by the increase of RGDC peptide densities grafted onto the material surface. With this study we proved that the density of peptides immobilized on the surface is a very important parameter influencing osteoblast or endothelial cell adhesion and focal contact formation.     

Predicting perinatal outcome in isolated congenital diaphragmatic hernia using fetal pulmonary artery diameters

Objective

The aim of the study was to evaluate the potential of fetal pulmonary artery (PA) diameters to predict perinatal death and pulmonary arterial hypertension (PAH) in congenital diaphragmatic hernia (CDH).

Study Design

In this prospective observational study, observed PA (main, right, and left) diameters were measured at the level of the 3 vessels in 21 fetuses with isolated CDH and in 85 controls at 22 to 36 weeks. The observed/expected (o/e) diameters of the main, contralateral, and ipsilateral PAs were calculated by comparing these measurements with reference values obtained in our previous study and correlated with perinatal death and postnatal PAH.

Results

The o/e PA diameters were significantly reduced in fetuses with CDH compared to controls (P < .001) and in fetuses with CDH who died (P < .050). However, there was no significant association between PA diameters and PAH (P ≥ .050).

Conclusions

The PA diameters might be useful to predict perinatal death in isolated CDH but not postnatal PAH, suggesting that PA diameters are probably related to the severity of pulmonary hypoplasia.     

Massive subdural haematomas in Menkes disease mimicking shaken baby syndrome

INTRODUCTION: Menkes disease is an X-linked inherited disorder of intestinal copper absorption resulting in copper deficiency. Cardinal features include hair abnormalities, facial dysmorphism, severe neurological impairment, hypothermia, arterial anomalies, bone abnormalities and a fatal outcome. CASE REPORT: We present a case of Menkes disease complicated by progressive macrocephaly following the development of massive subdural haematomas. These lesions associated with femoral metaphyseal spurs could be confused with nonaccidental injury such as that seen in the shaken baby syndrome. DISCUSSION: This case emphasises that Menkes disease, like glutaric aciduria type 1, should be included in the differential diagnosis of unexplained subdural haematomas and neurological deficits in infants.     

Matthew-Wood syndrome: report of two new cases supporting autosomal recessive inheritance and exclusion of FGF10 and FGFR2

We describe two fetal cases of microphthalmia/anophthalmia, pulmonary agenesis, and diaphragmatic defect. This rare association is known as Matthew-Wood syndrome (MWS; MIM 601186) or by the acronym "PMD" (Pulmonary agenesis, Microphthalmia, Diaphragmatic defect). Fewer than ten pre- and perinatal diagnoses of Matthew-Wood syndrome have been described to date. The cause is unknown, and the mode of transmission remains unclear. Most cases have been reported as isolated and sporadic, although recurrence among sibs has been observed once. Our two cases both occurred in consanguineous families, further supporting autosomal recessive transmission. In addition, in one family at least one of the elder sibs presented an evocatively similar phenotype. The spatiotemporal expression pattern of the FGF10 and FGFR2 genes in human embryos and the reported phenotypes of knockout mice for these genes spurred us to examine their coding sequences in our two cases of MWS. While in our patients, no causative sequence variations were identified in FGF10 or FGFR2, this cognate ligand-receptor pair and its downstream effectors remain functional candidates for MWS and similar associations of congenital ocular, diaphragmatic and pulmonary malformations.     

Prenatally diagnosed sacrococcygeal teratoma: a prognostic classification

Purpose

The objective of this study is to describe a prognostic classification for prenatally diagnosed sacrococcygeal teratoma (SCT).

Methods

Charts from 44 fetuses were reviewed. Three groups were defined as follows: group A—tumor diameter less than 10 cm, absent or mild vascularity and slow growth; group B—diameter 10 cm or greater, pronounced vascularity or high-output cardiac failure and fast growth; group C—diameter 10 cm or greater, predominantly cystic lesion with absent or mild vascularity and slow growth.

Results

Size at diagnosis, growth rate, and vascularity were higher in group B. Gestational age at delivery was lower in group B. Eleven of 21 died in the perinatal period in group B and none in groups A and C. In group C, drainage or shunting of the SCT has been performed in 6 of 10 cases.

Conclusions

Group A is associated to good maternal and perinatal outcome, as well as group C, although shunting or drainage of the SCT could be necessary. Large fast-growing SCT with rich vascularity is associated with a higher perinatal mortality and morbidity than smaller lesions with mild vascularity.