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

PURPOSE: The 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. METHODS: We 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 x 2 to 60 x 2 patients. RESULTS: This 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 x 2 patients), the same MTD was identified in 11% of the simulations. Even with larger sample sizes (40 x 2 patients), this figure reached 24% for OR=3. There is also a very high risk of identifying two different MTD (52% for 40 x 2 patients) although the risk is similar in both groups. CONCLUSIONS: Two 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.

Modifications in corneal biomechanics and intraocular pressure after deep sclerectomy.

PURPOSE: To compare preoperative and postoperative measurements of corneal biomechanical properties and intraocular pressure (IOP) using Goldmann applanation tonometry (GAT) and the ocular response analyzer (ORA) in eyes undergoing deep sclerectomy with collagen implant (DSCI). PATIENTS AND METHODS: Thirty eyes of 30 glaucomatous patients undergoing deep sclerectomy with collagen implant and 30 eyes of 30 normal subjects were included. Goldmann applanation IOP, central corneal thickness (CCT), and ORA measurements [corneal compensated IOP (IOPcc), Goldmann-correlated IOP (IOPg), corneal resistance factor (CRF), and corneal hysteresis (CH)] were taken the day before deep sclerectomy with collagen implant and on days 1, 8, and 30 after surgery. Preoperative CH values were correlated to the number of preoperative medications and to the CCT. Also, the ORA measurements of normal subjects were compared with the preoperative measurements of the glaucomatous patients. RESULTS: The 30 glaucomatous eyes showed a statistically significant difference between preoperative and day 1 postoperative GAT IOP, ORA IOPcc, IOPg, CRF, and CH measurements. No statistically significant difference was noted when comparing the GAT IOP, ORA IOPcc, IOPg, and CRF measurements between days 1, 8, and 30 after DSCI.On the contrary, CH values were statistically different when comparing days 1, 8, and 30 after DSCI. The 30 normal eyes showed no statistical difference when compared with the preoperative IOPg parameter in the 30 glaucomatous eyes; the mean CRF and the mean CH values were statistically significantly higher than the preoperative values of the glaucomatous group. CONCLUSIONS: CH statistically increased between preoperative and postoperative day 1 DSCI. On days 8 and 30, the change in CH values was statistically significant.

Outcomes in older patients after surgical treatment for hip fracture: a new approach to characterise the link between readmissions and the surgical stay.

BACKGROUND: in older patients, there is a high risk of hospital readmission within the first year after surgery for hip fracture, due to complications following treatment or to the evolution of prior comorbid conditions. OBJECTIVES: to identify factors associated with readmissions related to the index surgical stay. DESIGN: retrospective cohort study. SETTING: administrative claims databases. SUBJECTS: patients over 75 surgically treated for hip fracture in Paris area. METHODS: we analysed all admissions in 2005, and tracked for 1-year readmissions. First readmissions (FRs) were classified as related or unrelated to the index stay, according to rules defined a priori. We analysed the association between patient characteristics and the FR. RESULTS: among 5,709 patients, 32% had at least one readmission, 53% were FR related. Near 80% of related readmissions occurred within 3 months from discharge. Surgical conditions caused 47% of all related readmissions, and male gender, dementia, cancer or kidney diseases were independent risks factors. CONCLUSIONS: half of readmissions could be classified as related to the index stay and a great majority of these occurred early post discharge. Surgical conditions caused 47% of all related readmissions. Improvement in orthopedic-geriatric co-care is suitable to expect an impact on outcomes after surgery.

[Patients' perception of information received when a complementary medical examination is prescribed]. / Perception par les patients de l'information reçue lors d'un examen complémentaire.

Medical doctors are required to provide information to their patients regarding their medical procedures according to the law on patient information enacted on March 4, 2002. The objective of this study was to assess patients' awareness and satisfaction with respect to their perception of information obtained prior to or during a medical examination. A self-descriptive patient survey was conducted at the Groupe Hospitalier of Pitié-Salpêtrière in 2005 for this purpose. Data were collected at three distinct moments using a standard questionnaire. 147 patients were interviewed (101 had received and MRI and 46 a bronchoscopy). Twenty percent of the participants reported that they had not been provided with any specific medical or paramedical information before the examination and 4% had received no information at all. Health professionals must ensure that information is given to their patients in a manner that takes into account their expectations and responds to their concerns before a medical procedure is performed in order to improve its delivery and its intrinsic quality.

The corneal endothelium in an endotoxin-induced uveitis model: correlation between in vivo confocal microscopy and immunohistochemistry.

PURPOSE: To analyze the involvement of the corneal endothelium in uveitis to better understand the formation mechanisms and the keratic precipitate composition. In vivo confocal microscopy images were correlated with ex vivo immunostaining of corneal endothelium from rat eyes with endotoxin-induced uveitis (EIU). METHODS: EIU was induced in Lewis rats by lipopolysaccharide (LPS) injection. Slit-lamp examination and in vivo confocal microscopy were performed 6, 24, 48, 72, and 96 h after the LPS injection. One group of rats was killed at 24 h and the other rats at 96 h. Immunohistochemistry on corneal endothelium using antibodies to intercellular adhesion molecule (ICAM-1), phalloidin, CD68 (anti-macrophage), MCA967 (anti-granulocyte), T cell receptor alpha/beta (TCR alpha/beta; anti-lymphocyte), zonula occludens-1 (ZO-1), and occludin was performed on flat-mount corneas and was analyzed using a three dimensional (3D) laser confocal microscope. RESULTS: In vivo confocal microscopy showed numerous hyperreflective round dots on the corneal endothelium, in the anterior chamber, and in the anterior stroma corresponding to inflammatory cells with a maximum at 24 h after the injection and detectable until the 96th hour. Upon immunostaining, corneal endothelial cells in rats with EIU overexpressed ICAM-1. ZO-1 and occludin had a lower endothelial expression and more heterogeneous distribution in EIU rats than in controls, showing disruption of endothelial cell junctions. Compared to controls, CD68, MCA967, and TCR alpha/beta expression was observed in corneas in rats with EIU. The two techniques showed a circular peripheral network of corneal vessels derived from a large circumferential vascular structure resembling the major arterial circle of iris where the inflammatory cells marginalized to infiltrate the anterior stroma. CONCLUSIONS: The correlation between in vivo confocal microscopy and ex vivo immunostaining helped to better understand in vivo confocal microscopy images. The two new techniques applied here were very effective and complementary in evaluating the corneal endothelium involvement in EIU. Based on these findings, in vivo confocal microscopy in clinical practice could be very helpful to better analyze keratic precipitates and corneal modifications in patients with uveitis.

Th1 and Th2 responses on the ocular surface in uveitis identified by CCR4 and CCR5 conjunctival expression.

PURPOSE: To investigate CC chemokine receptor 4 (CCR4) and CC chemokine receptor 5 (CCR5) expression, known to be related to the Th2 and Th1 inflammatory pathways, respectively, and human leukocyte antigen-D related (HLA-DR) antigens as hallmarks for ocular surface inflammation in patients with uveitis using conjunctival impression cytologic specimens. DESIGN: Case-controlled study. METHODS: Conjunctival impression cytologic specimens were obtained from patients with anterior uveitis (n = 26), and their inflammatory profile was compared with those of patients with vernal keratoconjunctivitis (VKC; n = 24), keratoconjunctivitis sicca (KCS; n = 17), and normal subjects (n = 17). Expressions of CCR4, CCR5, and HLA-DR were analyzed using flow cytometry and were expressed by determining the percentage of cells expressing the markers in the conjunctival epithelium. RESULTS: CCR4 was overexpressed in the uveitis group (mean, 19.8% +/- 19.7% of positive cells) and in the VKC group (24.7% +/- 20.1%). CCR5 was expressed only weakly in uveitis patients (6.4% +/- 13.1%) and in the normal subjects (2.4% +/- 2.4%). HLA-DR expression by conjunctival cells was increased in the uveitis patients (57.4% +/- 21.1%) and in the KCS group (52.4% +/- 12.1%) compared with the VKC group (23.9% +/- 26.8%; P < .001) and normal subjects (22.1% +/- 19.1%; P < .001). CONCLUSIONS: CCR4, classically related to the Th2 system, and HLA-DR both were overexpressed by the conjunctival epithelium in uveitis patients, whereas CCR5, related to the Th1 system, was expressed weakly in uveitis patients. These preliminary results seem to suggest an involvement of the Th2 system on the ocular surface in uveitis. Exploration of the ocular surface in uveitis may represent a new way to understand better the immune pathways involved in this complex disease.

In vivo corneal confocal microscopy in marfan syndrome.

PURPOSE: To examine the cornea of patients with Marfan syndrome in comparison with a control group by using the in vivo confocal microscope. METHODS: Twenty-four eyes of 12 patients with Marfan syndrome had their corneas examined using the in vivo confocal microscope Heidelberg Retina Tomograph (HRT) II/Rostock Cornea Module. The control group included 24 eyes of 12 subjects who had their corneas examined by the same in vivo confocal microscope. RESULTS: Epithelium and neural plexus examination did not show any difference between the 2 groups. Examination of the stroma showed no significant differences concerning the morphology and density of keratocytes. The extracellular matrix of 16 of the 24 eyes of the Marfan group was clearly visible and showed thin highly reflective interconnected lines between keratocytes. In the healthy eye group, reflective lines were observed in only 5 of the 24 eyes. The endothelium of 14 corneas of the Marfan group showed brightly reflective particles. In no cornea of the control group were such particles observed. CONCLUSIONS: Highly reflective extracellular matrix of the stroma and brightly reflective particles among the endothelial cells were the 2 main corneal findings observed by using in vivo corneal confocal microscopy in patients with Marfan syndrome compared with a control group. Further studies need to be made to confirm these findings and eventually find new criteria for Marfan syndrome from the examination of in vivo corneal confocal microscopy.

Very low oral doses of vitamin B-12 increase serum concentrations in elderly subjects with food-bound vitamin B-12 malabsorption.

The BOSSANOVA study, a randomized double-blind trial, was designed to test the ability of very low oral doses of vitamin B-12 to increase the serum vitamin B-12 concentration in elderly subjects with food-bound vitamin B-12 malabsorption, and to determine whether there was a dose response. We also aimed to quantitatively assess the most efficient dose to be added to flour in addition to folic acid (flour cofortification with vitamin B-12 and folic acid). Sixty-seven patients were randomly assigned to 1 of 6 groups receiving various daily oral doses of vitamin B-12 (i.e., 2.5, 5, 10, 20, 40, or 80 microg/d) for 30 d. The dose-response was tested for different biological variables using a mixed model, taking into account the variable's initial value (between-subject effect), a linear log-dose effect, and a linear log (dosextime) interaction, where time was d 15 or d 30. We planned to determine the amount of oral vitamin B-12 that would increase the serum vitamin B-12 concentration by 37 pmol/L (50 ng/L). Significant between-subject effects were found for serum vitamin B-12, plasma homocysteine, and methylmalonic acid concentrations, but a log-dose effect was found only for vitamin B-12 (P<0.001). The slope of the line tended to be higher (P=0.07) at d 30 than at d 15. For a mean serum vitamin B-12 increase of 37 pmol/L, a dose of 5.9 (95% CI, 0.9-12.1) microg/d was needed. We concluded that very low oral doses of vitamin B-12 increased serum vitamin B-12 concentrations in elderly subjects with subclinical vitamin B-12 deficiency, following a log-dose pattern. Our results could be beneficial in the design of a public health program for safe flour cofortification with folic acid.

Effects of type of smoking (pipe, cigars or cigarettes) on biological indices of tobacco exposure and toxicity.

Although all forms of smoking are harmful, smoking pipes or cigars is associated with lower exposure to the lethal products of tobacco products and lower levels of morbidity and mortality than smoking cigarettes. Cytochrome P-450-1A (CYP1A) is a major pathway activating carcinogens from tobacco smoke. Our primary aim was to compare CYP1A2 activity in individuals smoking pipes or cigars only, cigarettes only and in non-smokers. We studied 30 smokers of pipes or cigars only, 28 smokers of cigarettes only, and 30 non-smokers male subjects matched for age. CYP1A2 activity was assessed as the caffeine metabolic ratio in plasma. One-day urine collection was used for determining exposure to products of tobacco metabolism. Nitrosamine and benzo[a]pyrene DNA adducts were measured in lymphocytes. CYP1A2 activity was greater (p<0.0001) in cigarette smokers (median: 0.61; interquartile range: 0.52-0.76) than in pipe or cigar smokers (0.27; 0.21-0.37) and non-smokers (0.34; 0.25-0.42) who did not differ significantly. Urinary cotinine and 1-hydroxypyrene levels were higher in cigarette smokers than in pipe or cigar smokers and higher in the later than in non-smokers. DNA adducts levels were significantly lower in pipe or cigar smokers than in cigarette smokers. In multivariate analysis, cigarette smoking was the only independent predictor of CYP1A2 activity (p<0.0001) and of 1-hydroxypyrene excretion in urine (p=0.0012). In this study, pipe or cigar smoking was associated with lower exposure to products of tobacco metabolism than cigarette smoking and to an absence of CYP1A2 induction. Cigarette smoking was the only independent predictor of CYP1A2 activity in smokers. However, inhalation behaviour, rather than the type of tobacco smoked, may be the key factor linked to the extent of tobacco exposure and CYP1A2 induction. Our results provide a reasonable explanation for the results of epidemiological studies showing pipe or cigar smoking to present fewer health hazards than cigarette smoking.