Pharmacodynamic evaluation of the epidermal growth factor receptor inhibitor OSI-774 in human epidermis of cancer patients.

BACKGROUND: OSI-774 is an inhibitor of the epidermal growth factor receptor tyrosine kinase (EGFR-TK) currently in clinical development. In preclinical models, the antitumor activity of OSI-774 was directly related to its ability to inhibit the EGFR-TK. On the basis of these data, we hypothesized that inhibition of the EGFR-TK will be required for this agent to be effective in the clinic. This study evaluated the pharmacodynamic effects of OSI-774 in normal skin tissues collected from patients treated with the agent in a Phase I study. METHODS: Patients with advanced cancer who were treated in a Phase I study of OSI-774 underwent a biopsy of normal skin epidermis at baseline and after the last dose of drug in the first course of treatment. The expression and activation of the EGFR, downstream signaling extracytoplasmatic-regulated kinase (Erk), and cell cycle regulator p27 were determined in paraffin-embedded skin tissues using an immunohistochemical method (IHC). The IHC data were analyzed using both a semiquantitative scoring system and an automatic absorbance quantitative IHC method. The number of cells with nuclear staining of p27 per 500 cells was determined. Plasma samples were collected to quantitate OSI-774 plasma concentrations. RESULTS: A total of 56 skin specimens was collected from 28 patients treated with OSI-774 at doses ranging from 25 to 200 mg/day. There was a significant decrease in phospho-EGFR (Tyr 1173) expression as determined semiquantitatively with OSI-774 treatment [2.75 +/- 0.51 (mean +/- SD) pretreatment versus 2.36 +/- 0.76 after treatment, pair comparison P = 0.01]. The quantitative ratio [(phopho-EGFR/EGFR) x 100] of phospho-EGFR (Tyr1173) decreased from 64.16 +/- 36.58 pretreatment to 48.87 +/- 35.37 post-treatment (pair comparison, P = 0.02). No significant differences were observed in phospho-Erk (Thr202/Tyr204) expression. The mean number of cells with nuclear staining for p27 increased from 185 +/- 101 (mean +/- SD) pretreatment to 253 +/- 111 post-treatment (pair comparison P = 0.02). A total of 12 (42.8%), 7 (25%), and 14 (50%) patients had >25% variation in the ratio of phospho-EGFR (Tyr1173), phospho-Erk (Thr202/Tyr204), and p27 expression, respectively. Only changes in p27 expression were related to the administered dose of OSI-774. CONCLUSIONS: OSI-774 exerted pharmacodynamic effects in skin tissues of 30-50% of patients treated with the agent. Up-regulation of p27, which is a downstream effect of EGFR inhibition, was dose related. Although there was a significant decrement in phospho-EGFR (Tyr1173), it was not related to the administered dose of OSI-774. On the basis of these findings and the relatively simple and reliable method to measure p27 expression, this biomarker appears to be the most promising and is being evaluated in Phase II studies as a predictor of clinical outcome.     

Acknowledgment of Ad Hoc Reviewers for Volume 13

Note

Acknowledgment of Ad Hoc Reviewers for Volume 13     

Biomechanical Effects of e-PTFE Implant Structure on Soft Tissue Implantation Stability: A Study in the Porcine Model

Successful implantation of biocompatible materials depends on physical aspects of its structure. Meshed implants are stable but cannot be easily removed. Nonporous materials are easily removed, but subject to extrusion. We hypothesized that the microporous structure of expanded polytetrafluoroethylene(e-PTFE) would permit limited fibrous ingrowth into the substance of the material, and that tubular implant shape would increase tissue integration while preserving ease of removal. A two-tailed in vivo study was done comparing implant retention, strength of fixation, and removability between tubular and solid-strip e-PTFE implants. Differences in implant retention within tissues were assessed by implanting 396 implants subcutaneously in five swine for observation periods ranging from 3 weeks to 12 months. Strength of implant attachment to host soft tissues was measured at 52 sites by extraction with a tensiometer with forces both parallel and perpendicular to the implant used. Implant porosity was assessed with scanning electron micrography of tubular and solid-strip e-PTFE implants. Measurements of the force and stress tolerances of the implant-tissue interface demonstrated significantly stronger attachment in tubular than strip-shaped implants (P < 0.005). The 11 N (2.75 lb) force sustained by the tubular implant exceeded the 3.4 N(<1 lb) force for the e-PTFE strip by a statistically significant margin on two-tailed Student's t-test (P < 0.005). Even greater forces were tolerated when applied at right angles to the axis of the tubular implant, emulating tissue suspension (21 N, 5.25 lb). The forces and stresses tolerated by both e-PTFE implants far exceeded the fracture stress measured for the implants. Implant extrusion rates were significantly smaller in tubular (0.85%) than in strip-shaped (4.4%) e-PTFE implants (P< 0.05). Standard error of the mean (SEM) demonstrated lesser porosity in tubular than strip implants, suggesting lesser direct tissue attachment. Tubular e-PTFE implant structure facilitates ingrowth of soft tissue through the tube's lumen. This increases the attachment to surrounding soft tissues, increasing fixation strength, decreasing extrusion rate, but still allowing easy removal. These properties may improve clinical applications in facial implantation.     

Prolonged pregnancy: evaluating gestation-specific risks of fetal and infant mortality

Objective To evaluate gestation-specific risks of stillbirth, neonatal and post-neonatal mortality.
Design Retrospective analysis of 171,527 notified births (1989–1991) and subsequent infant survival at one year, from community child health records.
Setting Notifications from maternity units in the North East Thames Region, London.
Main outcome measures The incidence of births, stillbirths, neonatal and post-neonatal deaths at each gestation after 28 completed weeks. Mortality rates per 1000 total or live births and per 1000 ongoing pregnancies at each gestation were calculated.
Results The rates of stillbirth at term (2.3 per 1000 total births) and post-term (1.9 per 1000 total births) were similar. When calculated per 1000 ongoing pregnancies, the rate of stillbirth increased six-fold from 0.35 per 1000 ongoing pregnancies at 37 weeks to 2.12 per 1000 ongoing pregnancies at 43 weeks of gestation. Neonatal and post-neonatal mortality rates fell significantly with advancing gestation, from 15 1.4 and 31.7 per 1000 live births at 28 weeks, to reach a nadir at 41 weeks of gestation (0.7 and 1.3 per 1000 live births, respectively), increasing thereafter in prolonged gestation to 1.6 and 2.1 per 1000 live births at 43 weeks of gestation. When calculated per 1000 ongoing pregnancies, the overall risk of pregnancy loss (stillbirth + infant mortality) increased eight-fold from 0.7 per 1000 ongoing pregnancies at 37 weeks to 5.8 per 1000 ongoing pregnancies at 43 weeks of gestation.
Conclusion The risks of prolonged gestation on pregnancy are better reflected by calculating fetal and infant losses per 1000 ongoing pregnancies. There is a significant increase in the risk of stillbirth, neonatal and post-neonatal mortality in prolonged pregnancy. This study provides accurate data on gestation-specific risks of pregnancy loss, enabling pregnant women and their carers to judge the appropriateness of obstetric intervention.     

Kinematic differentiation of prosodic categories in normal and disordered language development.

Prosody is complex and hierarchically organized but is realized as rhythmic movement sequences. Thus, observations of the development of rhythmic aspects of movement can provide insight into links between motor and language processes, specifically whether prosodic distinctions (e.g., feet and prosodic words) are instantiated in rhythmic movement output. This experiment examined 4-7-year-old children's (both normally developing and specifically language impaired) and adults' productions of prosodic sequences that were controlled for phonetic content but differed in morphosyntactic structure (i.e., content vs. function words). Primary analyses included kinematic measures of rhythmic structure (i.e., amplitude and duration of movements in weak vs. strong syllables) across content and function contexts. Findings showed that at the level of articulatory movement, adults produced distinct rhythmic categories across content and function word contexts, whereas children did not. Children with specific language impairment differed from normally developing peers only in their ability to produce well-organized and stable rhythmic movements, not in the differentiation of prosodic categories.     

Children's use of motor vehicle restraints: maternal psychological distress, maternal motor vehicle restraint practices, and sociodemographics.

OBJECTIVE: To determine the relative contribution of maternal psychological distress, maternal restraint use, and sociodemographic characteristics to the likelihood that a child would not be restrained in a motor vehicle. METHODS: We examined data on 6251 children aged 0-17 years from the 1998 National Health Interview Survey. The level of children's motor vehicle restraint use (low vs high) was examined by maternal psychological distress and motor vehicle restraint use. Multivariate regression analyses were used to model the odds of children's low use of motor vehicle restraints, controlling for potential confounders. RESULTS: According to maternal reports, more than 10% of children and nearly 13% of mothers reported low use of motor vehicle restraints. Multivariate analyses revealed that maternal use of restraints and psychological distress were both independently related to children's use of restraints, with maternal low use as the stronger correlate. Older children were more likely than younger children to be low users of motor vehicle restraints if the mother reported that she was a low user of restraints. Families with male children, black and Hispanic mothers, and 4 or more members reported lower use of restraints for their children. CONCLUSIONS: Children's low use of motor vehicle restraints was associated with low levels of maternal motor vehicle restraint use and maternal psychological distress. Moreover, maternal motor vehicle restraint practices become increasingly important as children age. Health care providers should consider maternal motor vehicle restraint use, maternal psychological distress, and child age in addition to sociodemographics when assessing children's motor vehicle safety.