An optimal three-stage design for phase II clinical trials

A phase II clinical trial in cancer therapeutics is usually a single-arm study to determine whether an experimental treatment (E) holds sufficient promise to warrant further testing. When the criterion of treatment efficacy is a binary endpoint (response/no response) with probability of response p, we propose a three-stage optimal design for testing H₀: p ≤ p₀ versus H₁: p ≥ p₁, where p₁ and p₀ are response rates such that E does or does not merit further testing at given levels of statistical significance (α) and power (1 ? β). The proposed design is essentially a combination of earlier proposals by Gehan and Simon. The design stops with rejection of H₁ at stage 1 when there is an initial moderately long run of consecutive treatment failures; otherwise there is continuation to stage 2 and (possibly) stage 3 which have decision rules analogous to those in stages 1 and 2 of Simon's design. Thus, rejection of H₁ is possible at any stage, but acceptance only at the final stage. The design is optimal in the sense that expected sample size is minimized when p = p₀, subject to the practical constraint that the minimum stage 1 sample size is at least 5. The proposed design has greatest utility when the true response rate of E is small, it is desirable to stop early if there is a moderately long run of early treatment failures, and it is practical to implement a three-stage design. Compared to Simon's optimal two-stage design, the optimal three-stage design has the following features: stage 1 is the same size or smaller and has the possibility of stopping earlier when 0 successes are observed; the expected sample size under the null hypothesis is smaller; stages 1 and 2 generally have more patients than stage 1 of the two-stage design, but a higher probability of early termination under H₀; and the total sample size and criteria for rejection of H₁ at stage 3 are similar to the corresponding values at the end of stage 2 in the two-stage optimal design.     

Pelvic Gliomatosis within Foci of Endometriosis

The third reported case of pelvic gliomatosis found within foci of endometriosis is documented 16 years after the removal of a benign cystic teratoma. Grossly at laparoscopy the lesions appear as typical deep fibrotic endometriotic implants.     

Gestational age and intrauterine growth retardation among white and black very low birthweight infants: a population-based cohort study

Summary. Very low birthweight (VLBW) is a commonly used endpoint in perinatal epidemiology, but the population of VLBW infants comprises a wide range of gestational ages and rates of fetal growth. We used data from a population-based study of all 1072 black and white VLBW liveborn infants born in 29 counties in Georgia between April 1986 and March 1988. Less than 1% of the VLBW infants were ≥ 37 weeks gestation; most were 29–32 weeks (26%) or 25 to 28 weeks (40%); 12% were 22 weeks or less. All infants 33 weeks gestation or greater were growth retarded. The population of VLBW infants seems to comprise three groups: approximately 11% very immature infants of 22 weeks or less; the majority of infants, born between 23 and 30 weeks, 90% of which are of normal weight for their gestational age; and a group of less premature, growth-retarded infants from 31 to 36 weeks. We found little or no difference in the distribution of gestational age or the percentage of intrauterine growth rates (IUGR) between black and white infants. In the USA the VLBW rate among black infants is over three times greater than that among white infants and consequently the rates of the three types of VLBW among black infants are likely to be triple those among white infants.     

Low peripheral plasma renin activity as a critical marker in pediatric hypertension

In evaluating hypertensive children and adolescents, the etiological considerations should include a set of inherited disorders that share very low plasma renin activity (PRA) as a common feature. In particular among these disorders, glucocorticoid remediable aldosteronism (GRA) appears to be emerging as an important etiology of hypertension in the pediatric population. We report the evaluation of a 9-year-old Caucasian girl who presented with severe hypertension and a strong family history of early-onset hypertension. Her suppressed PRA, her family history, and her failure to respond to conventional antihypertensive therapy raised GRA as a potential etiology. The diagnosis was confirmed by an elevated ratio of urinary 18-oxotetrahydrocortisol to urinary tetrahydroaldosterone and genetic testing, which demonstrated the chimeric gene duplication. The molecular pathogenesis of GRA and the clinical implications are reviewed. Received May 15, 1996; received in revised form and accepted September 16, 1996     

Social problem solving as a moderating variable between negative life stress and depressive symptoms

The present study sought to investigate the moderating function that social problem-solving effectiveness serves in relation to negative stressful life events and depressive symptomatology. It was also hypothesized that knowledge of problem solving would improve upon the prediction of level of depressive symptoms beyond the assessment of stressful events. Results involving 462 undergraduate students provide support for both predictions. Specifically, findings from a multiple regression analysis indicated that (1) differences in reported depressive mood between subjects under high and low stress levels were minimal for individuals characterized as effective problem-solvers, relative to those persons with problem-solving scores reflective of ineffective problem solving; and (2) assessment of problem-solving scores and their interaction with stress level provided for an additional three times the amount of explained variance in predicting depression scores beyond life stress scores. Additionally, a cross-validation of the regression analysis was conducted and found to result in a minimal amount of shrinkage that could be due to samplespecific characteristics.We would like to extend our appreciation to two anonymous reviewers for their helpful comments on an earlier draft of this article. The study was supported in part by a grant funded by Fairleigh Dickinson University to the first author.     

Differential actions of FSH and LH during folliculogenesis

In the gonadotrophin-dependent stage of follicular development, FSH- and LH-signalling pathways play an obligatory role in follicle differentiation, selection and survival. Under the effect of LH the theca-interstitial cell layer acts as an androgen producer. Thus, androgen diffusing into the mural granulosa cell layer represents the substrate for FSH-induced aromatase for follicular oestradiol synthesis. This is the landmark 'two cell-two gonadotrophin' concept in the physiology of ovarian function in mammals. The increase in plasma FSH during luteo-follicular transition is the basis for follicle selection. The rise of FSH to the threshold concentration represents a critical condition for the growth of the most sensitive follicle in a given time frame of the last 14 days of the dominant follicle odyssey. The gonadotrophin-induced follicular oestradiol secretion inhibits pituitary secretion of FSH, which in turn causes the concentration of FSH in the developing cohort follicles to drop below threshold concentrations and the arrest of the development of the less FSH-sensitive follicle (FSH threshold and window concept). In the gonadotrophin-dependent phase of follicular development, LH also seems to acts within a critical window of the hormone concentration framed between the minimal threshold and a ceiling for the normal functions of the follicle unit.     

Choline: Dietary Requirements and Role in Brain Development

Choline is needed for the maintenance of the structural integrity and signaling functions of cell membranes, for neurotransmission, and for transport of lipids and as a source of methyl groups. Choline can be made de novo in the body, but some individuals must also obtain choline in the diet to prevent deficiency symptoms. A number of environmental and genetic factors influence dietary requirements for choline, and average intakes in the population vary widely. Therefore, certain individuals may be at greater risk of choline deficiency. Choline is critical during fetal development, particularly during the development of the brain, where it can influence neural tube closure and lifelong memory and learning functions.     

The introduction of a new assessment system in restorative dentistry: the undergraduate and patient experience

In 2000, the University of Bristol Dental School Division of Restorative Dentistry carried out a review of the assessment methods used within the undergraduate programme. Following this review, a number of key recommendations were made and the system of formative assessment within the division was changed. Audits were conducted immediately prior to the introduction of the new system and 2 years after it had been introduced, the results of these audits are presented. There was no change in the number of failed appointments between the initial audit and the second audit. There was a reduction in the number of patients treated by more than one student from 25% to 14% (approximating to 3% if student withdrawal from the course is taken into account). The length of time taken to complete treatment reduced between the two audits with more than half of all patients having their treatment completed within 3 months of their initial examination in the second audit. Ninety-five percent of treatment plans were completed in the second audit compared with only 62% in the first audit. In the second audit, the outstanding 5% of cases were signed off as incomplete for satisfactory reasons by the member of supervisory staff (e.g. patients who had moved away or were discharged due to poor attendance). Student comments were mostly positive, the small number of negative comments related to some students being confused by the paperwork in the new system. The overall process has been an extremely positive experience which has resulted in an assessment system with increased clarity which appears to have reduced the stress levels reported by the undergraduate students on the programme and improved the quality of patient care within restorative dentistry.