Refined estimates of local recurrence risks by DCIS score adjusting for clinicopathological features: a combined analysis of ECOG-ACRIN E5194 and Ontario DCIS cohort studies.

PURPOSE: Better tools are needed to estimate local recurrence (LR) risk after breast-conserving surgery (BCS) for DCIS. The DCIS score (DS) was validated as a predictor of LR in E5194 and Ontario DCIS cohort (ODC) after BCS. We combined data from E5194 and ODC adjusting for clinicopathological factors to provide refined estimates of the 10-year risk of LR after treatment by BCS alone. METHODS: Data from E5194 and ODC were combined. Patients with positive margins or multifocality were excluded. Identical Cox regression models were fit for each study. Patient-specific meta-analysis was used to calculate precision-weighted estimates of 10-year LR risk by DS, age, tumor size and year of diagnosis. RESULTS: The combined cohort includes 773 patients. The DS and age at diagnosis, tumor size and year of diagnosis provided independent prognostic information on the 10-year LR risk (p ≤ 0.009). Hazard ratios from E5194 and ODC cohorts were similar for the DS (2.48, 1.95 per 50 units), tumor size ≤ 1 versus  > 1-2.5 cm (1.45, 1.47), age ≥ 50 versus < 50 year (0.61, 0.84) and year ≥ 2000 (0.67, 0.49). Utilization of DS combined with tumor size and age at diagnosis predicted more women with very low (≤ 8%) or higher (> 15%) 10-year LR risk after BCS alone compared to utilization of DS alone or clinicopathological factors alone. CONCLUSIONS: The combined analysis provides refined estimates of 10-year LR risk after BCS for DCIS. Adding information on tumor size and age at diagnosis to the DS adjusting for year of diagnosis provides improved LR risk estimates to guide treatment decision making.

Cytomegalovirus (CMV) DNA load is an independent predictor of CMV disease and survival in advanced AIDS.

The impact of cytomegalovirus (CMV) on human immunodeficiency virus type 1 (HIV-1) disease progression has been controversial. In this study, we sought to determine if CMV viral load is independent of HIV-1 viral load in predicting CMV disease and survival. Our findings indicate that in patients with advanced AIDS, CMV DNA load is an independent marker of CMV disease and survival and is more predictive than HIV-1 RNA load. Moreover, patients who respond to preemptive therapy with oral ganciclovir, with resulting undetectable levels of CMV DNA, in their plasma, have a significantly lower risk of developing CMV disease and higher rates of survival, despite stable or increasing HIV-1 RNA loads. These data provide support for CMV as an independent risk factor for mortality in persons with advanced AIDS and further suggest that effective preemptive therapy for CMV can improve patient survival rates.

Running average analysis of clinical trial ambulatory blood pressure data.

A method is presented for analyzing ambulatory blood pressure monitoring (ABPM) time series data obtained from well-controlled clinical trials. The method uses running averages based on fixed time-of-day intervals (rather than a fixed number of neighboring measurements). These "interval running averages" effectively estimate average blood pressure during the specified time intervals, adjusting for unequal spacing between measurements, embedded missing data, varying measurement times-of-day, and doses of study medication taken during ABP monitoring. Blood pressure changes from baseline may be computed using the interval running averages in order to separate treatment effects from patients' normal daily blood pressure cycles. To ensure valid estimation of treatment effects over time, study medication dosing times should be rigorously controlled in the trial design and conduct. Interval running average curves may be presented graphically, and from them summary statistics may be computed for purposes of statistical analysis. By allowing for the inherent complications of ABP data collection, the effect of antihypertensive treatment in well-controlled clinical trials can be discerned.

Misoprostol heals gastroduodenal injury in patients with rheumatoid arthritis receiving aspirin.

High-dose aspirin therapy for rheumatoid arthritis is frequently associated with severe gastrointestinal injury. To explore the possibility of reversing such damage, we conducted a double-blind, multicenter study with misoprostol, a prostaglandin E1 analog, which has demonstrated mucosal protective, gastric antisecretory, and ulcer healing properties. We also studied possible interference of misoprostol with continuing aspirin treatment in the management of patients with rheumatoid arthritis. Patients with confirmed rheumatoid arthritis and endoscopically documented gastroduodenal lesions were randomly assigned to receive 200 micrograms of misoprostol four times a day (123 patients) or placebo (116 patients). Each concurrently received 650 to 1300 mg of aspirin four times a day. After eight weeks of treatment, misoprostol was statistically superior to placebo in healing gastric mucosal injury (70% vs 25%) and duodenal mucosal injury (86% vs 53%). Patients with gastric or duodenal ulcers on admission had superior ulcer healing rates with misoprostol (67% vs 26%). There was no evidence of interference with the antirheumatic properties of aspirin. Mild to moderate adverse experiences were equally noted in misoprostol and placebo groups. Misoprostol, coadministered with aspirin, is well tolerated and highly effective in healing aspirin-associated gastroduodenal lesions in patients with rheumatoid arthritis without altering the therapeutic benefits of aspirin.

Analysis of covariance in parallel-group clinical trials with pretreatment baselines.

Analysis of covariance (ANCOVA) techniques are often employed in the analysis of clinical trials to try to account for the effects of varying pretreatment baseline values of an outcome variable on posttreatment measurements of the same variable. Baseline measurements of outcome variables are typically random variables, which violates the usual ANCOVA assumption that covariate values are fixed. Therefore, the usual ANCOVA hypothesis tests of treatment effects may be invalid, and the ANCOVA slope parameter estimator biased, for this application. We show, however, that if the pretreatment - posttreatment measurements have a bivariate normal distribution, then (i) the ANCOVA model with residual error independent of the covariate is a valid expression of the relationship between pretreatment and posttreatment measurements; (ii) the usual (fixed-covariate analysis) ANCOVA estimates of the slope parameter and treatment effect contrasts are unbiased; and (iii) the usual ANCOVA treatment effect contrast t-tests are valid significance tests for treatment effects. Moreover, as long as the magnitudes of the treatment effects do not depend on the "true" pretreatment value of the outcome variable, the true slope parameter must lie in the interval (0, 1) and the ANCOVA model has a clear interpretation as an adjustment (based on between- and within-subject variability) to an analysis of variance model applied to the posttreatment-pretreatment differences.

Met-enkephalin, age and anatomy: a microiontophoretic study in the hippocampus.

Met-enkephalin, administered microiontophoretically, produced a greater increase in firing in cells in area CA 3-4 in the hippocampus of both young and aged Fisher 344 rats than it did in the CA 1 area. Furthermore, the effect of met-enkephalin on neuronal firing rates was not as great in old rats as it was in young rats. Finally, 20-40 nA of met-enkephalin produced an increase in firing in old rats that was equivalent to the difference (2.5 spikes/sec) in baseline firing between old (2.6 spikes/sec) and young rats (5.1 spikes/sec).

Acetylcholine, aging and anatomy: differential effects in the hippocampus.

The response to acetylcholine (ACh) administered microiontophoretically was determined for single units in CA1 and CA3-4 areas of the hippocampi of both young (3-5 months) and old (24-26 months) Fisher 344 rats. Single units in CA1 showed a greater response to ACh (20 nA) than single units in CA3-4 in young and in old rats. However, the response to ACh in single units of young rats was significantly greater than in single units of old rats. Baseline firing rates in old rats were lower than those in young rats. However, there was no difference in baseline firing rates between the two areas of the hippocampus indicating that the differential response to ACh as a function of area cannot be attributed to a difference in baseline firing rate.