Keith B. G. Dear

A phase III double-blind randomised study of rectal sucralfate suspension in the prevention of acute radiation proctitis

BACKGROUND AND PURPOSEnA limited number of studies have suggested that oral sucralfate reduces the acute and late gastro-intestinal side-effects of pelvic radiotherapy and sucralfate enemas ameliorate symptoms of chronic proctitis. Sucralfate may act via local bFGF at the mucosal level in promoting angiogenesis and reducing epithelial associated microvascular injury. This multi-institutional study was designed to test the hypothesis that sucralfate given as an enema would have a significant protective effect against acute radiation induced rectal injury by direct application to the mucosa.nnnMATERIALS AND METHODSnEighty-six patients having radiotherapy for localised carcinoma of the prostate were randomised in a double-blind placebo-controlled study to receive either 15 ml of placebo suspension or 3 g of sucralfate in 15 ml suspension, given as a once daily enema during and for 2 weeks following radiotherapy. Assessment was based on the EORTC/RTOG acute toxicity criteria and a patient self-assessment diary.nnnRESULTSnThere was no significant difference between placebo and sucralfate for peak incidences of EORTC/RTOG proctitis. For the placebo and sucralfate arms 95 and 88% (difference 7 +/- 11%) suffered some degree of proctitis, with 71 and 61% (difference 10 +/- 19%) reaching grade 2, respectively. The median period to onset of grade 2 proctitis was 33.5 and 36 days, with the median duration being 9.5 and 15 days, respectively, again these difference being non-significant. Thirty-five and 37% of patients rated the effect of radiotherapy on bowel habit as a lot with a moderate or severe effect on normal daily living in 52 and 49%, respectively.nnnCONCLUSIONnThis study suggests that sucralfate given as a once daily enema does not substantially reduce the incidence of symptoms associated with acute radiation proctitis and its routine clinical use cannot be recommended. This cohort of patients will be followed to determine if any difference develops in relation to late toxicity.

Randomized trial of a hospital-based exercise training program after acute myocardial infarction: Cardiac autonomic effects

OBJECTIVESnThis study sought to determine whether a moderate intensity supervised exercise training program, performed immediately after an uncomplicated acute myocardial infarction, improves recovery in cardiac autonomic function compared with standard advice about activity at home.nnnBACKGROUNDnExercise training has beneficial effects on cardiac autonomic function and may improve prognosis after acute myocardial infarction.nnnMETHODSnThirty-nine male and 10 female patients, mean (+/-SE) age 57 +/- 1 years, with an uncomplicated acute myocardial infarction were randomized to either a 6-week moderate intensity supervised hospital-based exercise training program (exercise group) or to an unsupervised low intensity home walking program (control group). Outcome measures included changes in baroreflex sensitivity (phenylephrine bolus method) and heart rate variability (24-h Holter monitoring) and the endurance time at 85% of peak oxygen consumption.nnnRESULTSnAt baseline, there were no significant differences in left ventricular ejection fraction (57 +/- 2% vs. 53 +/- 2%), frequency of anterior infarction (27% vs. 18%) and peak creatine kinase (1,256 +/- 170 vs. 2,599 +/- 295 IU) between the exercise and control groups. Baroreflex sensitivity (10.5 +/- 1.0 vs. 8.4 +/- 1.2 ms/mm Hg) and time domain measures of heart rate variability were also similar. After completion of the program, the exercise group exercised for a median of 15 min (interquartile range 12 to 25) at a workload of 104 +/- 7 W compared with 7 min (interquartile range 3.5 to 12) at a workload of 89 +/- 8 W in the control group (p < 0.01). There were significant (p < 0.001) improvements in baroreflex sensitivity and heart rate variability for the 49 patients combined but no differences between the exercise and control groups. Baroreflex sensitivity improved by 3.4 +/- 1.0 and 1.7 +/- 1.0 ms/mm Hg and the standard deviation of 24-h RR intervals by 36 +/- 6 and 40 +/- 10 ms, respectively (p > 0.1).nnnCONCLUSIONSnA hospital-based exercise training program increased endurance capacity but did not improve recovery of cardiovascular antonomic function after uncomplicated acute myocardial infarction.

Iterative generalized least squares for meta-analysis of survival data at multiple times.

A method is presented for joint analysis of survival proportions reported at multiple times in published studies to be combined in a meta-analysis. Generalized least squares is used to fit linear models including between-trial and within-trial covariates, using current fitted values iteratively to derive correlations between times within studies. Multi-arm studies and nonrandomized historical controls can be included with no special handling. The method is illustrated with data from two previously published meta-analyses. In one, an early treatment difference is detected that was not apparent in the original analysis.

Tests for Homogeneity of the Risk Difference When Data Are Sparse

Test statistics for the homogeneity of the risk difference for a series of 2 x 2 tables when the data are sparse is proposed. A weighted least squares statistic is commonly used to test for equality of the risk difference over the tables; however, when the data are sparse, this statistic can have anticonservative Type I error rates. Simulation is used to compare the proposed test statistics to the weighted least squares statistic. The weighted least squares statistic has the most anticonservative Type I error rates of all the statistics compared. We suggest the use of one of our proposed test statistics instead of the weighted least squares statistic.

Comparison of family history measures used to identify high risk of coronary Heart disease

We examined 15 published continuous family history measures (scores) as well as two new formulations in terms of several desirable properties. We applied the scores to sample pedigrees and found that some systematically increase with family size. In contrast to aggregate scores, non‐aggregate scores are sensitive to the age, sex, and covariate status of individual relatives but are unstable when the families are small. We also applied these scores to our own population case‐control data, characterised by a high proportion of missing and false‐negative responses. In these small families, all scores provided significant discrimination between CHD cases and controls beyond the usual categorical definition of positive family history, but appeared no better than detailed categorical definitions or even simple counts. Our new formulations offer no solution to the problems of few data; most scores apply asymptotic approximations to differences between observed and expected number of affected relatives and are not suited to small families. All scores would be improved by ruling out families with only one affected relative, as is being done in the NHLBI Family Heart Study. We recommend that researchers, when using a family history measure, consider the number of informative families and other characteristics of their data prior to choosing any particular formulation. Genet. Epidemiol. 16:344–355, 1999.

Factors influencing the degree of erythematous skin reactions in humans

Dose-response relationships have been studied using an ordinal visual scale and reflectance spectrophotometry data from 123 treatment sites on 110 patients treated with 10 dose fractions over 12-14 days. Dose rates varied between 3 and 240 Gy/h and total doses of between 25 and 41 Gy were given using teletherapy apparatus. We found qualitative scoring of erythematous skin reactions to be subject to considerable inter- and intra-observer variation. Reflectance spectrophotometry provided more reproducible information, some of which was undetectable by naked eye. Baseline erythema readings were significantly higher in male patients and at anatomical sites of previous heavy UV exposure. In addition, a pronounced decline in erythema readings during the second week of therapy and reciprocal vicinity (abscopal) effects adjacent to the field, undetected by the eye, were observed in a subset of patients. Meaningful dose-response relationships could be derived only from reflectance data with peak change from the pretreatment baseline measure providing the best discrimination. Peak erythema measures following treatment were found to depend on the age and gender of the patient as well as the treatment site and its baseline erythema measurement. This was independent of the total dose administered or the instantaneous dose rate at which it was delivered. The rate of erythema development was also dose rate dependent but only weakly dependent on the biological dose intensity (Gy equiv./day) of the treatment course. The data raise the question of whether irradiation-induced erythema is exclusively a secondary phenomenon occurring as a result of basal cell killing. The short repair half time value of 0.06 h obtained by direct analysis is perplexing and may reflect a dose rate-dependent physiological vasodilatory response to irradiation and/or a multi-component cellular repair process.

Stability comparison of intercropping and monocropping systems

Methods of assessing stability are reviewed. These include using measures based on variances, regressions against environmental indices, and risk probabilities. A new approach using bivariate distributions of intercrop and monocrop yields is developed, leading to the calculation of relative risks for the two systems. The bivariate distribution methods proposed are illustrated by application to five sets of data on intercrop combinations each including sorghum.

Acute reaction parameters for human oropharyngeal mucosa.

Abstract The purpose of this study was to determine the influence of changes in dose rate over the range 0.8–240 Gy/h on acute oropharyngeal mucosal reactions in human subjects, and to estimate the values of the important parameters that influence these reactions. Sixty-one patients requiring radiotherapy to palliate incurable head and neck cancer were treated on a telecaesium unit, using opposing lateral portals to total midline doses, varying between 30 and 42 Gy in 10 daily fractions over 2 weeks, at dose rates of 0.8, 1.8, 3.0 and 240 Gy/h according to a central composite study design. The severity and time course of reactions were charted at least twice weekly for each patient, using the EORTC/RTOG acute mucosal reaction grading system. Duration of reaction at each grade was observed to provide a more sensitive reflection of effect than the proportion of patients reaching any particular reaction grade. Analysis of duration by direct and indirect methods suggest αβ ratios in the range 7–10 Gy and half-time (t12) values in the range 0.27–0.5 h, if mono-exponential repair kinetics are assumed. The t12 values are short and raise the question as to whether the repair kinetics of this tissue are well described by a mono-exponential function. Further prospective studies involving multiple daily fraction treatment regimes delivered at high dose rate, in which interfraction interval is deliberately varied, are needed to find out whether the parameters derived from this project are applicable to fractionated treatment courses at high dose rate.

Estimating correlations from epidemiological data in the presence of measurement error.

Analysis of a major multi-site epidemiologic study of heart disease has required estimation of the pairwise correlation of several measurements across subpopulations. Because the measurements from each subpopulation were subject to sampling variability, the Pearson product moment estimator of these correlations produces biased estimates. This paper proposes a model that takes into account within and between sub-population variation, provides algorithms for obtaining maximum likelihood estimates of these correlations and discusses several approaches for obtaining interval estimates.

UPWARD BIAS IN ESTIMATES OF PACEMAKER RELIABILITY : EFFECT OF UNREPORTED PATIENT MORTALITY

OBJECTIVESnThis study attempted to determine the effect of unreported patient deaths on estimates of pacemaker reliability.nnnBACKGROUNDnThe reliability of pacemakers is usually reported with reference to implant registration data and returned product analysis without censoring when follow-up data are missing.nnnMETHODSnWe studied 73 patients (mean [+/- SD] age 77 +/- 8 years) undergoing implantation of a ventricular-inhibited (VVI) pacemaker who were subsequently found to be at increased risk of experiencing premature pacemaker failure. Survival curves for patients and pacemakers were constructed by the Kaplan-Meier method with appropriate censoring at the time of unrelated death or elective explantation of a normal device. To examine the effect of unreported loss of follow-up data, patient mortality was then ignored, and follow-up for pacemakers without known failure was assumed to continue to the date of analysis.nnnRESULTSnThere were 13 device failures, with a median pacemaker survival time of 37 months. Twenty-three patients died, all of causes unrelated to the pacemaker system; median patient survival time was only 44 months. Ignoring this attrition inflated follow-up time from 122 to 188 patient-years and reduced the apparent pacemaker failures at 30 months by almost half, from 37% to only 20%. Modeling the process shows that when the patient mortality rate is more than half the pacemaker failure rate, ignoring censoring inflates the device survival estimate by > or = 10% from the median survival onward.nnnCONCLUSIONSnWhen medical device survival curves are generated by implant registration data and returned product analysis, they should be adjusted for unreported loss of follow-up.