The BIG 2.04 MRC/EORTC SUPREMO Trial: pathology quality assurance of a large phase 3 randomised international clinical trial of postmastectomy radiotherapy in intermediate-risk breast cancer.

INTRODUCTION: SUPREMO is a phase 3 randomised trial evaluating radiotherapy post-mastectomy for intermediate-risk breast cancer. 1688 patients were enrolled from 16 countries between 2006 and 2013. We report the results of central pathology review carried out for quality assurance. PATIENTS AND METHODS: A single recut haematoxylin and eosin (H&E) tumour section was assessed by one of two reviewing pathologists, blinded to the originally reported pathology and patient data. Tumour type, grade and lymphovascular invasion were reviewed to assess if they met the inclusion criteria. Slides from potentially ineligible patients on central review were scanned and reviewed online together by the two pathologists and a consensus reached. A subset of 25 of these cases was double-reported independently by the pathologists prior to the online assessment. RESULTS: The major contributors to the trial were the UK (75%) and the Netherlands (10%). There is a striking difference in lymphovascular invasion (LVi) rates (41.6 vs. 15.1% (UK); p = <0.0001) and proportions of grade 3 carcinomas (54.0 vs. 42.0% (UK); p = <0.0001) on comparing local reporting with central review. There was no difference in the locally reported frequency of LVi rates in node-positive (N+) and node-negative (N-) subgroups (40.3 vs. 38.0%; p = 0.40) but a significant difference in the reviewed frequency (16.9 vs. 9.9%; p = 0.004). Of the N- cases, 104 (25.1%) would have been ineligible by initial central review by virtue of grade and/or lymphovascular invasion status. Following online consensus review, this fell to 70 cases (16.3% of N- cases, 4.1% of all cases). CONCLUSIONS: These data have important implications for the design, powering and interpretation of outcomes from this and future clinical trials. If critical pathology criteria are determinants for trial entry, serious consideration should be given to up-front central pathology review.

Resolution-dependent estimates of multiple sclerosis lesion loads.

BACKGROUND: Changes in brain lesion loads assessed with magnetic resonance imaging obtained at 1.5 Telsa (T) are used as a measure of disease evolution in natural history studies and treatment trials of multiple sclerosis. METHODS: A comparison was made between the total lesion volume and individual lesions observed on 1.5 T images and on high-resolution 4 T images. Lesions were quantified using a computer-assisted segmentation tool. RESULTS: There was a 46% increase in the total number of lesions detected with 4 T versus 1.5 T imaging (p < 0.005). The 4 T also showed a 60% increase in total lesion volume when compared with the 1.5 T (p < 0.005). In several instances, the 1.5 T scans showed individual lesions that coalesced into larger areas of abnormality in the 4 T scans. The relationship between individual lesion volumes was linear (slope 1.231) showing that the lesion volume observed at 4 T increased with the size of the lesion detected at 1.5 T. The 4 T voxels were less than one quarter the size of those used at 1.5 T and there were no consistent differences between their signal-to-noise ratios. CONCLUSIONS: The increase in signal strength that accompanied the increase in field strength compensated for the loss in signal amplitude produced by the use of smaller voxels. This enabled the acquisition of images with improved resolution, resulting in increased lesion detection at 4 T and larger lesion volumes.

The Comprehensive Childhood Maltreatment Inventory: early development and reliability analyses.

OBJECTIVE: Our goal was to develop a reliable measure of childhood maltreatment that could be used to evaluate retrospective memories among adults across a broad range of potentially abusive caregiver behaviors. METHOD: These behaviors were organized into 31 items that query age at onset, frequency across 4 developmental periods, relationship of the perpetrator(s), and respondents' perception of the experience. Additional factors directly relevant to each of the individual 4 categories of childhood maltreatment were also queried. RESULTS: Preliminary data collected from 95 college students, find the measure to have excellent test-retest reliability, and 2 of 4 subscales to possess adequate internal consistency. CONCLUSIONS: Reasons for low internal consistency for the Physical Maltreatment and Physical Neglect categories and the relative importance of test-retest reliability as compared to internal consistency in a questionnaire of this type are discussed.

Results of implementation of a contemporary model for ambulance diversions in an integrated healthcare delivery system.

This brief report contains a description of a contemporary, coordinated new system for ambulance diversions, which was implemented in Edmonton area's Capital Health Region in January 1999. The development of this new system was precipitated by the combination of increasing pressures within the acute care system especially being felt within our emergency departments, and mounting evidence that the existing system for ambulance diversions was ineffectual in providing temporary relief of these pressures. The nature of the previous and the new system are compared and contrasted, and data are included to demonstrate that the new system has led to marked reductions in the number of ambulance diversions experienced regionally.

Plasma chemistry in peregrine falcons (Falco peregrinus): Reference values and physiological variations of importance for interpretation.

Reference values (inner limits of the percentiles P(2.5) and P(97.5) are given with a probability of 95%) for 21 plasma chemical variables were established in 79 peregrine falcons (Falco peregrinus). The following values were established: urea 0.8 to 3.9 mmol/l, creatinine 24 to 64 mumol/l, glucose 16.5 to 22.0 mmol/l, sodium 150 to 170 mmol/l, chloride 114 to 131 mmol/I, inorganic phosphorus 0.55 to 1.53 mmol/l, osmolal-ity 322 to 356 mOsmol/kg, alkaline phosphatase 31 to 121 IU/l, alanine aminotransferase 29 to 90 IU/l, aspartate aminotransferase 34 to 116 U/l, gamma glutamyl transferase 0 to 3 IU/l, lactate dehydrogenase 1008 to 2650 IU/l, creatine kinase 120 to 442 IU/l, cholinesterase 143 to 325 IU/1, glutamate dehydrogenase < 8 IU/l, total bile acids 5 to 69 mumol/l, uric acid 253 to 995 mumol/l, total protein 24 to 39 g/l, albumin 12.7 to 22.4 g/l. Reference values for the calculated albumin/globulin (A/G) ratio were 0.8 to 24. Based on previous studies, reference values for calcium were established using an adjustment formula using plasma total protein concentrations (before correction 1.86 to 2.49, after correction 1.97 to 2.46 mmol/l). Results of plasma potassium concentrations were erratic which was shown to be due to a time lag between sample collection and separation of plasma and cells.

Sucrose: a solute that accumulates in the guard-cell apoplast and guard-cell symplast of open stomata.

Stomatal conductances of Vicia faba leaves were recorded over a day. Coordinately, (a) guard cells dissected from leaflets were assayed, providing total sucrose content, and (b) guard cells dissected from rinsed epidermes were also assayed, providing symplastic sucrose content. Compared with that of pre-dawn samples, apoplastic sucrose content increased 4.8-5.2 x (2 experiments), reaching 1,130-1,300 fmol.guard-cell-pair-1 at midday, when conductance was highest (ca. 0.13 mol.m-2.s-1); symplastic sucrose content increased 2.5-3.5 x, reaching 350-390 fmol.guard-cell-pair-1. Thus, there is a correlation between transpiration and guard-cell sucrose content, particularly that portion localized to the apoplast. Moreover, apoplastic sucrose is apparently a source of guard-cell nutrition and, possibly, osmoticum.

Relationship of plasma total protein and albumin to total calcium in peregrine falcons (Falco peregrinus).

A significant correlation was found between total calcium and total protein concentration in 124 plasma samples of captive peregrine falcons (r = 0.65; P<0.01). About 42% of the variability in calcium was attributable to the change in the plasma total protein concentration (R2 = 0.417). The correlation between calcium and albumin was significant (r = 0.33; P<0.01), but significantly smaller than the correlation between calcium and total protein (P<0.01). Only 11% of the plasma calcium concentration was attributable to difference in concentration of albumin (R2 = 0.108). An adjustment formula for plasma calcium concentration in the peregrine falcon was derived on the basis of the total protein concentration: Adj.Ca (mmol/1) = Ca (mmol/1) -0.02 Total protein (g/1) + 0.67.

Digibind: emergency treatment for digitalis toxicity.

Digitalis is a commonly prescribed cardiovascular agent. The advent of Digibind constitutes an important pharmacologic breakthrough for the toxicities encountered with the use of this drug.

Chimpanzee holding, rehabilitation and breeding: facilities design and colony management.

A multipurpose chimpanzee facility was designed and constructed to provide the unique housing requirements of rehabilitating laboratory-raised, behaviorally-deficient chimpanzees. The housing complex provided quarantine facilities, single or group housing for long-term holding, and semi-free-ranging compounds for established breeding groups. The facilities were designed to accommodate 170 animals of diverse ages and group configurations. Reproductive performance of the chimpanzees resulted in the production of 0.41 live infants per adult female year. Information was also given on the care, diet, maintenance, health status, handling, and rehabilitation of the chimpanzee. Development of this facility has made it practical to house large numbers of chimpanzees economically and conveniently in an enriched environment which promotes breeding and contributes to the survival of this irreplaceable animal model.

Direct inguinal hernia in the cynomolgus monkey (Macaca fascicularis).

The surgical repair of a direct inguinal hernia in Macaca fascicularis using the posterior or preperitoneal approach is presented. The success of this surgical approach endorses it as an excellent method of repairing direct inguinal hernia in male primates.

A 2-year follow-up of 72 hyperactive boys. Classroom behavior and peer acceptance.

A 2-year, prospective follow-up of 72 hyperactive boys (94 per cent of the initial sample) examined classroom and home behavior, academic achievement, peer status, and depressive symptomatology for patients and a matched control group. Sixty-five per cent of the sample was still on medication at follow-up. The patient group continued to manifest behavioral and academic difficulty. Off-drug classroom behavior showed considerable stability from baseline to 2-year follow-up which did not appear to be significantly influenced by change of school or interim stimulant drug treatment. Academic difficulties, low peer status, and depressive symptoms exceeded that of the control group. Low peer status at 2 years were predicted for the patient group by baseline (but not current) classroom hyperactivity. The continued difficulties for this middle-class sample, in spite of faithful stimulant drug intake, ancillary educational and psychiatric support, are disappointing. However, as no untreated comparison group was available, the relative benefit of continued drug treatment could not be directly examined. Some indirect evidence, however, indicates that although drugs may continue to have a suppressant effect on impulsive and hyperactive behavior, peer status and academic achievement may not be improved. An "optimally medicated" group (86 per cent of responders from an initially randomly assigned group) had almost identical academic achievement and social acceptance as did a group of dropouts from drug treatment, or the sample as a whole.

Reproductive, gestational, and newborn physiology of the chimpanzee.

The Yerkes Regional Primate Research Center has successfully bred chimpanzees since 1930. Breeding statistics for the last 6 yr and problems of fetal waste and infant mortality are presented here. Experience with a potential advantages of semi-free-ranging breeding systems are presented. This 6-yr study period also produced considerable information on gestational and newborn physiology.