Impact of baseline BMI and weight change in CCTG adjuvant breast cancer trials.

BACKGROUND: We hypothesized that increased baseline BMI and BMI change would negatively impact clinical outcomes with adjuvant breast cancer systemic therapy. METHODS: Data from chemotherapy trials MA.5 and MA.21; endocrine therapy MA.12, MA.14 and MA.27; and trastuzumab HERA/MA.24 were analyzed. The primary objective was to examine the effect of BMI change on breast cancer-free interval (BCFI) landmarked at 5 years; secondary objectives included BMI changes at 1 and 3 years; BMI changes on disease-specific survival (DSS) and overall survival (OS); and effects of baseline BMI. Stratified analyses included trial therapy and composite trial stratification factors. RESULTS: In pre-/peri-/early post-menopausal chemotherapy trials (N = 2793), baseline BMI did not impact any endpoint and increased BMI from baseline did not significantly affect BCFI (P = 0.85) after 5 years although it was associated with worse BCFI (P = 0.03) and DSS (P = 0.07) after 1 year. BMI increase by 3 and 5 years was associated with better DSS (P = 0.01; 0.01) and OS (P = 0.003; 0.05). In pre-menopausal endocrine therapy trial MA.12 (N = 672), patients with higher baseline BMI had worse BCFI (P = 0.02) after 1 year, worse DSS (P = 0.05; 0.004) after 1 and 5 years and worse OS (P = 0.01) after 5 years. Increased BMI did not impact BCFI (P = 0.90) after 5 years, although it was associated with worse BCFI (P = 0.01) after 1 year. In post-menopausal endocrine therapy trials MA.14 and MA.27 (N = 8236), baseline BMI did not significantly impact outcome for any endpoint. BMI change did not impact BCFI or DSS after 1 or 3 years, although a mean increased BMI of 0.3 was associated with better OS (P = 0.02) after 1 year. With the administration of trastuzumab (N = 1395) baseline BMI and BMI change did not significantly impact outcomes. CONCLUSIONS: Higher baseline BMI and BMI increases negatively affected outcomes only in pre-/peri-/early post-menopausal trial patients. Otherwise, BMI increases similar to those expected in healthy women either did not impact outcome or were associated with better outcomes. CLINICAL TRIALS NUMBERS: CAN-NCIC-MA5; National Cancer Institute (NCI)-V90-0027; MA.12-NCT00002542; MA.14-NCT00002864; MA.21-NCT00014222; HERA, NCT00045032;CAN-NCIC-MA24; MA-27-NCT00066573.

Evaluating the accuracy of a three-term pencil beam algorithm in heterogeneous media.

The goal of this work was to evaluate the accuracy of our in-house analytical dose calculation code against MCNPX data in heterogeneous phantoms. The analytical model utilizes a pencil beam model based on Fermi-Eyges theory to account for multiple Coulomb scattering and a least-squares fit to Monte Carlo data to account for nonelastic nuclear interactions as well as any remaining, uncharacterized scatter (the 'nuclear halo'). The model characterized dose accurately (up to 1% of maximum dose in broad fields (4 × 4 cm2 and 10 × 10 cm2) and up to 0.01% in a narrow field (0.1 × 0.1 cm2) fit to MCNPX data). The accuracy of the model was benchmarked in three types of stylized phantoms: (1) homogeneous, (2) laterally infinite slab heterogeneities, and (3) laterally finite slab heterogeneities. Results from homogeneous phantoms and laterally infinite slab heterogeneities showed high levels of accuracy (>98% of points within 2% or 0.1 cm distance-to-agreement (DTA)). However, because range straggling and secondary particle production were not included in our model, central-axis dose differences of 2-4% were observed in laterally infinite slab heterogeneities when compared to Monte Carlo dose. In the presence of laterally finite slab heterogeneities, the analytical model resulted in lower pass rates (>96% of points within 2% or 0.1 cm DTA), which was attributed to the use of the central-axis approximation.

TLE3 is not a predictive biomarker for taxane sensitivity in the NCIC CTG MA.21 clinical trial.

BACKGROUND: TLE3, a nuclear transcriptional repressor downstream of WNT signalling pathways, has been hypothesised as predictive of benefit from adjuvant taxane. METHODS: MA.21 tissue microarrays were constructed from 1097 out of 2104 (52%) patients. TLE3 staining by immunohistochemistry used validated methodology. Continuous TLE3+ (percentage of cells staining positive) was assessed with both visual and automated scoring. The primary objective was to test the predictive effect of TLE3 on relapse-free survival using the MA.21 EC/T and CEF arms and the previously defined cut-point of 30% of cells staining positive in ⩾1 core/tumour. RESULTS: MA.21 patients had 83.2% TLE3 positive (TLE3+) tumours by visual score and 80.6% TLE3+ by automated image analysis while the previously observed rate of TLE3+ cases was 58.6%. TLE3 expression was significantly associated with ER expression (91.2% of ER-positive tumours were TLE3+; P<0.0001). At median 8-year follow-up, there was no evidence of a predictive effect of TLE3 expression with respect to taxane benefit using the established 30% or exploratory quartile cut-points. CONCLUSIONS: Proportionately more MA.21 patient tumours than expected were TLE3+. The pre-specified TLE3+ cut-point of 30% was not predictive of taxane benefit. TLE3 expression does not represent a viable biomarker for taxane benefit in breast cancer.

Seasonal migration of Cnaphalocrocis medinalis (Lepidoptera: Crambidae) over the Bohai Sea in northern China.

The rice leaf roller, Cnaphalocrocis medinalis (Guenée), is a serious insect pest of rice with a strong migratory ability. Previous studies on the migration of C. medinalis were mostly carried out in tropical or subtropical regions, however, and what the pattern of seasonal movements this species exhibits in temperate regions (i.e. Northern China, where they cannot overwinter) remains unknown. Here we present data from an 11-year study of this species made by searchlight trapping on Beihuang Island (BH, 38°24'N; 120°55'E) in the centre of the Bohai Strait, which provides direct evidence that C. medinalis regularly migrates across this sea into northeastern agricultural region of China, and to take advantage of the abundant food resources there during the summer season. There was considerable seasonal variation in number of C. medinalis trapped on BH, and the migration period during 2003-2013 ranged from 72 to 122 days. Some females trapped in June and July showed a relatively higher proportion of mated and a degree of ovarian development suggesting that the migration of this species is not completely bound by the 'oogenesis-flight syndrome'. These findings revealed a new route for C. medinalis movements to and from Northeastern China, which will help us develop more effective management strategies against this pest.

Do alternative methods of measuring tumor size, including consideration of multicentric/multifocal disease, enhance prognostic information beyond TNM staging in women with early stage breast cancer: an analysis of the NCIC CTG MA.5 and MA.12 clinical trials.

The AJCC staging criteria consider tumor size to be the largest dimension of largest tumor. Some case series suggest using summation of all tumor dimensions in patients with multicentric/multifocal (MC/MF) disease. We used data from NCIC CTG MA.5 and MA.12 clinical trials to examine alternative methods of assessing tumor size on breast-cancer-free-interval (BCFI). The 710 MA.5 pre-/peri-menopausal node positive and 672 MA.12 pre-menopausal node-negative/-positive patients have 10-year median follow-up. All patients received adjuvant chemotherapy. Tumors were centrally reviewed for grade, hormone receptor, and HER2 status. Continuous pathologic tumor size was: (1) largest dimension of largest tumor (cm); (2) tumor area (cm(2)); (3) volume of tumor (cm(3)); (4) with MC/MF disease, summation of (1)-(3) for up to 3 foci. We examined univariate and multivariate effects of tumor size on BCFI utilizing (un)stratified Cox regression and the Wald test statistic. In univariate analysis, larger tumor dimension was significantly associated with worse BFCI in node positive patients: p < 0.0001 for MA.5; p = 0.01 for MA.12. In MA.5 multivariate analysis, larger summation of largest tumor dimensions was associated with worse BCFI (p = 0.0003), while larger single dimension was associated with worse BCFI (p = 0.02) for MA.12. Presence of MC/MF and other tumor size measurements were not associated (p > 0.05) with BFCI. While physicians could consider the largest diameter of the largest focus of disease or the sum of the largest diameters of all foci in their T-stage determination, it appears that the current method of T-staging offers equivalent determinations of prognosis.

Innovative estimation of survival using log-normal survival modelling on ACCENT database.

BACKGROUND: The ACCENT database, with individual patient data for 20 898 patients from 18 colon cancer clinical trials, was used to support Food and Drug Administration (FDA) approval of 3-year disease-free survival as a surrogate for 5-year overall survival. We hypothesised substantive differences in survival estimation with log-normal modelling rather than standard Kaplan-Meier or Cox approaches. METHODS: Time to relapse, disease-free survival, and overall survival were estimated using Kaplan-Meier, Cox, and log-normal approaches for male subjects aged 60-65 years, with stage III colon cancer, treated with 5-fluorouracil-based chemotherapy regimens (with 5FU), or with surgery alone (without 5FU). RESULTS: Absolute differences between Cox and log-normal estimates with (without) 5FU varied by end point. The log-normal model had 5.8 (6.3)% higher estimated 3-year time to relapse than the Cox model; 4.8 (5.1)% higher 3-year disease-free survival; and 3.2 (2.2)% higher 5-year overall survival. Model checking indicated greater data support for the log-normal than the Cox model, with Cox and Kaplan-Meier estimates being more similar. All three model types indicate consistent evidence of treatment benefit on both 3-year disease-free survival and 5-year overall survival; patients allocated to 5FU had 5.0-6.7% higher 3-year disease-free survival and 5.3-6.8% higher 5-year overall survival. CONCLUSION: Substantive absolute differences between estimates of 3-year disease-free survival and 5-year overall survival with log-normal and Cox models were large enough to be clinically relevant, and warrant further consideration.

Flight periodicity and the vertical distribution of high-altitude moth migration over southern Britain.

The continuous operation of insect-monitoring radars in the UK has permitted, for the first time, the characterization of various phenomena associated with high-altitude migration of large insects over this part of northern Europe. Previous studies have taken a case-study approach, concentrating on a small number of nights of particular interest. Here, combining data from two radars, and from an extensive suction- and light-trapping network, we have undertaken a more systematic, longer-term study of diel flight periodicity and vertical distribution of macro-insects in the atmosphere. Firstly, we identify general features of insect abundance and stratification, occurring during the 24-hour cycle, which emerge from four years' aggregated radar data for the summer months in southern Britain. These features include mass emigrations at dusk and, to a lesser extent, at dawn and daytime concentrations associated with thermal convection. We then focus our attention on the well-defined layers of large nocturnal migrants that form in the early evening, usually at heights of 200-500 m above ground. We present evidence from both radar and trap data that these nocturnal layers are composed mainly of noctuid moths, with species such as Noctua pronuba, Autographa gamma, Agrotis exclamationis, A. segetum, Xestia c-nigrum and Phlogophora meticulosa predominating.

A radar study of emigratory flight and layer formation by insects at dawn over southern Britain.

Radar observations have consistently shown that high-altitude migratory flight in insects generally occurs after mass take-off at dusk or after take-off over a more extended period during the day (in association with the growth of atmospheric convection). In this paper, we focus on a less-studied third category of emigration - the 'dawn take-off' - as recorded by insect-monitoring radars during the summer months in southern England. In particular, we describe occasions when dawn emigrants formed notable layer concentrations centred at altitudes ranging from ca. 240 m to 700 m above ground, very probably due to the insects responding to local temperature maxima in the atmosphere, such as the tops of inversions. After persisting for several hours through the early morning, the layers eventually merged into the insect activity building up later in the morning (from 06.00-08.00 h onwards) in conjunction with the development of daytime convection. The species forming the dawn layers have not been positively identified, but their masses lay predominantly in the 16-32 mg range, and they evidently formed a fauna quite distinct from that in flight during the previous night. The displacement and common orientation (mutual alignment) characteristics of the migrants are described.

Evaluation of standard and state of the art analytical technology-bioassays.

The development of biological assays for assessing potency is a critical component for monitoring the quality of therapeutic biologicals. Traditional cell-based bioassays, which are the most widely used, are typically based on a terminal cellular response such as cell proliferation or inhibition. While these assays can be very user-friendly, results often take days and sensitivity is sometimes not sufficient for the needs of the development programme. Recent improvements in analytical technology have led to new approaches in bioassay development. Many of these assays exploit cell signalling pathways far upstream from a terminal cellular response. Bioassays based on a cell signal are much more rapid, sensitive, and indicate stability better than their predecessors. Many of these newer assays are "hybrid" assays which combine the receptor signalling of traditional bioassays with the sensitivity of detection found in immunoassays. One such method, the Kinase Receptor Activation Assay (KIRA), works through the detection of receptor phosphorylation following analyte stimulation. Validations of newer technology assays, such as KIRA, require an individualized strategy due to their unique attributes. A thorough assessment of robustness should be paramount in the validation of these assays. Several examples of new technology platforms for bioassays are also discussed.

Radar studies of the vertical distribution of insects migrating over southern Britain: the influence of temperature inversions on nocturnal layer concentrations.

Insects migrating over two sites in southern UK (Malvern in Worcestershire, and Harpenden in Hertfordshire) have been monitored continuously with nutating vertical-looking radars (VLRs) equipped with powerful control and analysis software. These observations make possible, for the first time, a systematic investigation of the vertical distribution of insect aerial density in the atmosphere, over temporal scales ranging from the short (instantaneous vertical profiles updated every 15 min) to the very long (profiles aggregated over whole seasons or even years). In the present paper, an outline is given of some general features of insect stratification as revealed by the radars, followed by a description of occasions during warm nights in the summer months when intense insect layers developed. Some of these nocturnal layers were due to the insects flying preferentially at the top of strong surface temperature inversions, and in other cases, layering was associated with higher-altitude temperature maxima, such as those due to subsidence inversions. The layers were formed from insects of a great variety of sizes, but peaks in the mass distributions pointed to a preponderance of medium-sized noctuid moths on certain occasions.

An aerial netting study of insects migrating at high altitude over England.

Day and night sampling of windborne arthropods at a height of 200 m above ground was undertaken at Cardington, Bedfordshire, UK, during July 1999, 2000 and 2002, using a net supported by a tethered balloon. The results from this study are compared with those from the classic aerial sampling programmes carried out by Hardy, Freeman and colleagues over the UK and North Sea in the 1930s. In the present study, aerial netting was undertaken at night as well as daytime, and so the diel periodicity of migration could be investigated, and comparisons made with the results from Lewis and Taylor's extensive survey of flight periodicity near ground level. In some taxa with day-time emigration, quite large populations could continue in high-altitude flight after dark, perhaps to a previously underrated extent, and this would greatly increase their potential migratory range. Any trend towards increases in night temperatures, associated with global warming, would facilitate movements of this type in the UK. Observations on the windborne migration of a variety of species, particularly those of economic significance or of radar-detectable size, are briefly discussed.

Impact of a nucleopolyhedrovirus bioinsecticide and selected synthetic insecticides on the abundance of insect natural enemies on maize in southern Mexico.

The impact of commonly used organophosphate (chlorpyrifos, methamidophos), carbamate (carbaryl), and pyrethroid (cypermethrin) insecticides on insect natural enemies was compared with that of a nucleopolyhedrovirus (Baculoviridae) of Spodoptera frugiperda (J. E. Smith) (Lepidoptera Noctuidae) in maize grown in southern Mexico. Analyses of the SELECTV and Koppert Side Effects (IOBC) databases on the impact of synthetic insecticides on arthropod natural enemies were used to predict approximately 75-90% natural enemy mortality after application, whereas the bioinsecticide was predicted to have no effect. Three field trails were performed in mid- and late-whorl stage maize planted during the growing season in Chiapas State, Mexico. Synthetic insecticides were applied at product label recommended rates using a manual knapsack sprayer fitted with a cone nozzle. The biological pesticide was applied at a rate of 3 x 10(12) occlusion bodies (OBs)/ha using identical equipment. Pesticide impacts on arthropods on maize plants were quantified at intervals between 1 and 22 d postapplication. The biological insecticide based on S. frugiperda nucleopolyhedrovirus had no adverse effect on insect natural enemies or other nontarget insect populations. Applications of the carbamate, pyrethroid, and organophosphate insecticides all resulted in reduced abundance of insect natural enemies, but for a relatively short period (8-15 d). Pesticide applications made to late-whorl stage maize resulted in lesser reductions in natural enemy populations than applications made at the mid-whorl stage, probably because of a greater abundance of physical refuges and reduced spray penetration of late-whorl maize.

Selection of a nucleopolyhedrovirus for control of Spodoptera frugiperda (Lepidoptera: Noctuidae): structural, genetic, and biological comparison of four isolates from the Americas.

Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae) is the principal pest of maize in tropical and subtropical regions of the Americas. Larvae of this species are susceptible to a nucleopolyhedrovirus (NPV) which has attracted interest as a potential biocontrol agent. Four strains of NPV isolated from infected S. frugiperda larvae in the United States, Nicaragua, and Argentina were subjected to a structural, genetic, and biological comparison to select a candidate isolate for use in biocontrol experiments in Mexico and Honduras. All isolates had an occlusion body polyhedrin protein of 32 kDa, but the virions of each isolate differed subtly in the pattern and abundance of certain structural polypeptides revealed by SDS-PAGE analysis. Restriction endonuclease analysis of viral DNA confirmed that these isolates were strains of a single virus species but showed that they were not genetically homogeneous; each isolate could be differentiated from the others using common restriction enzymes. Droplet feeding bioassays indicated that an isolate from Nicaragua (Sf-NIC) and an isolate from the United States (Sf-US) had the highest infectivity when tested against 2nd instars originating from a Honduran S. frugiperda colony. No significant differences were detected in the speed of kill of Sf-NIC (102.7 h), Sf-US (102.3 h) and Sf-AR (103.4 h), whereas that of Sf-2 (97.3 h) was significantly shorter. Additional bioassays of the Sf-NIC isolate against 2nd to 6th instars demonstrated that LC50 values increased with larval stage from 2.03 x 10(5) OBs/ml for 2nd instars to 1.84 x 10(8) OBs/ml for 5th instars. The concentration required to elicit a lethal infection of 6th instars was so high that a reliable estimate of LC50 could not be obtained. The mean time to death for each stage challenged with the Sf-NIC isolate increased with instar from an average of 102.7 h in 2nd instars to 136.9 h in 5th instars.

Visual responses of Musca domestica to pheromone impregnated targets in poultry units.

Field trials investigating the effect of visual cues on catches of Musca domestica (Diptera: Muscidae) at toxic targets impregnated with the female sex pheromone (Z)-9-tricosene, were conducted in a caged-layer deep-pit poultry unit in southern England. Targets treated with azamethiphos and baited with 2.5 g of 40% (Z)-9-tricosene impregnated beads caught significantly greater numbers of M. domestica than control targets. The greater attractiveness of the pheromone impregnated targets persisted for at least 5 weeks. The addition of longitudinal black stripes, or a regularly spaced pattern of black spots, to the white targets had no effect on catch rates. However, a pattern of clustered black spots, designed to imitate groups of feeding M. domestica, significantly increased target catches; this effect was particularly pronounced in the targets impregnated with (Z)-9-tricosene. Trials comparing the attractiveness of white and fluorescent yellow pheromone-treated targets under two different lighting regimes indicated that M. domestica does not have a significant preference for either colour. The implications of these results in relation to the control of M. domestica populations in poultry units are discussed.

Competing risks analyses for recurrence from primary breast cancer.

The effects of prognostic factors on local, regional or distant metastasis are standardly assessed separately. Competing risks analyses may be used to assess simultaneously the effects of factors on different types of first recurrence. Data for a cohort of 678 primary invasive breast cancer patients accrued between 1971 and 1990, updated to 1995, included type of first recurrence (local, regional, distant). We investigated the effects of the traditional factors of age, tumour size, nodal status, ER, PgR, adjuvant therapy (hormones, chemotherapy, radiotherapy) on type of recurrence and time to recurrence for all patients and for those aged > or = 65. For all ages of patients, there were five factors with significant associations with type or time to first recurrence. Adjuvant radiation was the only factor which had an effect (P < or = 0.05) on the type of first recurrence: being associated with a reduction in local recurrence. Age, nodal status, tumour size and adjuvant chemotherapy all had significant associations across all types of first recurrence, and in particular with time to recurrence for both local and distant metastasis. This indicates a potential lack of independence in these end-points. For patients > or = 65 years of age, there were no factors which differentially affected type of recurrence, while only nodal status and tumour size had significant associations with time to recurrence. Analyses were used to assess simultaneously the effects of traditional prognostic factors and treatment options on type of first recurrence and time to first recurrence. The extension to evaluations with newer prognostic factors would expedite the determination and mode of biologic activity for such factors.

Evaluation of three (Z)-9-tricosene formulations for control of Musca domestica (Diptera: Muscidae) in caged-layer poultry units.

A field trial comparing the effectiveness of toxic targets impregnated with different formulations of the Musca domestica L. female sex pheromone (Z)-9-tricosene was conducted in a caged-layer, deep-pit poultry unit in southern England. Targets baited with 5 g of technical grade (Z)-9-tricosene, or 5 g of a 40% polymer bead formulation, caught significantly greater numbers of M. domestica than control targets. This increase in attractiveness of the pheromone-impregnated targets persisted for at least 24 wk. However, mean daily catch rates of M. domestica at targets baited with 5 g of a 2% wettable powder formulation did not significantly differ from control levels. Technical grade and bead formulations of the pheromone attracted significantly more males than females. However, the catches of female M. domestica at these pheromone-impregnated targets were significantly greater than female catches at control targets. Monitoring with sticky cards indicated that the introduction of toxic targets successfully suppressed adult M. domestica population density for up to 13 wk. Possible hypotheses explaining the effect of (Z)-9-tricosene on female attraction are discussed.

Transcription of multiple cell wall protein-encoding genes in Saccharomyces cerevisiae is differentially regulated during the cell cycle.

The yeast cell wall consists of an internal skeletal layer and an outside protein layer. The synthesis of both beta-1,3-glucan and chitin, which together from the cell wall skeleton, is cell cycle-regulated. We show here that the expression of five cell wall protein-encoding genes (CWP1, CWP2, SED1, TIP1 and TIR1) is also cell cycle-regulated. TIP1 is expressed in G1 phase, CWP1, CWP2 and TIR1 are expressed in S/G2 phase, and SED1 in M phase. The data suggest that these proteins fulfil distinct functions in the cell wall.

A longitudinal study of beginning reading achievement and reading self-concept.

BACKGROUND: Although achievement-related self-perceptions are causally related to academic performance, it is not clear at what age this relationship starts to form, especially in terms of learning to read. AIMS: The aim of this longitudinal study was to examine the emerging causal interplay between reading self-concept and beginning reading performance. SAMPLE: One hundred and twelve children who started school at the age of 5 years participated in the study over a two and a half-year period. METHOD: Path analyses were used to examine the relationships between reading-related skills and reading self-concept at the start of Year 1, the middle of Year 2, and the middle of Year 3. RESULTS: Reading performance emerged as causally predominant over reading self-concept between the middle of Year 2 and the middle of Year 3. CONCLUSIONS: Initial reading-related experiences in school are associated with the development of reading self-concepts within the first two and a half years of schooling. This period may mark the time during which negative 'Matthew effects' develop for those who experience initial difficulties in learning to read.