A systematic review of the effectiveness of docetaxel and mitoxantrone for the treatment of metastatic hormone-refractory prostate cancer

A systematic review was performed to evaluate the clinical effectiveness of docetaxel in combination with prednisolone (docetaxel is licensed in the UK for use in combination with prednisone or prednisolone for the treatment of patients with metastatic hormone-refractory prostate cancer. Prednisone is not used in the UK, but it is reasonable to use docetaxel plus prednisone data in this review of docetaxel plus prednisolone) for the treatment of metastatic hormone-refractory prostate cancer. A scoping search identified a trial of docetaxel plus prednisone vs mitoxantrone plus prednisone, but did not identify any trials comparing docetaxel plus prednisolone/prednisone with any other treatments. Therefore, we considered additional indirect evidence that would enable a comparison of docetaxel plus prednisolone/prednisone with other chemotherapy regimens and active supportive care. Systematic searching (upto April 2005) identified seven randomised controlled trials. One large well-conducted trial assessed docetaxel plus prednisone vs mitoxantrone plus prednisone; this showed statistically significant improvements with 3-weekly docetaxel in terms of overall survival, quality of life, pain response and PSA decline. Two other chemotherapy regimens that included docetaxel with estramustine also showed improved outcomes in comparison with mitoxantrone plus prednisone. Three trials that compared mitoxantrone plus corticosteroids with corticosteroids alone were identified and their results for overall survival combined, which showed very little difference between the two groups. The addition of clodronate to mitoxantrone plus prednisone showed no significant differences in comparison with mitoxantrone plus prednisone alone. The evidence suggests that chemotherapy regimens containing 3-weekly docetaxel are superior to mitoxantrone or corticosteroids alone

Farm management factors associated with bulk tank total bacterial count in Irish dairy herds during 2006/07

Research has shown that total bacterial count (TBC), which is the bacterial growth per ml of milk over a fixed period of time, can be decreased by good hygiene and farm management practices. The objective of the current study was to quantify the associations between herd management factors and bulk tank TBC in Irish spring calving, grass-based dairy herds. The relationship between bulk tank TBC and farm management and infrastructure was examined using data from 400 randomly selected Irish dairy farms where the basal diet was grazed grass. Herd management factors associated with bulk tank TBC were identified using linear models with herd annual total bacterial score (i.e., arithmetic mean of the natural logarithm of bulk tank TBC) included as the dependent variable. All herd management factors were individually analysed in a separate regression model, that included an adjustment for geographical location of the farm. A multiple stepwise regression model was subsequently developed. Median bulk tank TBC for the sample herds was 18,483 cells/ml ranging from 10,441 to 130,458 cells/ml. Results from the multivariate analysis indicated that the following management practices were associated with low TBC; use of heated water in the milking parlour; participation in a milk recording scheme; and tail clipping of cows at a frequency greater than once per year. Increased level of hygiene of the parlour and cubicles were also associated with lower TBC. Herd management factors associated with bulk tank TBC in Irish grazing herds were generally in agreement with most previous studies from confinement systems of milk production

A review of genomic selection - Implications for the South African beef and dairy cattle industries

The major advancements in molecular technology over the past decades led to the discovery of DNA-markers, sequencing and genome mapping of farm animal species. New avenues were created for identifying major genes, genetic defects, quantitative trait loci (QTL) and ultimately applying genomic selection (GS) in livestock. The identification of specific regions of interest that affect quantitative traits aimed to incorporate markers linked to QTL into breeding programs by using marker assisted selection (MAS). Most QTL explained only a small proportion of the genetic variation for a trait with limited impact on genetic improvement. Single nucleotide polymorphism (SNP) markers created the possibility to genotype cattle in a single assay with hundreds of thousands of SNPs, providing sufficient genomic information to incorporate into breeding value estimation. Genomic selection is based on the principle of associating many genetic markers with phenotypic performance. A large database of genotyped animals with relevant phenotypes pertinent to a production system is therefore required. South Africa has a long history of animal recording for dairy and beef cattle. The challenge for implementation of GS would be the establishment of breed-specific training populations. Training populations should be genotyped using a high density SNP panel, and the most appropriate genomic prediction algorithm determined. The suitability of commercially available genotyping platforms to South African populations should be established. The aim of this review is to provide an overview of the developments that occurred over the past two decades to lay the foundation for genomic selection with special reference to application in the South African beef and dairy cattle industry.Authors wish to thank the Red Meat Research and Development South Africa for their support.http://www.sasas.co.zaam201

Motion-corrected multiparametric renal arterial spin labelling at 3T: Reproducibility and effect of vasodilator challenge

Objectives We investigated the feasibility and reproducibility of free-breathing motion-corrected multiple inversion time (multi-TI) pulsed renal arterial spin labelling (PASL), with general kinetic model parametric mapping, to simultaneously quantify renal perfusion (RBF), bolus arrival time (BAT) and tissue T1. Methods In a study approved by the Health Research Authority, 12 healthy volunteers (mean age, 27.6 ± 18.5 years; 5 male) gave informed consent for renal imaging at 3 T using multi-TI ASL and conventional single-TI ASL. Glyceryl trinitrate (GTN) was used as a vasodilator challenge in six subjects. Flow-sensitive alternating inversion recovery (FAIR) preparation was used with background suppression and 3D-GRASE (gradient and spin echo) read-out, and images were motion-corrected. Parametric maps of RBF, BAT and T1 were derived for both kidneys. Agreement was assessed using Pearson correlation and Bland-Altman plots. Results Inter-study correlation of whole-kidney RBF was good for both single-TI (r2 = 0.90), and multi-TI ASL (r2 = 0.92). Single-TI ASL gave a higher estimate of whole-kidney RBF compared to multi-TI ASL (mean bias, 29.3 ml/min/100 g; p <0.001). Using multi-TI ASL, the median T1 of renal cortex was shorter than that of medulla (799.6 ms vs 807.1 ms, p = 0.01), and mean whole-kidney BAT was 269.7 ± 56.5 ms. GTN had an effect on systolic blood pressure (p < 0.05) but the change in RBF was not significant. Conclusions Free-breathing multi-TI renal ASL is feasible and reproducible at 3 T, providing simultaneous measurement of renal perfusion, haemodynamic parameters and tissue characteristics at baseline and during pharmacological challenge

Subcellular Epithelial HMGB1 Expression Is Associated with Colorectal Neoplastic Progression, Male Sex, Mismatch Repair Protein Expression, Lymph Node Positivity, and an 'Immune Cold' Phenotype Associated with Poor Survival.

New treatment targets are needed for colorectal cancer (CRC). We define expression of High Mobility Group Box 1 (HMGB1) protein throughout colorectal neoplastic progression and examine the biological consequences of aberrant expression. HMGB1 is a ubiquitously expressed nuclear protein that shuttles to the cytoplasm under cellular stress. HMGB1 impacts cellular responses, acting as a cytokine when secreted. A total of 846 human tissue samples were retrieved; 6242 immunohistochemically stained sections were reviewed. Subcellular epithelial HMGB1 expression was assessed in a CRC Tissue Microarray (n = 650), normal colonic epithelium (n = 75), adenomatous polyps (n = 52), and CRC polyps (CaP, n = 69). Stromal lymphocyte phenotype was assessed in the CRC microarray and a subgroup of CaP. Normal colonic epithelium has strong nuclear and absent cytoplasmic HMGB1. With progression to CRC, there is an emergence of strong cytoplasmic HMGB1 (p < 0.001), pronounced at the leading cancer edge within CaP (p < 0.001), and reduction in nuclear HMGB1 (p < 0.001). In CRC, absent nuclear HMGB1 is associated with mismatch repair proteins (p = 0.001). Stronger cytoplasmic HMGB1 is associated with lymph node positivity (p < 0.001) and male sex (p = 0.009). Stronger nuclear (p = 0.011) and cytoplasmic (p = 0.002) HMGB1 is associated with greater CD4+ T-cell density, stronger nuclear HMGB1 is associated with greater FOXP3+ (p < 0.001) and ICOS+ (p = 0.018) lymphocyte density, and stronger nuclear HMGB1 is associated with reduced CD8+ T-cell density (p = 0.022). HMGB1 does not directly impact survival but is associated with an 'immune cold' tumour microenvironment which is associated with poor survival (p < 0.001). HMGB1 may represent a new treatment target for CRC

The role of mindfulness in distress and quality of life for men with advanced prostate cancer.

OBJECTIVE: To examine the extent to which mindfulness skills influence psychological distress and health-related quality of life (HRQOL) in men with metastatic or castration-resistant biochemical progression of prostate cancer. PATIENTS AND METHODS: A cross-sectional survey of 190 men (46 % response; mean age 71 years, SD = 8.7, range 40-91 years) with advanced prostate cancer, assessed psychological and cancer-specific distress, HRQOL. Mindfulness skills were assessed as potential predictors of adjustment outcomes. RESULTS: Overall, 39 % of men reported high psychological distress. One third had accessed psychological support previously although only 10 % were under current psychological care. One quarter had accessed a prostate cancer support group in the past six months. Higher HRQOL and lower cancer-specific and global psychological distress were related to non-judging of inner experience (p < 0.001). Higher HRQOL and lower psychological distress were related to acting with awareness (p < 0.001). Lower distress was also related to higher non-reactivity to inner experience and a lower level of observing (p < 0.05). CONCLUSIONS: Men with advanced prostate cancer are at risk of poor psychological outcomes. Psychological flexibility may be a promising target for interventions to improve adjustment outcomes in this patient group. CLINICAL TRIAL REGISTRY: Trial Registration: ACTRN12612000306819

Survival gains needed to offset persistent adverse treatment effects in localised prostate cancer

BACKGROUND: Men diagnosed with localised prostate cancer (LPC) face difficult choices between treatment options that can cause persistent problems with sexual, urinary and bowel function. Controlled trial evidence about the survival benefits of the full range of treatment alternatives is limited, and patients' views on the survival gains that might justify these problems have not been quantified. METHODS: A discrete choice experiment (DCE) was administered in a random subsample (n=357, stratified by treatment) of a population-based sample (n=1381) of men, recurrence-free 3 years after diagnosis of LPC, and 65 age-matched controls (without prostate cancer). Survival gains needed to justify persistent problems were estimated by substituting side effect and survival parameters from the DCE into an equation for compensating variation (adapted from welfare economics). RESULTS: Median (2.5, 97.5 centiles) survival benefits needed to justify severe erectile dysfunction and severe loss of libido were 4.0 (3.4, 4.6) and 5.0 (4.9, 5.2) months. These problems were common, particularly after androgen deprivation therapy (ADT): 40 and 41% overall (n=1381) and 88 and 78% in the ADT group (n=33). Urinary leakage (most prevalent after radical prostatectomy (n=839, mild 41%, severe 18%)) needed 4.2 (4.1, 4.3) and 27.7 (26.9, 28.5) months survival benefit, respectively. Mild bowel problems (most prevalent (30%) after external beam radiotherapy (n=106)) needed 6.2 (6.1, 6.4) months survival benefit. CONCLUSION: Emerging evidence about survival benefits can be assessed against these patient-based benchmarks. Considerable variation in trade-offs among individuals underlines the need to inform patients of long-term consequences and incorporate patient preferences into treatment decisions. © 2012 Cancer Research UK. All rights reserved

Use of partial least squares regression to impute SNP genotypes in Italian Cattle breeds

Background The objective of the present study was to test the ability of the partial least squares regression technique to impute genotypes from low density single nucleotide polymorphisms (SNP) panels i.e. 3K or 7K to a high density panel with 50K SNP. No pedigree information was used. Methods Data consisted of 2093 Holstein, 749 Brown Swiss and 479 Simmental bulls genotyped with the Illumina 50K Beadchip. First, a single-breed approach was applied by using only data from Holstein animals. Then, to enlarge the training population, data from the three breeds were combined and a multi-breed analysis was performed. Accuracies of genotypes imputed using the partial least squares regression method were compared with those obtained by using the Beagle software. The impact of genotype imputation on breeding value prediction was evaluated for milk yield, fat content and protein content. Results In the single-breed approach, the accuracy of imputation using partial least squares regression was around 90 and 94% for the 3K and 7K platforms, respectively; corresponding accuracies obtained with Beagle were around 85% and 90%. Moreover, computing time required by the partial least squares regression method was on average around 10 times lower than computing time required by Beagle. Using the partial least squares regression method in the multi-breed resulted in lower imputation accuracies than using single-breed data. The impact of the SNP-genotype imputation on the accuracy of direct genomic breeding values was small. The correlation between estimates of genetic merit obtained by using imputed versus actual genotypes was around 0.96 for the 7K chip. Conclusions Results of the present work suggested that the partial least squares regression imputation method could be useful to impute SNP genotypes when pedigree information is not available

Association of bovine leptin polymorphisms with energy output and energy storage traits in progeny tested Holstein-Friesian dairy cattle sires

peer-reviewedBackground: Leptin modulates appetite, energy expenditure and the reproductive axis by signalling via its receptor the status of body energy stores to the brain. The present study aimed to quantify the associations between 10 novel and known single nucleotide polymorphisms in genes coding for leptin and leptin receptor with performance traits in 848 Holstein-Friesian sires, estimated from performance of up to 43,117 daughter-parity records per sire. Results: All single nucleotide polymorphisms were segregating in this sample population and none deviated (P > 0.05) from Hardy-Weinberg equilibrium. Complete linkage disequilibrium existed between the novel polymorphism LEP-1609, and the previously identified polymorphisms LEP-1457 and LEP-580. LEP-2470 associated (P < 0.05) with milk protein concentration and calf perinatal mortality. It had a tendency to associate with milk yield (P < 0.1). The G allele of LEP-1238 was associated (P < 0.05) with reduced milk fat concentration, reduced milk protein concentration, longer gestation length and tended to associate (P < 0.1) with an increase in calving difficulty, calf perinatal mortality and somatic cells in the milk. LEP-963 exhibited an association (P < 0.05) with milk fat concentration, milk protein concentration, calving difficulty and gestation length. It also tended to associate with milk yield (P < 0.1). The R25C SNP associated (P < 0.05) with milk fat concentration, milk protein concentration, calving difficulty and length of gestation. The T allele of the Y7F SNP significantly associated with reduced angularity (P < 0.01) and reduced milk protein yield (P < 0.05). There was also a tendency (P < 0.1) for Y7F to associate with increased body condition score, reduced milk yield and shorter gestation (P < 0.1). A80V associated with reduced survival in the herd (P < 0.05). Conclusions Several leptin polymorphisms (LEP-2470, LEP-1238, LEP-963, Y7F and R25C) associated with the energetically expensive process of lactogenesis. Only SNP Y7F associated with energy storage. Associations were also observed between leptin polymorphisms and calving difficulty, gestation length and calf perinatal mortality. The lack of an association between the leptin variants investigated with calving interval in this large data set would question the potential importance of these leptin variants, or indeed leptin, in selection for improved fertility in the Holstein-Friesian dairy cow.Department of Agriculture, Food and Fisheries, Ireland - Research Stimulus Fund (RSF-06-0353; RSF-06-0409); Irish Dairy Research Trust; Teagasc Walsh Fellowshi