The mammalian target of rapamycin inhibitor RAD001 (everolimus) in early breast cancer

The mammalian target of rapamycin (mTOR) plays a key role in tumour cell cycle control, proliferation and survival, and has been implicated in resistance to endocrine therapy in breast cancer. RAD001 (everolimus) is a novel macrolide that inhibits mTOR and its downstream substrates in vitro. This study explores the use of RAD001 at a dose of 5mg daily in women with early breast cancer. 31 postmenopausal women were given RAD001 for 14 days prior to primary surgical intervention for early breast cancer. RAD001 was well tolerated in most patients, 5 did not complete treatment due to drug adverse effects. Tumour samples before (pre) and after (post) 14 days treatment were assessed for changes in proliferation and markers of the mTOR pathway. Significant reductions in proliferation (Ki67) and oestrogen receptor (ER) expression were seen, and the downstream effects of the mTOR pathway inhibited (p-S6 (ser235/236 and ser 240/244) and nuclear expression of p-Akt). Gene expression profiling from these tumour samples has confirmed these findings, demonstrating reduction in expression of proliferative genes and oestrogen dependence genes with RAD001 treatment. The mTOR protein exists in two distinct complexes, raptor and rictor, and it has previously been thought that mTOR inhibitors such as RAD001 only have effects upon raptor. The implication of this if correct would be upregulation of Akt (Protein Kinase B), which has been shown to be present in more aggressive and resistant tumour types. The cell line study described herein has demonstrated no upregulation in p-Akt expression with RAD001 treatment, and in one cell line inhibition of p-Akt was sustained with prolonged cell treatment

A population-based audit of surgical practice and outcomes of oncoplastic breast conservations in Scotland – an analysis of 589 patients

Introduction: Current evidence for oncoplastic breast conservation (OBC) is based on single institutional series. Therefore, we carried out a population-based audit of OBC practice and outcomes in Scotland. Methods: A predefined database of patients treated with OBC was completed retrospectively in all breast units practicing OBC in Scotland. Results: 589 patients were included from 11 units. Patients were diagnosed between September 2005 and March 2017. High volume units performed a mean of 19.3 OBCs per year vs. low volume units who did 11.1 (p = 0.012). 23 different surgical techniques were used. High volume units offered a wider range of techniques (8–14) than low volume units (3–6) (p = 0.004). OBC was carried out as a joint operation involving a breast and a plastic surgeon in 389 patients. Immediate contralateral symmetrisation rate was significantly higher when OBC was performed as a joint operation (70.7% vs. not joint operations: 29.8%; p < 0.001). The incomplete excision rate was 10.4% and was significantly higher after surgery for invasive lobular carcinoma (18.9%; p = 0.0292), but was significantly lower after neoadjuvant chemotherapy (3%; p = 0.031). 9.2% of patients developed major complications requiring hospital admission. Overall the complication rate was significantly lower after neoadjuvant chemotherapy (p = 0.035). The 5 year local recurrence rate was 2.7%, which was higher after OBC for DCIS (8.3%) than invasive ductal cancer (1.6%; p = 0.026). 5-year disease-free survival was 91.7%, overall survival was 93.8%, and cancer-specific survival was 96.1%. Conclusion: This study demonstrated that measured outcomes of OBC in a population-based multi-centre setting can be comparable to the outcomes of large volume single centre series

Australian Child Wellbeing Project Technical Report

The Australian Child Wellbeing Project (ACWP) was conducted from 2012 – 2015 using a mixed-methods, child-centred approach. Young people’s perspectives were used to inform a nationally representative survey of children’s wellbeing in the middle years. The aims of the ACWP survey were to benchmark child wellbeing in Australia and to provide useful information for services that promote young people’s healthy development. A final outcome of this project was to make the extensive ACWP database publically available in order to provide further opportunity to exploit the rich data and improve understanding. Accordingly, this technical report consolidates the research conducted by ACER during the three-year study. It provides supporting information about technical aspects of the main survey and its resulting reports, and for facilitating secondary data analyses of the ACWP database. Specifically, it details issues related to survey design, implementation and data analysis. Results from the ACWP main survey are not reported in the technical report, but are presented in the final report. This technical report and data user guide contains an overview of the design, sampling, and data collection activities of the ACWP main study conducted in 2014. In addition, it reports the technical aspects of the first and second stage statistical and thematic analyses presented in the ACWP Final Report, along with guidelines about using the ACWP database

Accuracy of reading liquid based cytology slides using the ThinPrep Imager compared with conventional cytology: prospective study

Objective To compare the accuracy of liquid based cytology using the computerised ThinPrep Imager with that of manually read conventional cytology

Moral Uncertainty and the Criminal Law

In this paper we introduce the nascent literature on Moral Uncertainty Theory and explore its application to the criminal law. Moral Uncertainty Theory seeks to address the question of what we ought to do when we are uncertain about what to do because we are torn between rival moral theories. For instance, we may have some credence in one theory that tells us to do A but also in another that tells us to do B. We examine how we might decide whether or not to criminalize some conduct when we are unsure as to whether or not the conduct is morally permitted, and whether or not it is permissible to criminalize the conduct. We also look at how we might make sentencing decisions under moral uncertainty. We argue that Moral Uncertainty Theory can be an illuminating way to address these questions, but find that doing so is a lot more complicated than applying Moral Uncertainty Theory to individual conduct