Although many preclinical studies have implicated β3 integrin receptors (αvβ3 and αIIbβ3) in cancer progression, β3 inhibitors have shown only modest efficacy in patients with advanced solid tumours. The limited efficacy of β3 inhibitors in patients could arise from our incomplete understanding of the precise function of β3 integrin and, consequently, inappropriate clinical application. Data from animal studies are conflicting and indicate heterogeneity with respect to the relative contributions of β3-expressing tumour and stromal cell populations in different cancers. Here we aimed to clarify the function and relative contributions to metastasis of tumour versus stromal β3 integrin in clinically relevant models of spontaneous breast cancer metastasis, with particular emphasis on bone metastasis. We show that stable down-regulation of tumour β3 integrin dramatically impairs spontaneous (but not experimental) metastasis to bone and lung without affecting primary tumour growth in the mammary gland. Unexpectedly, and in contrast to subcutaneous tumours, orthotopic tumour vascularity, growth and spontaneous metastasis were not altered in mice null for β3 integrin. Tumour β3 integrin promoted migration, protease expression and trans-endothelial migration in vitro and increased vascular dissemination in vivo, but was not necessary for bone colonization in experimental metastasis assays. We conclude that tumour, rather than stromal, β3 expression is essential and is required early for efficient spontaneous breast cancer metastasis to bone and soft tissues. Accordingly, differential gene expression analysis in cohorts of breast cancer patients showed a strong association between high β3 expression, early metastasis and shorter disease-free survival in patients with oestrogen receptor-negative tumours. We propose that β3 inhibitors may be more efficacious if used in a neoadjuvant setting, rather than after metastases are established.

Objectives Conduct a prospective comparative effectiveness cohort study comparing two models of advance care planning (ACP) provision in community aged care: ACP conducted by the client's case manager (CM) ('Facilitator') and ACP conducted by an external ACP service ('Referral') over a 6-month period. Methods This Australian study involved CMs and their clients. Eligible CM were English speaking, ≥18 years, had expected availability for the trial and worked ≥3 days per week. CMs were recruited via their organisations, sequentially allocated to a group and received education based on the group allocation. They were expected to initiate ACP with all clients and to facilitate ACP or refer for ACP. Outcomes were quantity of new ACP conversations and quantity and quality of new advance care directives (ACDs). results 30 CMs (16 Facilitator, 14 Referral) completed the study; all 784 client's files (427 Facilitator, 357 Referral) were audited. ACP was initiated with 508 (65%) clients (293 Facilitator, 215 Referral; p<0.05); 89 (18%) of these (53 Facilitator, 36 Referral) and 41 (46%) (13 Facilitator, 28 Referral; p<0.005) completed ACDs. Most ACDs (71%) were of poor quality/ not valid. A further 167 clients (facilitator 124; referral 43; p<0.005) reported ACP was in progress at study completion. conclusions While there were some differences, overall, models achieved similar outcomes. ACP was initiated with 65% of clients. However, fewer clients completed ACP, there was low numbers of ACDs and document quality was generally poor. The findings raise questions for future implementation and research into community ACP provision. IntrOductIOnAdvance care planning (ACP) is a coordinated communication process between a person, their family/carer(s) and healthcare providers and aims to clarify the person's values, treatment preferences and goals of medical treatment should the person lose capacity to make or communicate such decisions in the future. 1 In Australia, formal ACP programmes usually operate within health, institutional or aged care settings and involve trained staff.1 These programmes are often located at public health services. While discussions are the main focus, an important and often desirable outcome of ACP is the completion of a written advance care directive (ACD) that documents the person's preferences and/or the appointment of a substitute decision maker.1 ACP has been shown to improve care, including end-of-life care, 2 3 to improve the likelihood that a person's preferences will be known and respected [2][3][4] and to improve the psychological outcomes in surviving relatives. The Australian Government Home Care Package (HCP) programme provides funding for personal/health/nursing support to frail or unwell Australians to assist them to remain at home rather than enter residential care. 5 HCPs assisted 60 000 people in 2013; this number is expected to increase to 100 000 by Research 2016/2017, with predictions that 80% of aged care services will be delivered in this form by 2050.5 Each client i...