Search

Background:Personalisation in social care services has become a feature of the delivery of long-term care for disabled people in many developed welfare states.Aim:Scotland has used the devolution of health and social care powers to develop a personalisation scheme (known as ‘Self-directed Support’). The authors apply a theoretical and empirical framework to understand the experience of contemporary disabled users of personalised services.Methods:The authors use a Scottish data set of six focus groups and a survey of 126 disabled people and family carers.Results:The data showed that flexible funding and the ability to provide services that cross agency boundaries were instrumental in moving towards equitable outcomes.Conclusions:Although there are clear policy and practice barriers to inter-agency working in personalised care services, the evidence suggests that it is worth investing in overcoming these barriers for disabled people and family carers.

Purpose Most abuse affecting older adults in the UK, as across Europe, takes place within caring relationships, where one person is disabled and needs care/support. This paper critically appraises two of the key theoretical explanations. First, feminist theories of “intimate partner abuse” tell us that it is mostly men who perpetrate abuse against women. Second, “carer strain”: the stress caused by caring responsibilities, often with inadequate help from services. Neither fully reflects the complex dynamics of “dangerous care” leading to a lack of voice and choice in safeguarding responses. This paper aims to articulate the need for an overarching theoretical framework, informed by a deeper understanding of the intersectional risk factors that create and compound the diverse experiences of harm by disabled people and family carers over the life course. Design/methodology/approach The critical synthesis of the theoretical approaches informing UK policy and practice presented here arises from a structured literature review and discussions held with three relevant third sector agencies during the development of a research proposal. Findings No single theory fully explains dangerous care and there are significant gaps in policy, resources and practice across service sectors, highlighting the need for joint training, intersectional working and research across service sectors. Originality/value Drawing both on existing literature and on discussions across contrasting policy and practice sectors, this paper raises awareness of some less well-acknowledged complexities of abuse and responses to abuse in later life.

The human epidermal growth factor receptor 2 (HER2, also known as ERBB2) oncogene is overexpressed in approximately 25% of breast cancer tumors and is associated with a high rate of brain metastasis. Patients with brain metastases have a poor prognosis and limited treatment options available. Since about half of HER2+ tumors are also hormone receptor positive, and cross talk has been shown to occur between these two signaling pathways, it is plausible that these tumors could benefit from the addition of hormonal therapy on top of HER2 inhibition. OP-1250 is a complete estrogen receptor antagonist (CERAN) and selective estrogen receptor degrader (SERD), and has been shown to effectively inhibit estrogen receptor positive (ER+) breast cancer growth in both cell-based assays and xenograft studies. OP-1250 has favorable pharmacokinetic properties and demonstrated brain penetrance in non-clinical models. While extensively characterized in ER+/HER2- breast cancer models, OP-1250 had not previously been tested in a HER2+ context. Here we report OP-1250 inhibited estrogen receptor-driven proliferation and effectively degraded the estrogen receptor in multiple ER+/HER2+ cell lines. OP-1250 combined effectively with HER2 inhibitors tucatinib and trastuzumab, demonstrating that inhibition of both HER2 and estrogen receptor signaling was more effective in inhibiting breast cancer cell proliferation than inhibiting either pathway alone. The addition of OP-1250 to a HER2 inhibitor also resulted in greater tumor shrinkage in multiple ER+/HER2+ xenograft models. Our data suggests a potential clinical benefit in the addition of OP-1250 on top of HER2 inhibition for the treatment of ER+/HER2+ breast cancer and provides strong rationale for a clinical study evaluating the combination of OP-1250 and HER2 targeted agents, which is planned for 2022. Citation Format: Alison D Parisian, Leslie Hodges-Gallagher, Richard Sun, Susanna Barratt, Gopinath S Palanisamy, Julia Lawrence, Pamela Klein, David C Myles, Cyrus L Harmon, Peter J Kushner. The complete estrogen receptor antagonist OP-1250 can combine with HER2 inhibition to inhibit estrogen receptor-driven cellular proliferation and shrink xenograft tumors in ER+/HER2+ breast cancer models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-07.

Background: ER+, HER2- metastatic breast cancer (MBC) patients will receive sequential, endocrine based therapy, either as monotherapy or in combination with a targeted agent until endocrine resistance develops. OP-1250 is a small molecule Complete Estrogen Receptor Antagonist (CERAN) that completely inactivates ER by blocking the 2 activation functions of ER transcription (AF-1 & AF-2). While complete antagonism is believed to be the most critical mechanism of action, OP-1250 is also a strong degrader of the ER. OP-1250 demonstrates anti-cancer activity in preclinical models, including activity against brain metastases and in tumors with activating mutations in ESR1. OP-1250 is orally bioavailable with favorable pharmacokinetics (PK) yielding high and steady drug levels in multiple species. The characteristics of OP-1250 including PK, ability to cross the blood brain barrier, and complete antagonism of the ER suggest that OP-1250 may have superior efficacy over standard of care and experimental agents, both as a monotherapy and in combination with other targeted therapies. Methods: OP-1250-001 is a phase I/II first-in-human study to determine the Dose Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D) and to characterize the safety, PK profile and preliminary efficacy in subjects with ER+, HER2- MBC. Eligible patients received prior endocrine therapy. OP-1250 was given orally, once a day continuously in 28-day cycles. Using a rolling 6 design, cohorts of 3 - 6 subjects were sequentially enrolled and monitored for DLTs. The study allows for expansion of 1 or 2 doses for further evaluation of safety and PK to best inform selection of the RP2D. The phase II portion will evaluate the preliminary activity of OP-1250 in 3 cohorts: 1) measurable disease; and 2 exploratory cohorts: 2) evaluable & non-measurable; and 3) central nervous system metastasis. Plasma is being collected for ctDNA sequencing to evaluate ESR1 and other relevant mutations. Results: Between August 5, 2020 and June 4, 2021, 28 subjects with a median age of 63 (range 37-82) have been enrolled. Of the 27 subjects for whom detailed data on prior therapy was reported, all subjects received > 1 prior endocrine therapy for MBC (74% received > 2 and 37% received > 3; range 1-6). All of the 27 subjects received a CDK4/6 inhibitor and 23 of 27 (85%) had received fulvestrant. 20 subjects of 28 (71%) subjects had visceral disease affecting the liver, lung, peritoneum, and/or pleura. OP-1250 was escalated through 5 dose cohorts (range 30 - 300 mg qd). 26 patients were evaluable for a DLT. As of the data cut-off date, no DLTs occurred. Most of the TEAE were grade 1 or 2. OP-1250 is orally bioavailable and extensively distributed with an effective half-life of approximately 2-3 days. Cmax and AUC show dose proportional increase. By cycle 2, exposure levels are at steady state with limited fluctuations and at all doses significantly higher than those seen with fulvestrant. Importantly, OP-1250 has now demonstrated clinical activity at doses that were well tolerated and within the predicted exposure windows where maximum efficacy was observed in preclinical models. Detailed response and safety data will be presented. Conclusion: OP-1250 is continuing evaluation in a phase I/II study. The population enrolled reflects the evolving standard of care in that all pts received prior CDK4/6 inhibitors and the majority also received fulvestrant. OP-1250 is well tolerated with a favorable PK across dose levels ensuring target coverage throughout the dosing interval. No MTD has been identified and selection of the RP2D will be based on consideration of long-term tolerability, efficacy, and the ability to combine with targeted agents. (NCT04505826) Citation Format: Manish Patel, Carlos Alemany, Zahi Mitri, Della Makower, Virginia Borges, Joseph Sparano, Trinh Le, Pamela Klein, Julia Lawrence, Peter Kushner, Demiana Faltaos, Cyrus Harmon, David Myles, JoAnne Zujewski, Erika Hamilton. Preliminary data from a phase I/II, multicenter, dose escalation study of OP-1250, an oral CERAN/SERD, in subjects with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-12.

For all undergraduate, postgraduate and school-based routes to qualified teacher status, Learning to Teach in the Secondary School is an essential introduction to the key skills and knowledge needed to become a secondary teacher. Underpinned by evidence-informed practice and focusing on what you need to know to thrive in the classroom, the eighth edition is fully updated in light of changes in the field, covers new topics and provides additional guidance on topics such as developing your resilience, using digital technologies, closing the achievement gap and using data to inform your teaching and pupil learning. The text includes a wealth of examples and tasks to demonstrate how to successfully apply theory to practice and how to critically reflect on and analyse your practice to maximise pupil learning. The wide range of pedagogical features supports both school- and university-based work up to Masters level. Written by experts in the field, the 37 concise units create unit-by-unit coverage that can be dipped into, offering guidance on all aspects of learning to teach including: Managing your workload Lesson planning Curriculum Motivating pupils Promoting behaviour for learning Assessment, marking and feedback Special educational needs and disabilities (SEND) Applying for jobs, developing as a professional and networking Learning to Teach in the Secondary School provides practical help and guidance for many of the situations and potential challenges you are faced with in school. The text is extended by a companion website that includes additional information as well as specific units covering England, Northern Ireland, Scotland and Wales. Supported by the subject-specific titles in the Learning to Teach Subjects in the Secondary School Series, it is an essential purchase for every aspiring secondary school teacher.

Background: Endocrine therapy administered sequentially as monotherapy or in combination with targeted therapy is the primary treatment for HR+, and HER2- metastatic breast cancer (MBC). Most patients with HR+, HER2- MBC will develop resistance to available therapies. More effective therapies are needed for HR+, HER2- MBC and for the treatment of endocrine therapy-resistant disease. OP-1250 is a small molecule Complete Estrogen Receptor ANtagonist (CERAN) that completely inactivates ER, blocking the activity of both the AF1 and AF2 transcriptional activation functions, inhibits ER-driven breast cancer cell growth, and induces ER degradation. OP-1250 demonstrates anti-cancer activity in vitro and in vivo, including activity against mouse models of metastases in the brain and tumors with activating mutations in ESR1. OP-1250 is orally bioavailable with a favorable pharmacokinetic (PK) profile enabling once-daily dosing. OP-1250’s complete ER antagonism is hypothesized to result in superior efficacy compared to agents that only partially antagonize and/or degrade but do not completely antagonize ER. Trial design: Goals of this phase 1/2 are to determine the Dose Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D), to characterize the safety and PK profile, and to determine the preliminary activity of OP-1250 in subjects with HR+, HER2- MBC. Ph 1 (Dose Escalation) will evaluate escalating doses of orally administered OP-1250 to determine the safety, pharmacology, MTD (if any) and/or the RP2D. Cohorts of 3 to 6 subjects will be sequentially enrolled and monitored for DLTs during cycle 1. Eligibility criteria include males, and both pre- and post-menopausal females, age 18 or older, with ER+, HER2- advanced or MBC (pre-menopausal women must be on an LHRH antagonist); prior CDK4/6 and SERD and fulvestrant are permitted; ECOG of 0 or 1. The objectives of the phase 1 are: identification of the DLT, MTD and/or RP2D and assessment of the safety and tolerability and PK of OP-1250. Objectives of the phase 2 are to assess the objective response rate (ORR) of OP-1250 in 1) subjects with HR+, HER2- MBC who have progressed on endocrine therapy and have no evidence of central nervous system (CNS) metastases, 2) in patients with non-measurable disease, and 3) in patients with CNS disease. Correlative analyses include ER, PR, Ki67 in tumor biopsies and ctDNA pre- and post-therapy for activating mutations in ESR1. Summary: OP-1250, a complete estrogen receptor antagonist (CERAN), is currently being evaluated in a phase 1/2 study in ER+, HER2- MBC. For more information, please contact clinical@olema.com (NCT04505826) Citation Format: Carlos Alemany, Manish Patel, Zahi Mitri, Joseph Sparano, Virginia Borges, Della Makower, Pam Klein, Julia Lawrence, Trinh Le, Jo Anne Zujewski, Erika Harmilton. A phase 1/2 dose escalation and expansion study of OP-1250 in adults with advanced and/or metastatic hormone receptor-positive (HR+), HER2-negative (HER2−) breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P037.