Randomised Trial of No, Short-term, or Long-term Androgen Deprivation Therapy with Postoperative Radiotherapy After Radical Prostatectomy: Results from the Three-way Comparison of RADICALS-HD (NCT00541047).

Background And Objective: The use and duration of androgen deprivation therapy (ADT) with postoperative radiotherapy (RT) have been uncertain. RADICALS-HD compared adding no ("None"), 6-months ("Short"), or 24-mo ("Long") ADT to study efficacy in the long term.

Methods: Participants with prostate cancer were indicated for postoperative RT and agreed randomisation between all durations.

Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol.

Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival.

Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland.

Clinical testing of transcriptome-wide expression profiles in high-risk localized and metastatic prostate cancer starting androgen deprivation therapy: an ancillary study of the STAMPEDE abiraterone Phase 3 trial.

Metastatic and high-risk localized prostate cancer respond to hormone therapy but outcomes vary. Following a pre-specified statistical plan, we used Cox models adjusted for clinical variables to test associations with survival of multi-gene expression-based classifiers from 781 patients randomized to androgen deprivation with or without abiraterone in the STAMPEDE trial. Decipher score was strongly prognostic (p<2×10) and identified clinically-relevant differences in absolute benefit, especially for localized cancers.

Docetaxel for Nonmetastatic Prostate Cancer: Long-Term Survival Outcomes in the STAMPEDE Randomized Controlled Trial.

Background: STAMPEDE previously reported adding upfront docetaxel improved overall survival for prostate cancer patients starting long-term androgen deprivation therapy. We report long-term results for non-metastatic patients using, as primary outcome, metastatic progression-free survival (mPFS), an externally demonstrated surrogate for overall survival.

Methods: Standard of care (SOC) was androgen deprivation therapy with or without radical prostate radiotherapy.

Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial.

Background: STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL).

Methods And Findings: Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT.

Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol.

Background: Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population.

Methods: These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland.

Successful Psychological Strategies of Experienced Chronic Fatigue Patients: A Qualitative Study.

Trying to care for patients with medically unexplained symptoms (MUS) can lead to frustration and disappointment for both patients and health care professionals alike. Learning positive ways to assist patients avoids professionals collapsing into therapeutic nihilism. We sought to understand how people with such symptoms can live well despite (or even because of) their condition.

Association of Bone Metastatic Burden With Survival Benefit From Prostate Radiotherapy in Patients With Newly Diagnosed Metastatic Prostate Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Prostate radiotherapy (RT) improves survival in men with low-burden metastatic prostate cancer. However, owing to the dichotomized nature of metastatic burden criteria, it is not clear how this benefit varies with bone metastasis counts and metastatic site.

Objective: To evaluate the association of bone metastasis count and location with survival benefit from prostate RT.

'There is no sick leave at the university': how sick leave constructs the good employee.

This paper examines the role of sick leave in constructing the identity of a good worker. The setting is a public funded New Zealand university. Within a qualitative research design, interviews were conducted with a range of employees and managers about their use and management of sick leave.

The Automated Bone Scan Index as a Predictor of Response to Prostate Radiotherapy in Men with Newly Diagnosed Metastatic Prostate Cancer: An Exploratory Analysis of STAMPEDE's "M1|RT Comparison".

Background: Prostate radiotherapy (RT) is a first-line option for newly diagnosed men with low-burden metastatic prostate cancer. The current criterion to define this clinical state is based on manual bone metastasis counts, but enumeration of bone metastases is limited by interobserver variations, and it does not account for metastasis volume or lesional coalescence. The automated bone scan index (aBSI) is a quantitative method of evaluating bone metastatic burden in a standardised and reproducible manner.

This is a platform alteration: a trial management perspective on the operational aspects of adaptive and platform and umbrella protocols.

Background: There are limited research and literature on the trial management challenges encountered in running adaptive platform trials. This trial design allows both (1) the seamless addition of new research comparisons when compelling clinical and scientific research questions emerge, and (2) early stopping of accrual to individual comparisons that do not show sufficient activity without affecting other active comparisons. Adaptive platform design trials also offer many potential benefits over traditional trials, from faster time to accrual to contemporaneously recruiting multiple research comparisons, added flexibility to focus on more promising research comparisons via pre-planned interim analyses and potentially shorter time to primary results.

Mind the gap? The platform trial as a working environment.

Background: Trials have become bigger and more complicated due to the complexity introduced by biomarker stratification, and the advent of multi-arm multi-stage trials, and umbrella and basket platform designs. The trials unit at University College London has been at the forefront of this work, with ground-breaking trials such as STAMPEDE and FOCUS4. The trial management and data management teams on these trials have summarised the operational challenges, to enable the broader clinical trials community to learn from their experiences.

Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.

Background: Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy.

Methods: We did a randomised controlled phase 3 trial at 117 hospitals in Switzerland and the UK.

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy.

Background: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design.

Methods: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy).

SWIM (sickle with ibuprofen and morphine) randomised controlled trial fails to recruit: lessons learnt.

Objectives: Sickle With Ibuprofen and Morphine (SWIM) trial was designed to assess whether co-administration of ibuprofen (a non-steroidal anti-inflammatory drug) resulted in a reduction of opioid consumption delivered by patient-controlled analgesia (PCA) for acute pain in sickle cell disease.

Design: A randomised, placebo-controlled, double-blind trial.

Setting: UK multicentre trial in acute hospital setting.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.

Background: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy.

Flexible trial design in practice - stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial.

Background: Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) is a randomized controlled trial that follows a novel multi-arm, multi-stage (MAMS) design. We describe methodological and practical issues arising with (1) stopping recruitment to research arms following a pre-planned intermediate analysis and (2) adding a new research arm during the trial.

Methods: STAMPEDE recruits men who have locally advanced or metastatic prostate cancer who are starting standard long-term hormone therapy.

Intracellular domain of brain endothelial intercellular adhesion molecule-1 is essential for T lymphocyte-mediated signaling and migration.

To examine the role of the ICAM-1 C-terminal domain in transendothelial T lymphocyte migration and ICAM-1-mediated signal transduction, mutant human (h)ICAM-1 molecules were expressed in rat brain microvascular endothelial cells. The expression of wild-type hICAM-1 resulted in a significant increase over basal levels in both adhesion and transendothelial migration of T lymphocytes. Endothelial cells (EC) expressing ICAM-1 in which the tyrosine residue at codon 512 was substituted with phenylalanine (hICAM-1(Y512F)) also exhibited increased lymphocyte migration, albeit less than that with wild-type hICAM-1.

Ezrin and moesin co-localise with ICAM-1 in brain endothelial cells but are not directly associated.

The precise mechanism by which ICAM-1 transduces signals from adherent lymphocytes remains elusive. The ERM proteins ezrin and moesin were found to strongly co-localise with both ICAM-1 and F-actin in brain microvascular endothelial cells suggesting a potential role in mediating ICAM-1 signalling. Such strong co-localisation was maintained following treatment of cells with cytochalasin D, which inhibits actin polymerization and which is capable of inhibiting ICAM-1-induced signalling.