SPIRE - combining SGI-110 with cisplatin and gemcitabine chemotherapy for solid malignancies including bladder cancer: study protocol for a phase Ib/randomised IIa open label clinical trial.

BACKGROUND: Urothelial bladder cancer (UBC) accounts for 10,000 new diagnoses and 5000 deaths annually in the UK (Cancer Research UK, http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer , Cancer Research UK, Accessed 26 Mar 2018). Cisplatin-based chemotherapy is standard of care therapy for UBC for both palliative first-line treatment of advanced/metastatic disease and radical neoadjuvant treatment of localised muscle invasive bladder cancer. However, cisplatin resistance remains a critical cause of treatment failure and a barrier to therapeutic advance in UBC. Based on supportive pre-clinical data, we hypothesised that DNA methyltransferase inhibition would circumvent cisplatin resistance in UBC and potentially other cancers. METHODS: The addition of SGI-110 (guadecitabine, a DNA methyltransferase inhibitor) to conventional doublet therapy of gemcitabine and cisplatin (GC) is being tested within the phase Ib/IIa SPIRE clinical trial. SPIRE incorporates an initial, modified rolling six-dose escalation phase Ib design of up to 36 patients with advanced solid tumours followed by a 20-patient open-label randomised controlled dose expansion phase IIa component as neoadjuvant treatment for UBC. Patients are being recruited from UK secondary care sites. The dose escalation phase will determine a recommended phase II dose (RP2D, primary endpoint) of SGI-110, by subcutaneous injection, on days 1-5 for combination with GC at conventional doses (cisplatin 70 mg/m2, IV infusion, day 8; gemcitabine 1000 mg/m2, IV infusion, days 8 and 15) in every 21-day cycle. In the dose expansion phase, patients will be randomised 1:1 to GC with or without SGI-110 at the proposed RP2D. Secondary endpoints will include toxicity profiles, SGI-110 pharmacokinetics and pharmacodynamic biomarkers, and pathological complete response rates in the dose expansion phase. Analyses will not be powered for formal statistical comparisons and descriptive statistics will be used to describe rates of toxicity, efficacy and translational endpoints by treatment arm. DISCUSSION: SPIRE will provide evidence for whether SGI-110 in combination with GC chemotherapy is safe and biologically effective prior to future phase II/III trials as a neoadjuvant therapy for UBC and potentially in other cancers treated with GC. TRIAL REGISTRATION: EudraCT Number: 2015-004062-29 (entered Dec 7, 2015) ISRCTN registry number: 16332228 (registered on Feb 3, 2016).

Teaching staff to respond effectively to cognitively impaired residents who display self-protective behaviors.

A randomized controlled trial (RCT) was implemented to evaluate the effectiveness of a 7 1/2 hour educational program designed to provide staff with the knowledge, skill, and confidence to manage physical self-protective behaviors of cognitively impaired long-term care residents. This RCT using a pretest/post-test design was conducted using consenting staff members (n = 40) who were randomly allocated to either a control or experimental group. The main outcome measure was a skills lab that evaluated participants 'responses to simulated patients. Both groups participated in the skills lab prior to training, and six weeks after the experimental group completed the program. Pre- and post-training and skills lab observational field notes were subjected to thematic content analysis. Twenty-eight staff members completed both pre- and post-training assessment measurements. Descriptive statistics and paired t-test analyses yielded statistically significant differences in change scores for performance indicators in three simulation scenarios. Analysis of the qualitative data support the finding that, once trained, staff felt better prepared to manage self-protective behaviors. The results suggest that an initiative to educate staff will enhance knowledge, improve performance, and provide the confidence necessary for staff to respond positively to overt physical behaviors in cognitively impaired elders.

Cementation for femoral head osteonecrosis: a preliminary clinic study.

Treatment for femoral head osteonecrosis has been less successful in late stages of the disease, after progression to collapse. The current authors treated 21 patients (22 hips) with Stage III osteonecrosis by a technique of open reduction and fixation with methylmethacrylate cement (cementation). The followup ranged from 1 to 3 years (average, 1.7 years). Patient progress was followed using preoperative and postoperative Harris hip scores, Western Ontario and McMaster Universities Osteoarthritis Index, and a health status questionnaire (Short Form-36). Patients were staged preoperatively using the Association Research Circulation Osseous international classification system and radiographic evaluation was done intraoperatively and postoperatively. The Harris hip score, Western Ontario and McMaster Universities Osteoarthritis Index, and Short Form-36 physical health scores improved significantly from 53.5 to 78.0, 66.0 to 48.1, and 27.0 to 40.0, respectively. The outcome was worse for patients with more advanced disease. Six patients, all with severe disease, had total hip arthroplasty. Cementation is technically simple, enables patients' immediate postoperative pain relief and improvement in mobility, and has the potential to restore and maintain the sphericity of the femoral head after collapse. The high failure rate (27%) at short-term followup, although comparable with other reported techniques, does not support generalized use for Stage III disease. Currently the use of this procedure is restricted to symptomatic, young patients (younger than 40 years), preferably with mild to moderate Stage III disease (degree of head involvement < 30% and degree of collapse < 4 mm).