Neutrophil function in patients with cystic fibrosis and chronic pulmonary infection.

The thesis investigates reasons for a failure of neutrophils to clear pulmonary bacterial infection in cystic fibrosis (CF). Patients with CF experience bacterial colonization of the lungs associated with progressive lung injury and poor prognosis. Neutrophil responsiveness in vitro was determined in patients with CF at different clinical states, and compared to healthy subjects. Neutrophils from the patients were able to phagocytose and kill Pseudomonas aeruginosa effectively, but the presence of sputum sol reduced intracellular killing. Superoxide generation and elastase release in response to fMLP were shown to be reduced in neutrophils from patients with an exacerbation of respiratory symptoms. This was not observed when the cells were stimulated with PMA, which acts intracellularly, rather than through cell surface receptors. There was no difference in the down-regulation of cell surface L-selectin and up-regulation of CD11b in response to fMLP suggesting no alteration in number or function of the fMLP receptors. There was increased adherence to nylon columns by neutrophils from patients with CF. Infection resulted in a greater proportion of band neutrophils, and this correlated with the reduced superoxide generation and elastase release, although it was not possible to separate the band forms to prove this conclusively. Alterations in circulating lipid and fatty acid composition inpatients could potentially affect neutrophil membrane composition and fluidity and therefore signal processing or release of products. The reason for the observed reduced responsiveness appears to be multifactorial. Band cell number post receptor signalling and/or receptor desensitization may result in the observed reduced responsiveness, which returns towards healthy subject levels after treatment of an exacerbation, is likely to be the result of chronic infection

Prospective review of radiotherapy trials through implementation of standardised multi-centre workflow and IT infrastructure

Objective: We sought to develop a process that would allow us to perform a prospective review of outlining in trials using expert reviewers based in multiple centres. Methods: We implemented a specific information technology infrastructure and workflow that could serve all organizations involved in the radiotherapy quality assurance (RTQA) process. Results: Data were processed and packaged in the computational environment for radiotherapy research (CERR) binary format and securely transmitted to the expert reviewer at the designated remote organization. It was opened and reviewed using the distributed CERR-compiled application, and a standardized report was sent to the respective centre. Centres were expected to correct any unacceptable deviations and resubmit outlining for approval prior to commencing treatment. 75% of reviews were completed and fed back to centres within 3 working days. There were no delays in treatment start date. Conclusion: Our distributed RTQA review approach provides a method of prospective outlining review at multiple centres, without compromising the quality, delaying the start of treatment or the need for significant additional infrastructure resources. Future progress in the area of prospective individual case review will need to be supported by additional resources for clinician time to undertake the reviews. Advances in knowledge: Trial groups around the world have formulated different approaches to address the need for the prospective review of radiotherapy (RT) data with clinical trials, in line with available resources. We report a UK solution that has allowed the workload for outlining review to be distributed across a wider group of volunteer reviewers without the need for any additional infrastructure costs and has already been adopted within the UK RT trials community

Comparison of investigator-delineated gross tumour volumes and quality assurance in pancreatic cancer: analysis of the on-trial cases for the SCALOP trial

Background and purpose We performed a retrospective central review of tumour outlines in patients undergoing radiotherapy in the SCALOP trial. Materials and methods The planning CT scans were reviewed retrospectively by a central review team, and the accuracy of investigators’ GTV (iGTV) and PTV (iPTV) was compared to the trials team-defined gold standard (gsGTV and gsPTV) using the Jaccard Conformity Index (JCI) and Geographical Miss Index (GMI). The prognostic value of JCI and GMI was also assessed. The RT plans were also reviewed against protocol-defined constraints. Results 60 patients with diagnostic-quality planning scans were included. The median whole volume JCI for GTV was 0.64 (IQR: 0.43–0.82), and the median GMI was 0.11 (IQR: 0.05–0.22). For PTVs, the median JCI and GMI were 0.80 (IQR: 0.71–0.88) and 0.04 (IQR: 0.02–0.12) respectively. Tumour was completely missed in 1 patient, and ⩾ 50% of the tumour was missed in 3. Patients with JCI for GTV ⩾ 0.7 had 7.12 (95% CIs: 1.83–27.67, p = 0.005) higher odds of progressing by 9 months in multivariate analysis. Major deviations in RT planning were noted in 4.5% of cases. Conclusions Radiotherapy workshops and real-time central review of contours are required in RT trials of pancreatic cancer

Developing a pressure ulcer risk factor minimum data set and risk assessment framework

AIM: To agree a draft pressure ulcer risk factor Minimum Data Set to underpin the development of a new evidenced-based Risk Assessment Framework.BACKGROUND: A recent systematic review identified the need for a pressure ulcer risk factor Minimum Data Set and development and validation of an evidenced-based pressure ulcer Risk Assessment Framework. This was undertaken through the Pressure UlceR Programme Of reSEarch (RP-PG-0407-10056), funded by the National Institute for Health Research and incorporates five phases. This article reports phase two, a consensus study.DESIGN: Consensus study.METHOD: A modified nominal group technique based on the Research and Development/University of California at Los Angeles appropriateness method. This incorporated an expert group, review of the evidence and the views of a Patient and Public Involvement service user group. Data were collected December 2010-December 2011.FINDINGS: The risk factors and assessment items of the Minimum Data Set (including immobility, pressure ulcer and skin status, perfusion, diabetes, skin moisture, sensory perception and nutrition) were agreed. In addition, a draft Risk Assessment Framework incorporating all Minimum Data Set items was developed, comprising a two stage assessment process (screening and detailed full assessment) and decision pathways.CONCLUSION: The draft Risk Assessment Framework will undergo further design and pre-testing with clinical nurses to assess and improve its usability. It will then be evaluated in clinical practice to assess its validity and reliability. The Minimum Data Set could be used in future for large scale risk factor studies informing refinement of the Risk Assessment Framework

SCOPE1: a randomised phase II/III multicentre clinical trial of definitive chemoradiation, with or without cetuximab, in carcinoma of the oesophagus

<p>Abstract</p> <p>Background</p> <p>Chemoradiotherapy is the standard of care for patients with oesophageal cancer unsuitable for surgery due to the presence of co-morbidity or extent of disease, and is a standard treatment option for patients with squamous cell carcinoma of the oesophagus. Modern regimens of chemoradiotherapy can lead to significant long-term survival. However the majority of patients will die of their disease, most commonly with local progression/recurrence of their tumours. Cetuximab may overcome one of the principal mechanisms of tumour radio-resistance, namely tumour repopulation, in patients treated with chemoradiotherapy.</p> <p>The purpose of this research is first to determine whether the addition of cetuximab to definitive chemoradiotherapy for treatment of patients with non-metastatic carcinoma of the oesophagus is active (in terms of failure-free rate), safe, and feasible within the context of a multi-centre randomised controlled trial in the UK. If the first stage is successful then the trial will continue to accrue sufficient patients to establish whether the addition of cetuximab to the standard treatment improves overall survival.</p> <p>Methods/Design</p> <p>SCOPE1 is a two arm, open, randomised multicentre Phase II/III trial. Eligible patients will have histologically confirmed carcinoma of the oesophagus and have been chosen to receive definitive chemoradiotherapy by an accredited multidisciplinary team including a specialist Upper GI surgeon. 420 patients will be randomised to receive definitive chemoradiotherapy with or without cetuximab using a 1:1 allocation ratio.</p> <p>During Phase II of the study, the trial will assess safety (toxicity), activity (failure-free rate) and feasibility (recruitment rate and protocol dose modifications/delays) in 90 patients in the experimental arm. If the experimental arm is found to be active, safe, and feasible by the Independent Data Monitoring Committee then recruitment will continue into Phase III. This second stage will recruit a further 120 patients into each arm and compare the overall survival of both groups.</p> <p>All patients randomised into Phase II will contribute to the Phase III comparison of overall survival. In addition to overall survival, Phase III of the study will also assess toxicity, health related quality of life and cost effectiveness. A detailed radiotherapy protocol and quality assurance procedure has been incorporated into this trial.</p> <p>Trial registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN47718479">ISRCTN47718479</a></p

Palliative radiotherapy after oesophageal cancer stenting (ROCS): a multicentre, open-label, phase 3 randomised controlled trial

Background: patients with advanced oesophageal cancer have a median survival of 3-6 months, and most require intervention for dysphagia. Self-expanding metal stent (SEMS) insertion is the most typical form of palliation in these patients, but dysphagia deterioration and re-intervention are common. This study examined the efficacy of adjuvant external beam radiotherapy (EBRT) compared with usual care alone in preventing dysphagia deterioration and reducing service use after SEMS insertion.Methods: this was a multicentre, open-label, phase 3 randomised controlled trial based at cancer centres and acute care hospitals in England, Scotland, and Wales. Patients (aged ≥16 years) with incurable oesophageal carcinoma receiving stent insertion for primary management of dysphagia were randomly assigned (1:1) to receive usual care alone or EBRT (20 Gy in five fractions or 30 Gy in ten fractions) plus usual care after stent insertion. Usual care was implemented according to need as identified by the local multidisciplinary team (MDT). Randomisation was via the method of minimisation stratified by treating centre, stage at diagnosis (I-III vs IV), histology (squamous or non-squamous), and MDT intent to give chemotherapy (yes vs no). The primary outcome was difference in proportions of participants with dysphagia deterioration (&gt;11 point decrease on patient-reported European Organisation for Research and Treatment of Cancer quality of life questionnaire-oesophagogastric module [QLQ-OG25], or a dysphagia-related event consistent with such a deterioration) or death by 12 weeks in a modified intention-to-treat (ITT) population, which excluded patients who did not have a stent inserted and those without a baseline QLQ-OG25 assessment. Secondary outcomes included survival, quality of life (QoL), morbidities (including time to first bleeding event or hospital admission for bleeding event and first dysphagia-related stent complications or re-intervention), and cost-effectiveness. Safety analysis was undertaken in the modified ITT population. The study is registered with the International Standard Randomised Controlled Trial registry, ISRCTN12376468, and ClinicalTrials.gov, NCT01915693, and is completed.Findings: 220 patients were randomly assigned between Dec 16, 2013, and Aug 24, 2018, from 23 UK centres. The modified ITT population (n=199) comprised 102 patients in the usual care group and 97 patients in the EBRT group. Radiotherapy did not reduce dysphagia deterioration, which was reported in 36 (49%) of 74 patients receiving usual care versus 34 (45%) of 75 receiving EBRT (adjusted odds ratio 0·82 [95% CI 0·40-1·68], p=0·59) in those with complete data for the primary endpoint. No significant difference was observed in overall survival: median overall survival was 19·7 weeks (95% CI 14·4-27·7) with usual care and 18·9 weeks (14·7-25·6) with EBRT (adjusted hazard ratio 1·06 [95% CI 0·78-1·45], p=0·70; n=199). Median time to first bleeding event or hospital admission for a bleeding event was 49·0 weeks (95% CI 33·3-not reached) with EBRT versus 65·9 weeks (52·7-not reached) with usual care (adjusted subhazard ratio 0·52 [95% CI 0·28-0·97], p=0·038; n=199). No time versus treatment interaction was observed for prespecified QoL outcomes. We found no evidence of differences between trial group in time to first stent complication or re-intervention event. The most common (grade 3-4) adverse event was fatigue, reported in 19 (19%) of 102 patients receiving usual care alone and 22 (23%) of 97 receiving EBRT. On cost-utility analysis, EBRT was more expensive and less efficacious than usual care.Interpretation: patients with advanced oesophageal cancer having SEMS insertion for the primary management of their dysphagia did not gain additional benefit from concurrent palliative radiotherapy and it should not be routinely offered. For a minority of patients clinically considered to be at high risk of tumour bleeding, concurrent palliative radiotherapy might reduce bleeding risk and the need for associated interventions.Funding: National Institute for Health Research Health Technology Assessment Programme.</p

Efficacy of early PET-CT directed switch to carboplatin and paclitaxel based definitive chemoradiotherapy in patients with oesophageal cancer who have a poor early response to induction cisplatin and capecitabine in the UK: a multi-centre randomised controlled phase II trial induction cisplatin and capecitabine in the UK: a multi-centre randomised controlled phase II trial

Background: The utility of early metabolic response assessment to guide selection of the systemic component of definitive chemoradiotherapy (dCRT) for oesophageal cancer is uncertain.// Methods: In this multi-centre, randomised, open-label, phase II substudy of the radiotherapy dose-escalation SCOPE2 trial we evaluated the role of 18F-Fluorodeoxyglucose positron emission tomography (PET) at day 14 of cycle 1 of three-weekly induction cis/cap (cisplatin (60 mg/m2)/capecitabine (625 mg/m2 days 1–21)) in patients with oesophageal squamous cell carcinoma (OSCC) or adenocarcinoma (OAC). Non-responders, who had a less than 35% reduction in maximum standardised uptake value (SUVmax) from pre-treatment baseline, were randomly assigned to continue cis/cap or switch to car/pac (carboplatin AUC 5/paclitaxel 175 mg/m2) for a further induction cycle, then concurrently with radiotherapy over 25 fractions. Responders continued cis/cap for the duration of treatment. All patients (including responders) were randomised to standard (50Gy) or high (60Gy) dose radiation as part of the main study. Primary endpoint for the substudy was treatment failure-free survival (TFFS) at week 24. The trial was registered with International Standard Randomized Controlled Trial Number 97125464 and ClinicalTrials.gov NCT02741856.// Findings: This substudy was closed on 1st August 2021 by the Independent Data Monitoring Committee on the grounds of futility and possible harm. To this point from 22nd November 2016, 103 patients from 16 UK centres had participated in the PET-CT substudy; 63 (61.2%; 52/83 OSCC, 11/20 OAC) of whom were non-responders. Of these, 31 were randomised to car/pac and 32 to remain on cis/cap. All patients were followed up until at least 24 weeks, at which point in OSCC both TFFS (25/27 (92.6%) vs 17/25 (68%); p = 0.028) and overall survival (42.5 vs. 20.4 months, adjusted HR 0.36; p = 0.018) favoured cis/cap over car/pac. There was a trend towards worse survival in OSCC + OAC cis/cap responders (33.6 months; 95%CI 23.1-nr) vs. non-responders (42.5 (95%CI 27.0-nr) months; HR = 1.43; 95%CI 0.67–3.08; p = 0.35).// Interpretation: In OSCC, early metabolic response assessment is not prognostic for TFFS or overall survival and should not be used to personalise systemic therapy in patients receiving dCRT

Searching for Programme theories for a realist evaluation: a case study comparing an academic database search and a simple Google search

Background: Realist methodologies are increasingly being used to evaluate complex interventions in health and social care. Programme theory (ideas and assumptions of how a particular intervention works) development is the first step in a realist evaluation or a realist synthesis, with literature reviews providing important evidence to support this. Deciding how to search for programme theories is challenging and there is limited guidance available. Using an example of identifying programme theories for a realist evaluation of Pressure Ulcer Risk Assessment Instruments in clinical practice, the authors explore and compare several different approaches to literature searching and highlight important methodological considerations for those embarking on a programme theory review. Methods: We compared the performance of an academic database search with a simple Google search and developed an optimised search strategy for the identification primary references (i.e. documents providing the clearest examples of programme theories) associated with the use of Pressure Ulcer Risk Assessment Instruments (PU-RAIs). We identified the number of primary references and the total number of references retrieved per source. We then calculated the number needed to read (NNR) expressed as the total number of titles and abstracts screened to identify one relevant reference from each source. Results: The academic database search (comprising CINAHL, The Cochrane Library, EMBASE, HMIC, Medline) identified 2 /10 primary references with a NNR of 1395.The Google search identified 7/10 primary references with a NNR of 10.1. The combined NNR was 286.3. The optimised search combining Google and CINAHL identified 10/10 primary references with a NNR of 40.2. Conclusion: The striking difference between the efficiency of the review’s academic database and Google searches in finding relevant references prompted an in-depth comparison of the two types of search. The findings indicate the importance of including grey literature sources such as Google in this particular programme theory search, while acknowledging the need for transparency of methods. Further research is needed to facilitate improved guidance for programme theory searches to enhance practice in the realist field and to save researcher time and therefore resource