An evidence based approach towards optimising the management of patients with squamous cell carcinoma of the skin

Cutaneous squamous cell carcinoma (SCC) is a common cancer yet its treatment is under-researched. The objective of this thesis was to develop a proposal for a randomised controlled trial (RCT) to address uncertainties relating to the management of the condition, and to ultimately improve the management of affected patients. Two systematic reviews were initially conducted to appraise the current evidence base for SCC treatments. Only one RCT was eligible for inclusion in the Cochrane systematic review; a small study which found no significant difference in time to recurrence between patients treated with post-operative 13-cis retinoic acid and interferon, and those not receiving adjuvant treatment. Systematic review and meta-analysis of observational studies included 118 studies. Pooled estimates of recurrence were lowest after cryotherapy and curettage and electrodesiccation, although lesions treated by these modalities were mostly small and low-risk. Although pooled recurrence after Mohs surgery appeared lower than after conventional excision or radiotherapy, the differences were not significant with overlapping 95% confidence intervals. For photodynamic therapy, pooled recurrence after apparently successful initial treatment was particularly high (26%). Evidence relating to the effectiveness of topical and systemic treatments was very limited. Estimates of recurrence were used to inform the sample size calculation for the proposed RCT. A survey of healthcare professionals was conducted to establish research priorities and identify clinically important management uncertainties from which initial trial scenarios were formulated. High-risk SCCs were identified as a research priority, with optimal surgical management and the role of adjuvant radiotherapy being key areas of uncertainty. Through multi-disciplinary collaboration, a proposal for a two-stage RCT has been developed; in the first stage, locoregional recurrence after conventional surgery with a controlled excision margin will be compared with Mohs surgery, and in the second stage locoregional recurrence will be compared between patients treated with adjuvant radiotherapy versus those receiving no adjuvant treatment. Feasibility work conducted during the development of the trial has involved: a) A retrospective analysis of SCCs treated over twelve-months to determine the number of patients and types of SCCs potentially eligible for recruitment into the proposed trial and to further inform the sample size calculation. Within five years of treatment 6% of 357 patients experienced local recurrence, 3% had regional recurrence and 1.5% died of their SCC. Comparison of the most recent American Joint Cancer Council (AJCC7) and an alternative Brigham and Women’s Hospital (BWH) classification showed that approximately 50% of SCCs were T2 in both schemes and eligible for entry into the first stage of the proposed trial. However, an additional BHW T2b substage better stratified outcomes dependent on the number of risk features, and indicated that 19% of all SCCs would potentially be also eligible for the second stage of the trial. b) A questionnaire and focus group study to assess the acceptability of the RCT and to identify possible barriers to recruitment. Participants had a desire to be better informed about SCC, wanting information relating to the trial to be provided in a variety of formats. 71% of participants were hypothetically willing to be randomised into the surgical stage of the proposed trial but had more concerns about the second stage involving adjuvant radiotherapy. Lack of equipoise and confusion about the concept of randomisation will need to be carefully addressed when presenting the trial to participants. The proposed trial will be the first to directly compare treatments for the types of SCC seen commonly in clinical practice. For the trial to be adequately powered, an estimated 5400 participants will need to be recruited, so a multi-centre, multi-disciplinary approach will be necessary

An evidence based approach towards optimising the management of patients with squamous cell carcinoma of the skin

Cutaneous squamous cell carcinoma (SCC) is a common cancer yet its treatment is under-researched. The objective of this thesis was to develop a proposal for a randomised controlled trial (RCT) to address uncertainties relating to the management of the condition, and to ultimately improve the management of affected patients. Two systematic reviews were initially conducted to appraise the current evidence base for SCC treatments. Only one RCT was eligible for inclusion in the Cochrane systematic review; a small study which found no significant difference in time to recurrence between patients treated with post-operative 13-cis retinoic acid and interferon, and those not receiving adjuvant treatment. Systematic review and meta-analysis of observational studies included 118 studies. Pooled estimates of recurrence were lowest after cryotherapy and curettage and electrodesiccation, although lesions treated by these modalities were mostly small and low-risk. Although pooled recurrence after Mohs surgery appeared lower than after conventional excision or radiotherapy, the differences were not significant with overlapping 95% confidence intervals. For photodynamic therapy, pooled recurrence after apparently successful initial treatment was particularly high (26%). Evidence relating to the effectiveness of topical and systemic treatments was very limited. Estimates of recurrence were used to inform the sample size calculation for the proposed RCT. A survey of healthcare professionals was conducted to establish research priorities and identify clinically important management uncertainties from which initial trial scenarios were formulated. High-risk SCCs were identified as a research priority, with optimal surgical management and the role of adjuvant radiotherapy being key areas of uncertainty. Through multi-disciplinary collaboration, a proposal for a two-stage RCT has been developed; in the first stage, locoregional recurrence after conventional surgery with a controlled excision margin will be compared with Mohs surgery, and in the second stage locoregional recurrence will be compared between patients treated with adjuvant radiotherapy versus those receiving no adjuvant treatment. Feasibility work conducted during the development of the trial has involved: a) A retrospective analysis of SCCs treated over twelve-months to determine the number of patients and types of SCCs potentially eligible for recruitment into the proposed trial and to further inform the sample size calculation. Within five years of treatment 6% of 357 patients experienced local recurrence, 3% had regional recurrence and 1.5% died of their SCC. Comparison of the most recent American Joint Cancer Council (AJCC7) and an alternative Brigham and Women’s Hospital (BWH) classification showed that approximately 50% of SCCs were T2 in both schemes and eligible for entry into the first stage of the proposed trial. However, an additional BHW T2b substage better stratified outcomes dependent on the number of risk features, and indicated that 19% of all SCCs would potentially be also eligible for the second stage of the trial. b) A questionnaire and focus group study to assess the acceptability of the RCT and to identify possible barriers to recruitment. Participants had a desire to be better informed about SCC, wanting information relating to the trial to be provided in a variety of formats. 71% of participants were hypothetically willing to be randomised into the surgical stage of the proposed trial but had more concerns about the second stage involving adjuvant radiotherapy. Lack of equipoise and confusion about the concept of randomisation will need to be carefully addressed when presenting the trial to participants. The proposed trial will be the first to directly compare treatments for the types of SCC seen commonly in clinical practice. For the trial to be adequately powered, an estimated 5400 participants will need to be recruited, so a multi-centre, multi-disciplinary approach will be necessary

Systematic review of respiratory viral pathogens identified in adults with community-acquired pneumonia in Europe

Community-acquired pneumonia (CAP) is an important respiratory disease and the fifth leading cause of mortality in Europe. The development of molecular diagnostic tests has highlighted the contributions of respiratory viruses to the aetiology of CAP, suggesting the incidence of viral pneumonia may have been previously underestimated. We performed a systematic review and meta analysis to describe the overall identification of respiratory viruses in adult patients with CAP in Europe, following PRISMA guidelines (PROSPERO; CRD42016037233). We searched EMBASE, MEDLINE, CINAHL, WHOLIS, COCHRANE library and grey literature sources for relevant studies, and screened these against protocol eligibility criteria. Two researchers performed data extraction and risk of bias assessments, independently, using a piloted form. Results were synthesised narratively, and random effects meta-analyses performed to calculate pooled estimates of effect; heterogeneity was quantified using I2.Twenty-eight studies met inclusion criteria of which 21 were included in the primary meta-analysis. The pooled proportion of patients with identified respiratory viruses was 22.0% (95% CI: 18.0%-27.0%), rising to 29.0% (25.0%–34.0%) in studies where polymerase chain reaction (PCR) diagnostics were performed. Influenza virus was the most frequently detected virus in 9% (7%-12%) of adults with CAP. Respiratory viruses make a substantial contribution to the aetiology of CAP in adult patients in Europe; one or more respiratory viruses are detected in about one quarter of all cases

Corticosteroids as Adjunctive Therapy in the Treatment of Influenza: An Updated Cochrane Systematic Review and Meta-analysis

Objective: Corticosteroids may be beneficial in sepsis but uncertainty remains over their effects in severe influenza. This systematic review updates the current evidence regarding corticosteroids in the treatment of influenza and examines the effect of dose on outcome.Data Sources: Electronic databases (MEDLINE, EMBASE, CINAHL, LILACS, CENTRAL, Web of Science) and trial registries were searched to October 2018 for randomised controlled trials (RCTs), quasi-experimental designs and observational cohort studies reporting corticosteroid versus no corticosteroid treatment in individuals with influenza. Study Selection and Data Extraction:Two researchers independently assessed studies for inclusion. Risk of bias was assessed using the Cochrane Risk of Bias tool (RCTs) or Newcastle-Ottawa Scale (observational studies). Where appropriate, we estimated the effect of corticosteroids by random effects meta-analyses using the generic inverse variance method. Meta‐regression analysis was used to assess the association of corticosteroid dose and mortality. Data Synthesis: We identified 30 eligible studies, all observational apart from one RCT. Twenty-one observational studies were included in the meta-analysis of mortality, which suggested an adverse association with corticosteroid therapy (Odds ratio (OR) 3.90, 95% confidence interval (CI) 2.31 to 6.60, 15 studies; adjusted hazard ratio 1.49, 95% CI 1.09 to 2.02, 6 studies). Risk of bias assessment was consistent with potential confounding by indication. Pooled analysis of seven studies showed increased odds of hospital-acquired infection in people treated with corticosteroids (unadjusted OR 2.74, 95% CI 1.51 to 4.95). Meta-regression of the effect of dose on mortality did not reveal an association, but reported doses of corticosteroids in included studies were high (mostly >40 mg methylprednisolone (or equivalent) per day).Conclusions:Corticosteroid treatment in influenza is associated with increased mortality and hospital-acquired infection, but the evidence relates mainly to high corticosteroid doses and is of low quality with potential confounding by indication a major concern.

Effectiveness of 2009 pandemic influenza A(H1N1) vaccines: a systematic review and meta-analysis

Background: The clinical effectiveness of monovalent influenza A(H1N1)pdm09 vaccines has not been comprehensively summarised. We undertook a systematic review and meta-analysis to assess vaccine effectiveness (VE) for adjuvanted and unadjuvanted vaccines. Methods: We searched healthcare databases and grey literature from 11 June 2009 to 12 November 2014. Two researchers independently assessed titles and abstracts to identify studies for full review. Random effects meta-analyses estimated the pooled effect size of vaccination compared to placebo or no vaccination for crude and adjusted odds ratios (OR) to prevent laboratory confirmed influenza illness (LCI) and related hospitalization. VE was calculated as (1-pooled OR) ∗ 100. Narrative synthesis was undertaken where meta-analysis was not possible. Results: We identified 9229 studies of which 38 at moderate risk of bias met protocol eligibility criteria; 23 were suitable for meta-analysis. Pooled adjusted VE against LCI with adjuvanted and unadjuvanted vaccines both reached statistical significance (adjuvanted: VE = 80%; 95% confidence interval [CI] 59–90%; unadjuvanted: VE = 66%; 95% CI 47–78%); in planned secondary analyses, VE in adults often failed to reach statistical significance and pooled point estimates were lower than observed in children. Overall pooled adjusted VE against hospitalization was 61% (95% CI 14–82%); in planned secondary analyses, adjusted VE attained statistical significance in adults aged 18–64 years and children for adjuvanted vaccines. Adjuvanted vaccines were significantly more effective in children compared to adults for both outcomes. Conclusions: Adjuvanted and unadjuvanted monovalent influenza A(H1N1)pdm09 vaccines were both effective in preventing LCI. Overall, the vaccines were also effective against influenza-related hospitalization. For both outcomes adjuvanted vaccines were more effective in children than in adults

Design and Fabrication of RESURF MOSFETs on 4H-SiC(0001), (1120), and 6H-SiC(0001)

Background: Skin diseases are very common and can have a large impact on the quality of life of patients and caregivers. This programme addressed four diseases: (1) eczema, (2) vitiligo, (3) squamous cell skin cancer (SCC) and (4) pyoderma gangrenosum (PG). Objective: To set priorities and reduce uncertainties for the treatment and prevention of skin disease in our four chosen diseases. Design: Mixed methods including eight systematic reviews, three prioritisation exercises, two pilot randomised controlled trials (RCTs), three feasibility studies, two core outcome initiatives, four funding proposals for national RCTs and one completed national RCT. Setting: Secondary care, primary care and the general population. Participants: Patients (and their caregivers) with eczema, vitiligo, SCC and PG, plus health-care professionals with an interest in skin disease. Interventions: Our three intervention studies included (1) barrier enhancement using emollients from birth to prevent eczema (pilot RCT); (2) handheld narrowband ultraviolet light B therapy for treating vitiligo (pilot RCT); and (3) oral ciclosporin (Neoral®, Novartis Pharmaceuticals) compared with oral prednisolone for managing PG (pragmatic national RCT). Results: Systematic reviews included two overarching systematic reviews of RCTs of treatments for eczema and vitiligo, an umbrella review of systematic reviews of interventions for the prevention of eczema, two reviews of treatments for SCC (one included RCTs and the second included observational studies), and three reviews of outcome measures and outcome reporting. Three prioritisation partnership exercises identified 26 priority areas for future research in eczema, vitiligo and SCC. Two international consensus initiatives identified four core domains for future eczema trials and seven core domains for vitiligo trials. Two pilot RCTs and three feasibility studies critically informed development of four trial proposals for external funding, three of which are now funded and one is pending consideration by funders. Our pragmatic RCT tested the two commonly used systemic treatments for PG (prednisolone vs. ciclosporin) and found no difference in their clinical effectiveness or cost-effectiveness. Both drugs showed limited benefit. Only half of the participants’ ulcers had healed by 6 months. For those with healed ulcers, recurrence was common (30%). Different side effect profiles were noted for each drug, which can inform clinical decisions on an individual patient basis. Three researchers were trained to PhD level and a dermatology patient panel was established to ensure patient involvement in all aspects of the programme. Conclusions: Findings from this programme of work have already informed clinical guidelines and patient information resources. Feasibility studies have ensured that large national pragmatic trials will now be conducted on important areas of treatment uncertainty that address the needs of patients and the NHS. There is scope for considerable improvement in terms of trial design, conduct and reporting for RCTs of skin disease, which can be improved through wider collaboration, registration of trial protocols and complete reporting and international consensus over core outcome sets. Three national trials have now been funded as a result of this work. Two international initiatives to establish how best to measure the core outcome domains for eczema and vitiligo are ongoing