Feasibility of recruitment to an oral dysplasia trial in the United Kingdom

Background: Oral epithelial dysplasia (OED) has a malignant potential. Therapeutic options for OED remain both limited and without good evidence. Despite surgery being the most common method of treating OED, recurrence and potentially significant morbidity remain problematic. Consequently, there has been much interest in non-surgical treatments for OED. Cyclo-oxygenase (COX) up-regulation is known to occur in the dysplasia-carcinoma sequence and evidence now exists that COX-2 is a prognostic marker of malignant transformation in OED. COX-inhibitors are therefore considered a potential therapeutic strategy for treating this condition. We aimed to provide both proof of principal evidence supporting the effect of topical COX inhibition, and determine the feasibility of recruitment to an OED chemoprevention trial in the UK. Methods: Recruitment of 40 patients with oral leukoplakia to 4 study arms was planned. The total daily dose of Aspirin would increase in each group and be used in the period between initial diagnostic and follow-up biopsies. Results: During the 15-month recruitment period, 15/50 screened patients were eligible for recruitment, and 13 (87%) consented. Only 1 had OED diagnosed on biopsy. 16 patients were intolerant of, or already taking Aspirin and 16 patients required no biopsy. Initial recruitment was slow, as detection relied on clinicians identifying potentially eligible patients. Pre-screening new patient letters and directly contacting patients listed for biopsies improved screening of potentially eligible patients. However, as the incidence of OED was so low, it had little impact on trial recruitment. The trial was terminated, as recruitment was unlikely to be achieved in a single centre. Conclusion: This feasibility trial has demonstrated the low incidence of OED in the UK and the difficulties in conducting a study because of this. With an incidence of around 1.5/100,000/year and a high proportion of those patients already taking or intolerant of Aspirin, a large multi-centred trial would be required to fulfil the recruitment for this study. The ability of topical non-steroidal anti-inflammatory drugs to modify COX and prostaglandin expression remains an important but unanswered question. Collaboration with centres in other parts of the world with higher incidences of the disease may be required to ensure adequate recruitment. ISRCTN: 31503555

A literature review of applied adaptive design methodology within the field of oncology in randomised controlled trials and a proposed extension to the CONSORT guidelines

Background: The application of adaptive design methodology within a clinical trial setting is becoming increasingly popular. However the application of these methods within trials is not being reported as adaptive designs hence making it more difficult to capture the emerging use of these designs. Within this review, we aim to understand how adaptive design methodology is being reported, whether these methods are explicitly stated as an 'adaptive design' or if it has to be inferred and to identify whether these methods are applied prospectively or concurrently. Methods: Three databases; Embase, Ovid and PubMed were chosen to conduct the literature search. The inclusion criteria for the review were phase II, phase III and phase II/III randomised controlled trials within the field of Oncology that published trial results in 2015. A variety of search terms related to adaptive designs were used. Results: A total of 734 results were identified, after screening 54 were eligible. Adaptive designs were more commonly applied in phase III confirmatory trials. The majority of the papers performed an interim analysis, which included some sort of stopping criteria. Additionally only two papers explicitly stated the term 'adaptive design' and therefore for most of the papers, it had to be inferred that adaptive methods was applied. Sixty-five applications of adaptive design methods were applied, from which the most common method was an adaptation using group sequential methods. Conclusion: This review indicated that the reporting of adaptive design methodology within clinical trials needs improving. The proposed extension to the current CONSORT 2010 guidelines could help capture adaptive design methods. Furthermore provide an essential aid to those involved with clinical trials

The "Hurried" Child: Myth vs. Reality

Based on a national survey and a qualitative study, examines the view that children are overscheduled with activities to the point of stress. Looks at how busy children are, how social class affects participation, and which children show stress symptoms

A randomised trial evaluating Bevacizumab as adjuvant therapy following resection of AJCC stage IIB, IIC and III cutaneous melanoma : an update

At present, there are no standard therapies for the adjuvant treatment of malignant melanoma. Patients with primary tumours with a high-Breslow thickness (stages IIB and IIC) or with resected loco-regional nodal disease (stage III) are at high risk of developing metastasis and subsequent disease-related death. Given this, it is important that novel therapies are investigated in the adjuvant melanoma setting. Since angiogenesis is essential for primary tumour growth and the development of metastasis, anti-angiogenic agents are attractive potential therapeutic candidates for clinical trials in the adjuvant setting. Therefore, we initiated a phase II trial in resected high-risk cutaneous melanoma, assessing the efficacy of bevacizumab versus observation. In the interim safety data analysis, we demonstrate that bevacizumab is a safe therapy in the adjuvant melanoma setting with no apparent increase in the surgical complication rate after either primary tumour resection and/or loco-regional lymphadenectomy

Cabazitaxel in platinum pre-treated patients with locally advanced or metastatic transitional cell carcinoma who developed disease progression after platinum based chemotherapy : results of the phase II CAB-B1 trial

There is a paucity of chemotherapy options for patients with urothelial cancers who have relapsed following platinum based chemotherapy (CT). CAB-B1 was a single centre phase II randomised controlled trial of Cabazitaxel (CAB; 25mg/m2 q3 week for 6 cycles) versus best supportive care (BSC) in patients with histologically proven transitional cell carcinoma (TCC), locally advanced or metastatic, who had recurred after receiving platinum based treatment. Primary outcome was overall response rate (ORR) using RESIST. Secondary outcomes included Progression Free Survival (PFS) and Overall Survival (OS). Between January 2013 and October 2016, 20 patients were randomised (10 on each arm). BSC included paclitaxel CT for 9 patients and radiotherapy for 1 patient. 8 patients completed 6 cycles of CT (3 on CAB; 5 on BSC). 2 patients had an ORR on CAB and 1 patient on BSC. Median OS was 5.8 months (95% confidence interval (CI) 0.7-14.6) for CAB patients and 7.5 months (95% CI 1.0-10.8) for BSC patients. Median PFS was 4.8 months (95% CI 0.7-8.3) for CAB patients and 3.7 months (95% CI 1.0-7.0) for BSC patients. CAB-B1 successfully reached the efficacy target for 1st stage, showing that there could be a role for CAB in these patients

Evaluation of the accuracy of serum MMP-9 as a test for colorectal cancer in a primary care population

Background Bowel cancer is common and is a major cause of death. Meta-analysis of randomised controlled trials estimates that screening for colorectal cancer using faecal occult blood (FOB) test reduces mortality from colorectal cancer by 16%. However, FOB testing has a low positive predictive value, with associated unnecessary cost, risk and anxiety from subsequent investigation, and is unacceptable to a proportion of the target population. Increased levels of an enzyme called matrix metalloproteinase 9 (MMP-9) have been found to be associated with colorectal cancer, and this can be measured from a blood sample. Serum MMP-9 is potentially an accurate, low risk and cost-effective population screening tool. This study aims to evaluate the accuracy of serum MMP-9 as a test for colorectal cancer in a primary care population. Methods/Design People aged 50 to 69 years, who registered in participating general practices in the West Midlands Region, will be asked to complete a questionnaire that asks about symptoms. Respondents who describe any colorectal symptoms (except only abdominal bloating and/or anal symptoms) and are prepared to provide a blood sample for MMP9 estimation and undergo a colonoscopy (current gold standard investigation) will be recruited at GP based clinics by a research nurse. Those unfit for colonoscopy will be excluded. Colonoscopies will be undertaken in dedicated research clinics. The accuracy of MMP-9 will be assessed by comparing the MMP-9 level with the colonoscopy findings, and the combination of factors (e.g. symptoms and MMP-9 level) that best predict a diagnosis of malignancy (invasive disease or polyps) will be determined. Discussion Colorectal cancer is a major cause of morbidity and mortality. Most colorectal cancers arise from adenomas and there is a period for early detection by screening, but available tests have risks, are unacceptable to many, have high false positive rates or are expensive. This study will establish the potential of serum MMP-9 as a screening test for colorectal cancer. If it is confirmed as accurate and acceptable, this serum marker has the potential to assist with reducing the morbidity and mortality from colorectal cancer

Ethnicity data collection in the UK: the healthcare professional's perspective

The collection of ethnicity data has been demonstrated to be important in healthcare. However, despite recent efforts by the UK government, it remains incomplete and unvalidated. In order to be able to assess inequalities and target resources appropriately, it is essential to have complete and accurate data. This paper examines the reasons for the gaps in ethnicity data based on the perceptions and experiences of the healthcare professionals who are charged with collecting these data. A questionnaire was used to assess perceptions of ethnicity data collection, including any barriers encountered as well as the perceived importance of collecting these data. Respondents were asked whether routine ethnicity data collection was limited to specific disease areas, and approximately what proportion was complete in these areas. There were also questions concerning preferred methods of collection (e.g. self-report). The questionnaire was completed by 30 respondents, who included healthcare managers, clinicians, nurses and other staff working in the healthcare setting. The findings confirmed that the collection of patients’ ethnicity data is deemed important by the healthcare professionals, but showed that there remains uncertainty and unease as to how best to collect these data or how to explain to patients how the data will be used. The majority of healthcare professionals agreed that it was important to record patients’ ethnicity, but no clear rationale was given to staff about the use of these data, and no training was provided on the best way to collect the data.</p

Double reading in breast cancer screening : cohort evaluation in the CO-OPS trial

Purpose: To investigate the effect of double readings by a second radiologist on recall rates, cancer detection and characteristics of cancers detected in the National Health Service Breast Screening Program in England. Materials and Methods: In this retrospective analysis we evaluated 805,206 women through screening and diagnostic test results by extracting one year of routine data from 33 English breast screening centers. Centers used double reading of digital mammograms, with arbitration if there were discrepant reads. Information on reader decisions, with results of follow-up tests, were used to explore the effect of the second reader. The statistical tests used were the test for equality of proportions, the χ2 test for independence and the t-test. Results: The first reader recalled 4·76%, (38295/805206, 95% CI 4·71%-4·80%) of women. Two readers recalled 6·19% in total, (49857/805206, 95% CI 6·14%- 6·24%), but arbitration of discordant reads reduced recall rate to 4·08%, (32863/805206, 95% CI 4·04%-4·12%, p<0.001). 7055 cancers were detected of which 627 (8·89%, 95% CI 8·22%-9·55%, p<0.001) were detected by the second reader only. These additional cancers were more likely to be ductal carcinoma in situ, (30·5% (183/600) vs 22.0% (1344/6114), p<0.001); and additional invasive cancers were smaller (mean 14·2mm vs 16·7mm, p<0.001), had fewer involved nodes, and were likely to be lower grade. Conclusion: Double reading with arbitration reduces recall and increases cancer detection compared to single reading. Cancers detected only by the second reader were smaller, lower grade, and had less nodal involvement

Ce(OH)2Cl and lanthanide-substituted variants as precursors to redox-active CeO2 materials

The cerium(III) hydroxide chloride Ce(OH)2Cl crystallises directly as a polycrystalline powder from a solution of CeCl3·7H2O in poly(ethylene) glycol (Mn = 400) heated at 240 °C and is found to be isostructural with La(OH)2Cl, as determined from high-resolution synchrotron powder X-ray diffraction (P21/m, a = 6.2868(2) Å, b = 3.94950(3) Å, c = 6.8740(3) Å, β = 113.5120(5)°). Replacement of a proportion of the cerium chloride in synthesis by a second lanthanide chloride yields a set of materials Ce1−xLnx(OH)2Cl for Ln = La, Pr, Gd, Tb. For La the maximum value of x is 0.2, with an isotropic expansion of the unit cell, but for the other lanthanides a wider composition range is possible, and the lattice parameters show an isotropic contraction with increasing x. Thermal decomposition of the hydroxide chlorides at 700 °C yields mixed-oxides Ce1−xLnxO2−δ that all have cubic fluorite structures with either expanded (Ln = La, Gd) or contracted (Ln = Pr, Tb) unit cells compared to CeO2. Scanning electron microscopy shows a shape memory effect in crystal morphology upon decomposition, with clusters of anisotropic sub-micron crystallites being seen in the precursor and oxide products. The Pr- and Tb-substituted oxides contain the substituent in a mixture of +3 and +4 oxidation states, as seen by X-ray absorption near edge structure spectroscopy at the lanthanide LIII edges. The mixed oxide materials are examined using temperature programmed reduction in 10%H2 in N2, which reveals redox properties suitable for heterogeneous catalysis, with the Pr-substituted materials showing the greatest reducibility at lower temperature

Optimising patient recall of adverse events over prolonged time periods

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