Suzanne Breeman

IMMUNOHISTOCHEMICAL LOCALIZATION OF CYTOCHROME P450 CYP1B1 IN BREAST CANCER WITH MONOCLONAL ANTIBODIES SPECIFIC FOR CYP1B1

Cytochrome P450 CYP1B1 is a recently identified member of the CYP1 P450 family. We have shown that this P450 displays increased expression in several types of human cancer, indicating that CYP1B1 is a potential tumor biomarker. In this study we developed monoclonal antibodies (MAbs) to CYP1B1 that are effective on formalin-fixed, paraffin-embedded tissue sections and investigated the presence of CYP1B1 in a series of primary breast cancers. The MAbs were generated using a synthetic peptide coupled to carrier protein as the immunogen. The MAbs specifically recognized CYP1B1 and did not recognize either CYP1A1 or CYP1A2, related CYP1 forms. The MAbs were tested by immunohistochemistry and were found to be effective on formalin-fixed, paraffin-embedded tissue sections. The majority of breast cancers showed positive immunoreactivity for CYP1B1, and in each case CYP1B1 was specifically localized to tumor cells. The presence of CYP1B1 in breast cancer cells is likely to contribute to their metabolism of estradiol because CYP1B1 is a specific estradiol hydroxylase.

Patellar resurfacing in total knee replacement: five-year clinical and economic results of a large randomized controlled trial.

BACKGROUND There is conflicting evidence regarding the merits of patellar resurfacing during total knee arthroplasty, as many of the previous randomized controlled trials have not been adequately powered. METHODS A pragmatic, multicenter, randomized controlled trial was initiated in 1999 in the United Kingdom. Within a partial factorial design, 1715 patients were randomly allocated to receive or not receive patellar resurfacing during total knee arthroplasty. The primary outcome measure was the Oxford Knee Score; secondary measures included the Short Form-12, the EuroQoL 5D, cost, cost-effectiveness, and the need for subsequent knee surgery. RESULTS The mean Oxford Knee Score was 35 points at five years postoperatively in both groups. There was no significant difference between the groups with respect to the mean Oxford Knee Score (difference, 0.59 point; 95% confidence interval, -0.58 to 1.76 points) or any other outcome measure at five years postoperatively. The outcome was not affected by whether the patella was domed or anatomic. There was no significant difference between the two groups with respect to the prevalence of knee-related readmission, of minor or intermediate reoperation, or of subsequent patella-related surgery. The total health care cost for the primary arthroplasty, subsequent monitoring, and any revision surgery did not differ significantly between the two groups. CONCLUSIONS In the largest randomized controlled trial of patellar resurfacing reported to date, the functional outcome, reoperation rate, and total health care cost five years after primary total knee arthroplasty were not significantly affected by the addition of patellar resurfacing to the surgical procedure.

Five-year results of a randomised controlled trial comparing mobile and fixed bearings in total knee replacement

There is conflicting evidence about the merits of mobile bearings in total knee replacement, partly because most randomised controlled trials (RCTs) have not been adequately powered. We report the results of a multicentre RCT of mobile versus fixed bearings. This was part of the knee arthroplasty trial (KAT), where 539 patients were randomly allocated to mobile or fixed bearings and analysed on an intention-to-treat basis. The primary outcome measure was the Oxford Knee Score (OKS) plus secondary measures including Short Form-12, EuroQol EQ-5D, costs, cost-effectiveness and need for further surgery. There was no significant difference between the groups pre-operatively: mean OKS was 17.18 (sd 7.60) in the mobile-bearing group and 16.49 (sd 7.40) in the fixed-bearing group. At five years mean OKS was 33.19 (sd 16.68) and 33.65 (sd 9.68), respectively. There was no significant difference between trial groups in OKS at five years (-1.12 (95% confidence interval -2.77 to 0.52) or any of the other outcome measures. Furthermore, there was no significant difference in the proportion of patients with knee-related re-operations or in total costs. In this appropriately powered RCT, over the first five years after total knee replacement functional outcomes, re-operation rates and healthcare costs appear to be the same irrespective of whether a mobile or fixed bearing is used.

Clinical effectiveness and cost-effectiveness of surgical options for the management of anterior and/or posterior vaginal wall prolapse: two randomised controlled trials within a comprehensive cohort study – results from the PROSPECT Study

BACKGROUND The use of mesh in prolapse surgery is controversial, leading to a number of enquiries into its safety and efficacy. OBJECTIVE To compare synthetic non-absorbable mesh inlay, biological graft and mesh kit with a standard repair in terms of clinical effectiveness, adverse effects, quality of life (QoL), costs and cost-effectiveness. DESIGN Two randomised controlled trials within a comprehensive cohort (CC) study. Allocation was by a remote web-based randomisation system in a 1 :1 : 1 ratio (Primary trial) or 1 : 1 : 2 ratio (Secondary trial), and was minimised on age, type of prolapse repair planned, need for a concomitant continence procedure, need for a concomitant upper vaginal prolapse procedure and surgeon. Participants and outcome assessors were blinded to randomisation; participants were unblinded if they requested the information. Surgeons were not blinded to allocated procedure. SETTING Thirty-five UK hospitals. PARTICIPANTS Primary study: 2474 women in the analysis (including 1348 randomised) having primary anterior or posterior prolapse surgery. Secondary study: 398 in the analysis (including 154 randomised) having repeat anterior or posterior prolapse surgery. CC3: 215 women having either uterine or vault prolapse repair. INTERVENTIONS Anterior or posterior repair alone, or with mesh inlay, biological graft or mesh kit. MAIN OUTCOME MEASURES Prolapse symptoms [Pelvic Organ Prolapse Symptom Score (POP-SS)]; prolapse-specific QoL; cost-effectiveness [incremental cost per quality-adjusted life-year (QALY)]. RESULTS Primary trials: adjusting for baseline and minimisation covariates, mean POP-SS was similar for each comparison {standard 5.4 [standard deviation (SD) 5.5] vs. mesh 5.5 (SD 5.1), mean difference (MD) 0.00, 95% confidence interval (CI) -0.70 to 0.71; standard 5.5 (SD 5.6) vs. graft 5.6 (SD 5.6), MD -0.15, 95% CI -0.93 to 0.63}. Serious non-mesh adverse effects rates were similar between the groups in year 1 [standard 7.2% vs. mesh 7.8%, risk ratio (RR) 1.08, 95% CI 0.68 to 1.72; standard 6.3% vs. graft 9.8%, RR 1.57, 95% CI 0.95 to 2.59]. There were no statistically significant differences between groups in any other outcome measure. The cumulative mesh complication rates over 2 years were 2 of 430 (0.5%) for standard repair (trial 1), 46 of 435 (10.6%) for mesh inlay and 2 of 368 (0.5%) for biological graft. The CC findings were comparable. Incremental costs were £363 (95% CI -£32 to £758) and £565 (95% CI £180 to £950) for mesh and graft vs. standard, respectively. Incremental QALYs were 0.071 (95% CI -0.004 to 0.145) and 0.039 (95% CI -0.041 to 0.120) for mesh and graft vs. standard, respectively. A Markov decision model extrapolating trial results over 5 years showed standard repair had the highest probability of cost-effectiveness, but results were surrounded by considerable uncertainty. Secondary trials: there were no statistically significant differences between the randomised groups in any outcome measure, but the sample size was too small to be conclusive. The cumulative mesh complication rates over 2 years were 7 of 52 (13.5%) for mesh inlay and 4 of 46 (8.7%) for mesh kit, with no mesh exposures for standard repair. CONCLUSIONS In women who were having primary repairs, there was evidence of no benefit from the use of mesh inlay or biological graft compared with standard repair in terms of efficacy, QoL or adverse effects (other than mesh complications) in the short term. The Secondary trials were too small to provide conclusive results. LIMITATIONS Women in the Primary trials included some with a previous repair in another compartment. Follow-up is vital to identify any long-term potential benefits and serious adverse effects. FUTURE WORK Long-term follow-up to at least 6 years after surgery is ongoing to identify recurrence rates, need for further prolapse surgery, adverse effects and cost-effectiveness. TRIAI REGISTRATION Current Controlled Trials ISRCTN60695184. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 95. See the NIHR Journals Library website for further project information.

Patient reported clinical outcomes: the challenges and implications for randomised controlled trials

Objectives Clinical outcomes are an important component of randomised controlled trials (RCTs) and are often used to complement patient reported outcomes measures such as health-related quality of life. Although clinical outcomes were traditionally collected through clinical examination or laboratory results, routine data sources and self-reporting by patients are now being increasingly used. We describe patient reported clinical outcomes and the challenges associated with collection of data in this way.

The importance of rapport and relationship building when recruiting to clinical trials: a qualitative investigation of trial recruitment consultations in a surgical RCT

Results The key findings highlighted the importance of; a) the context to the recruitment consultation, b) the current health status of potential participants at the time of trial invitation, and c) the trial information exchange process. These findings were underpinned by an overarching theme relating to recruiter rapport and relationship building with potential participants. The recruiter demonstrated an important role in terms of being empathetic, reassuring, supportive and attentive when discussing the trial with the participants. Conclusions Previous studies have shown that exploring treatment preferences, within the context of recruitment consultations, facilitated recruitment. VUE-Qual has provided a rich insight into how information is discussed in recruitment consultations between potential participants and recruiter in the context of a surgical prolapse trial. It has also identified aspects of the recruitment consultation that should be explored more systematically in other trial recruitment settings to potentially improve the recruitment process.

Telephone calls to boost response rates in the collection of outcome data

Using telephone calls in the context of randomised controlled trials (RCTs) is not a new idea. There are a number of ways in which telephone calls can be used, including, for example: as a precursor to sending questionnaires or reminder questionnaires (to let the participant know to expect a questionnaire), as a follow-up reminder to participants who have not completed postal questionnaires, to collect primary outcome data when a postal questionnaire has not been returned, or to replace postal questionnaires. There is, however, limited data available in terms of the implications and impact of such telephone calls. We will present data for different applications of telephone calls, across a number of different RCTs in different disease areas and in different study populations. Our data suggests that using telephone calls either as precursors to a questionnaire, or as a reminder, can increase the return rate. There can also be added value from a telephone call if it is possible to collect primary outcome data as part of the call, and we will present examples of this. There is, however, resource implications in terms of the number of telephone calls required to achieve contact with the participant, as well as ethical issues around securing approval for such calls.