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Featured researches published by Tim Mould.


The Lancet | 2016

Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial

Ian Jacobs; Usha Menon; Andy Ryan; Aleksandra Gentry-Maharaj; Matthew Burnell; Jatinderpal Kalsi; Nazar Najib Amso; Sophia Apostolidou; Elizabeth Benjamin; Derek Cruickshank; Danielle N Crump; Susan K Davies; Anne Dawnay; Stephen Dobbs; Gwendolen Fletcher; Jeremy Ford; Keith M. Godfrey; Richard Gunu; Mariam Habib; Rachel Hallett; Jonathan Herod; Howard Jenkins; Chloe Karpinskyj; Simon Leeson; Sara Lewis; William R Liston; Alberto Lopes; Tim Mould; John Murdoch; David H. Oram

Summary Background Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality. Methods In this randomised controlled trial, we recruited postmenopausal women aged 50–74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032. Findings Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202 638 women: 50 640 (25·0%) to MMS, 50 639 (25·0%) to USS, and 101 359 (50·0%) to no screening. 202 546 (>99·9%) women were eligible for analysis: 50 624 (>99·9%) women in the MMS group, 50 623 (>99·9%) in the USS group, and 101 299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345 570 MMS and 327 775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0–12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0–14 of 15% (95% CI −3 to 30; p=0·10) with MMS and 11% (−7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (−20 to 31) in years 0–7 and 23% (1–46) in years 7–14, and in the USS group, of 2% (−27 to 26) in years 0–7 and 21% (−2 to 42) in years 7–14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (−2 to 40) and a reduction of 8% (−27 to 43) in years 0–7 and 28% (−3 to 49) in years 7–14 in favour of MMS. Interpretation Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7–14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening. Funding Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal.


British Journal of Obstetrics and Gynaecology | 1996

Women's involvement with the decision preceding their caesarean section and their degree of satisfaction

Tim Mould; S. Chong; J. A. D. Spencer; Stephen Gallivan

Objective To assess the extent to which women contribute to1 the decision for caesarean section and their satisfaction with the decision and procedure.


BMJ | 2008

Recruitment to multicentre trials—lessons from UKCTOCS: descriptive study

Usha Menon; Aleksandra Gentry-Maharaj; Andrew M. Ryan; Aarti Sharma; Matthew Burnell; Rachel Hallett; Sara Lewis; Alberto Lopez; Keith M. Godfrey; David H. Oram; Jonathan Herod; Karin Williamson; Mourad W. Seif; Ian A. Scott; Tim Mould; Robert Woolas; John Murdoch; Stephen Dobbs; Nazar Najib Amso; Simon Leeson; Derek Cruickshank; Alistair McGuire; Stewart Campbell; Lesley Fallowfield; Steve Skates; Mahesh Parmar; Ian Jacobs

Objective To describe the factors that contributed to successful recruitment of more than 200 000 women to the UK Collaborative Trial of Ovarian Cancer Screening, one of the largest ever randomised controlled trials. Design Descriptive study. Setting 13 NHS trusts in England, Wales, and Northern Ireland. Participants Postmenopausal women aged 50-74; exclusion criteria included ovarian malignancy, bilateral oophorectomy, increased risk of familial ovarian cancer, active non-ovarian malignancy, and participation in other ovarian cancer screening trials. Main outcome measures Achievement of target recruitment, acceptance rates of invitation, and recruitment rates. Results The trial was set up in 13 centres with 27 adjoining local health authorities. The coordinating centre team was led by one of the senior investigators, who was closely involved in planning and day to day trial management. Of 1 243 282 women invited, 23.2% (288 955) replied that they were eligible and would like to participate. Of those sent appointments, 73.6% (205 090) attended for recruitment. The acceptance rate varied from 19% to 33% between trial centres. Measures to ensure target recruitment included named coordinating centre staff supporting and monitoring each centre, prompt identification and resolution of logistic problems, varying the volume of invitations by centre, using local non-attendance rates to determine the size of recruitment clinics, and organising large ad hoc clinics supported by coordinating centre staff. The trial randomised 202 638 women in 4.3 years. Conclusions Planning and trial management are as important as trial design and require equal attention from senior investigators. Successful recruitment needs constant monitoring by a committed proactive management team that is willing to explore individual solutions for different centres and use central resources to improve local recruitment. Automation of trial processes with web based trial management systems is crucial in large multicentre randomised controlled trials. Recruitment can be further enhanced by using information videos and group discussions. Trial registration Current Controlled Trials ISRCTN22488978.


Lancet Oncology | 2011

Sensitivity of transvaginal ultrasound screening for endometrial cancer in postmenopausal women: a case-control study within the UKCTOCS cohort

Ian Jacobs; Aleksandra Gentry-Maharaj; Matthew Burnell; Ranjit Manchanda; Naveena Singh; Aarti Sharma; Andrew M. Ryan; Mourad W. Seif; Nazar Najib Amso; Gillian Turner; Carol Brunell; Gwendolen Fletcher; Rani Rangar; Kathy Ford; Keith M. Godfrey; Alberto Lopes; David H. Oram; Jonathan Herod; Karin Williamson; Ian A. Scott; Howard Jenkins; Tim Mould; Robert Woolas; John Murdoch; Stephen Dobbs; Simon Leeson; Derek Cruickshank; Steven J. Skates; Lesley Fallowfield; Mahesh Parmar

BACKGROUND The increase in the worldwide incidence of endometrial cancer relates to rising obesity, falling fertility, and the ageing of the population. Transvaginal ultrasound (TVS) is a possible screening test, but there have been no large-scale studies. We report the performance of TVS screening in a large cohort. METHODS We did a nested case-control study of postmenopausal women who underwent TVS in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) following recruitment between April 17, 2001, and Sept 29, 2005. Endometrial thickness and endometrial abnormalities were recorded, and follow-up, through national registries and a postal questionnaire, documented the diagnosis of endometrial cancer. Our primary outcome measure was endometrial cancer and atypical endometrial hyperplasia (AEH). Performance characteristics of endometrial thickness and abnormalities for detection of endometrial cancer within 1 year of TVS were calculated. Epidemiological variables were used to develop a logistic regression model and assess a screening strategy for women at higher risk. Our study is registered with ClinicalTrials.gov, number NCT00058032, and with the International Standard Randomised Controlled Trial register, number ISRCTN22488978. FINDINGS 48,230 women underwent TVS in the UKCTOCS prevalence screen. 9078 women were ineligible because they had undergone a hysterectomy and 2271 because their endometrial thickness had not been recorded; however, 157 of these women had an endometrial abnormality on TVS and were included in the analysis. Median follow-up was 5·11 years (IQR 4·05-5·95). 136 women with endometrial cancer or AEH within 1 year of TVS were included in our primary analysis. The optimum endometrial thickness cutoff for endometrial cancer or AEH was 5·15 mm, with sensitivity of 80·5% (95% CI 72·7-86·8) and specificity of 86·2% (85·8-86·6). Sensitivity and specificity at a 5 mm or greater cutoff were 80·5% (72·7-86·8) and 85·7% (85·4-86·2); for women with a 5 mm or greater cutoff plus endometrial abnormalities, the sensitivity and specificity were 85·3% (78·2-90·8) and 80·4% (80·0-80·8), respectively. For a cutoff of 10 mm or greater, sensitivity and specificity were 54·1% (45·3-62·8) and 97·2% (97·0-97·4). When our analysis was restricted to the 96 women with endometrial cancer or AEH who reported no symptoms of postmenopausal bleeding at the UKCTOCS scan before diagnosis and had an endometrial thickness measurement available, a cutoff of 5 mm achieved a sensitivity of 77·1% (67·8-84·3) and specificity of 85·8% (85·7-85·9). The logistic regression model identified 25% of the population as at high risk and 39·5% of endometrial cancer or AEH cases were identified within this high risk group. In this high-risk population, a cutoff at 6·75 mm achieved sensitivity of 84·3% (71·4-93·0) and specificity of 89·9% (89·3-90·5). INTERPRETATION Our findings show that TVS screening for endometrial cancer has good sensitivity in postmenopausal women. The burden of diagnostic procedures and false-positive results can be reduced by limiting screening to a higher-risk group. The role of population screening for endometrial cancer remains uncertain, but our findings are of immediate value in the management of increased endometrial thickness in postmenopausal women undergoing pelvic scans for reasons other than vaginal bleeding.


Journal of Clinical Oncology | 2015

Risk Algorithm Using Serial Biomarker Measurements Doubles the Number of Screen-Detected Cancers Compared With a Single-Threshold Rule in the United Kingdom Collaborative Trial of Ovarian Cancer Screening

Usha Menon; Andrew M. Ryan; Jatinderpal Kalsi; Aleksandra Gentry-Maharaj; Anne Dawnay; Mariam Habib; Sophia Apostolidou; Naveena Singh; Elizabeth Benjamin; Matthew Burnell; Susan Davies; Aarti Sharma; Richard Gunu; Keith M. Godfrey; Alberto Lopes; David Oram; Jonathan Herod; Karin Williamson; Mourad W. Seif; Howard Jenkins; Tim Mould; Robert Woolas; John Murdoch; Stephen Dobbs; Nazar Najib Amso; Simon Leeson; Derek Cruickshank; Ian A. Scott; Lesley Fallowfield; Martin Widschwendter

Purpose Cancer screening strategies have commonly adopted single-biomarker thresholds to identify abnormality. We investigated the impact of serial biomarker change interpreted through a risk algorithm on cancer detection rates. Patients and Methods In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 46,237 women, age 50 years or older underwent incidence screening by using the multimodal strategy (MMS) in which annual serum cancer antigen 125 (CA-125) was interpreted with the risk of ovarian cancer algorithm (ROCA). Women were triaged by the ROCA: normal risk, returned to annual screening; intermediate risk, repeat CA-125; and elevated risk, repeat CA-125 and transvaginal ultrasound. Women with persistently increased risk were clinically evaluated. All participants were followed through national cancer and/or death registries. Performance characteristics of a single-threshold rule and the ROCA were compared by using receiver operating characteristic curves. Results After 296,911 women-years of annual incidence screening, 640 women underwent surgery. Of those, 133 had primary invasive epithelial ovarian or tubal cancers (iEOCs). In all, 22 interval iEOCs occurred within 1 year of screening, of which one was detected by ROCA but was managed conservatively after clinical assessment. The sensitivity and specificity of MMS for detection of iEOCs were 85.8% (95% CI, 79.3% to 90.9%) and 99.8% (95% CI, 99.8% to 99.8%), respectively, with 4.8 surgeries per iEOC. ROCA alone detected 87.1% (135 of 155) of the iEOCs. Using fixed CA-125 cutoffs at the last annual screen of more than 35, more than 30, and more than 22 U/mL would have identified 41.3% (64 of 155), 48.4% (75 of 155), and 66.5% (103 of 155), respectively. The area under the curve for ROCA (0.915) was significantly (P = .0027) higher than that for a single-threshold rule (0.869). Conclusion Screening by using ROCA doubled the number of screen-detected iEOCs compared with a fixed cutoff. In the context of cancer screening, reliance on predefined single-threshold rules may result in biomarkers of value being discarded.


British Journal of Cancer | 2007

Enhanced repair of DNA interstrand crosslinking in ovarian cancer cells from patients following treatment with platinum-based chemotherapy

P Wynne; C Newton; Jonathan A. Ledermann; Adeola Olaitan; Tim Mould; John A. Hartley

Despite high tumour response rates to platinum-based chemotherapy in ovarian cancer survival is poor due to the emergence of drug resistance. Mechanistic studies in clinical material have been hampered by the unavailability of sensitive methods to detect the critical drug-induced effects in individual cells. A modification of the single cell gel electrophoresis (comet) assay allows the sensitive detection of DNA interstrand crosslinking in both tumour and normal cells derived directly from clinical material. Tumour cells isolated from 50 ovarian cancer patients were treated ex vivo with 100 μM cisplatin for 1 h and crosslink formation and repair (unhooking) measured. No significant difference in the peak level of crosslinking in tumour cells was observed between patients who were either newly diagnosed or previously treated with platinum-based therapy, or between tumour and mesothelial cells from an individual patient. This indicates no difference in cellular mechanisms such as drug transport or detoxification. In contrast, the percentage repair (unhooking) of DNA interstrand crosslinks was much greater in the group of treated patients. At 24 h in the 36 newly diagnosed patient tumour samples, only one gave >50% repair and 23 gave <10% repair; however, 19 out of 22 treated patient samples gave >10% repair and 14 showed >50% repair. The estimated median difference (newly diagnosed minus treated) was −52 (95% CI −67 to −28), and the P-value from a Mann–Whitney test was <0.001. In eight patients, it was possible to obtain tumour samples prior to any chemotherapy, and also on relapse or at interval debulking surgery following platinum-based chemotherapy. In these patients, the mean % repair prior to therapy was 2.85 rising to 71.23 following treatment. These data demonstrate increased repair of DNA interstrand crosslinks in ovarian tumour cells following platinum therapy which may contribute to clinical acquired resistance.


International Journal of Cancer | 2009

DNA methylation analysis in liquid‐based cytology for cervical cancer screening

Sophia Apostolidou; Richard Hadwin; Matthew Burnell; Allison Jones; Donna Baff; Nitisha Pyndiah; Tim Mould; Ian Jacobs; Simon Beddows; Gabrijela Kocjan; Martin Widschwendter

Cervical cancer is the second most common type of cancer in women worldwide. Preinvasive disease can be detected by cervical cytology. All currently available cytology technologies rely on the visual analysis of exfoliated cells from the uterine cervix. Improvement of conventional cytological screening has been proposed by the introduction of molecular‐based markers applied to liquid‐based cytology (LBC), the suspension of cells collected from the cervix. DNA methylation changes occur very early in carcinogenesis and identification of appropriate DNA methylation markers in such samples should be able to distinguish high‐grade squamous intraepithelial lesions (HSIL) from nonspecific cytology changes and the normal cervix. To address this potential, we have undertaken a proof‐of‐principle study of methylation status of LBC samples from HSIL cytology cases compared against matched normal controls. Using quantitative methylation‐specific PCR on 28 genes, we found SOX1, HOXA11 and CADM1 to significantly discriminate between the groups analyzed (p < 0.01). Area under the receiver operating characteristic (ROC) curve (AUC) demonstrated that methylation of SOX1, HOXA11 and CADM1 could discriminate between HSIL cases and controls with high sensitivity and specificity (AUC 0.910, 0.844 and 0.760, respectively). The results were further validated in an independent set. This proof‐of‐principle study is the first to validate the results in an independent case/control set and presents HOXA11, a gene that is important for cervical development, as a potentially useful DNA marker in LBC samples. Further assessment of these preliminary estimates will need to be performed in a larger cohort to confirm clinical utility.


Ultrasound in Obstetrics & Gynecology | 2012

Risk of epithelial ovarian cancer in asymptomatic women with ultrasound-detected ovarian masses: a prospective cohort study within the UK collaborative trial of ovarian cancer screening (UKCTOCS)

Aarti Sharma; Sophia Apostolidou; Matthew Burnell; Stewart Campbell; Mariam Habib; A Gentry-Maharaj; Nazar Najib Amso; Mourad W. Seif; Gwendolen Fletcher; N. Singh; Elizabeth Benjamin; Carol Brunell; Gill Turner; Rani Rangar; Keith M. Godfrey; David H. Oram; Jonathan Herod; Karin Williamson; Howard Jenkins; Tim Mould; Robert Woolas; John Murdoch; Stephen Dobbs; Simon Leeson; Derek Cruickshank; Evangelia-Ourania Fourkala; Andrew M. Ryan; M. Parmar; Ian Jacobs; Usha Menon

To estimate the risk of primary epithelial ovarian cancer (EOC) and slow growing borderline or Type I and aggressive Type II EOC in postmenopausal women with adnexal abnormalities on ultrasound.


International Journal of Gynecological Cancer | 2010

Increasing the effectiveness of referral of ovarian masses from cancer unit to cancer center by using a higher referral value of the risk of malignancy index.

Amer Raza; Tim Mould; Meg Wilson; Mike Burnell; Les Bernhardt

Hypothesis: Higher risk of malignancy index (RMI) with multidisciplinary approach will reduce the number of referrals of ovarian masses, thus reducing the stress for patients and workload at the cancer center. Methods: Prospective observational study in which all patients with pelvic masses and an RMI lower than 450 were treated at the local hospital after discussion at multidisciplinary input. Patients with an RMI higher than 450 were referred to tertiary cancer centers. Records of multidisciplinary meetings, operative details, and histologic examination results were evaluated. Data were analyzed to calculate the predictive values and the sensitivity of this approach. Results: If the RMI cutoff of 450 alone is considered, 1 woman with invasive cancer would not have been referred. The sensitivity for invasive epithelial ovarian cancer was 96.2% or 25 of 26 patients (95% confidence interval [CI], 80.4-99.9) with a positive predictive value of 96.3% or 26 of 27 patients (95% CI, 81.0-99.9). The specificity was 98.7% or 77 of 78 patients (95% CI, 93.1-100.0). The negative predictive value was 98.7% or 76 of 77 patients (95% CI, 93.0-100.0). Conclusions: A higher RMI with multidisciplinary approach to refer patients with pelvic masses has the potential to reduce the numbers of benign cases, thus reducing stress for patients and reducing workload at centers.


International Journal of Gynecology & Obstetrics | 2008

Uterine tumor resembling ovarian sex cord tumors treated by hysteroscopy.

Eleftherios Anastasakis; Adam Magos; Tim Mould; D. L. Economides

Uterine tumors resembling ovarian sex cord tumors (UTROSCT) were first described in 1976 [1]. All reported cases were treated by abdominal hysterectomy. We present a case of UTROSCT managed by hysteroscopy and conservation of the uterus resulting in successful child bearing. A 28-year-old woman (gravida 0, para 0) presented with intermenstrual bleeding. Ultrasound revealed an endometrial polyp arising from the posterior uterine muscular layer. The polyp was removed at hysteroscopy. The histopathologic examination reported that the endometrium was normal. In the stroma there was focal periglandular condensation together with expanded areas demonstrating prominent ovarian sex cord-like architecture. Scattered mitotic figures were seen (up to 2 per 10 high power fields). The sex cord-like areas were positive for vimentin, the epithelial marker cytokeratin CAM 5.2, estrogen receptor (ER), and progesterone receptor (PR). Patchy positivity for inhibin and calretinin confirmed their sex cord stromal differentiation. The stroma between the sex cord-like areas was positive for actin and focally for desmin, but CD10 was only positive in the more normal areas of the endometrial stroma (Fig. 1).

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Matthew Burnell

University College London

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Usha Menon

University College London

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Adeola Olaitan

University College Hospital

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Derek Cruickshank

James Cook University Hospital

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Keith M. Godfrey

University Hospital Southampton NHS Foundation Trust

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